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1. Pf7: an open dataset of Plasmodium falciparum genome variation in 20,000 worldwide samples

Author

Hamid, M.M.A., Abdelraheem, M.H., Acheampong, D.O., Ahouidi, A., Ali, M, Almagro-Garcia, J., Amambua-Ngwa, A., Amaratunga, C., Amenga-Etego, L., Andagalu, B., Anderson, T., Andrianaranjaka, V., Aniebo, I., Aninagyei, E., Ansah, F., Ansah, P.O., Apinjoh, T., Arnaldo, P., Ashley, E., Auburn, S., Awandare, G.A., Ba, H., Baraka, V., Barry, A., Bejon, P., Bertin, G.I., Boni, M.F., Borrmann, S., Bousema, T., Bouyou-Akotet, M., Branch, O., Bull, P.C., Cheah, H., Chindavongsa, K., Chookajorn, T., Chotivanich, K., Claessens, A., Conway, D.J., Corredor, V., Courtier, E., Craig, A., D'Alessandro, U., Dama, S., Day, N., Denis, B., Dhorda, M., Diakite, M., Djimde, A., Dolecek, C., Dondorp, A., Doumbia, S., Drakeley, C., Drury, E., Duffy, P., Echeverry, D.F., Egwang, T.G., Enosse, S.M.M., Erko, B., Fairhurst, R.M., Faiz, A., Fanello, C.A., Fleharty, M., Forbes, M., Fukuda, M., Gamboa, D., Ghansah, A., Golassa, L., Goncalves, S., Harrison, G.L.A., Healy, Sara A., Hendry, J.A., Hernandez-Koutoucheva, A., Hien, T.T., Hill, C.A., Hombhanje, F., Hott, A., Htut, Y., Hussein, M., Imwong, M., Ishengoma, D., Jackson, S.A., Jacob, C.G., Jeans, J., Johnson, K.J., Kamaliddin, C., Kamau, E., Keatley, J., Kochakarn, T., Konate, D.S., Konaté, A., Kone, A., Kwiatkowski, D.P., Kyaw, M.P., Kyle, D., Lawniczak, M., Lee, S.K., Lemnge, M., Lim, P., Lon, C., Yavo, W., Pluijm, R.W. van der, Hamid, M.M.A., Abdelraheem, M.H., Acheampong, D.O., Ahouidi, A., Ali, M, Almagro-Garcia, J., Amambua-Ngwa, A., Amaratunga, C., Amenga-Etego, L., Andagalu, B., Anderson, T., Andrianaranjaka, V., Aniebo, I., Aninagyei, E., Ansah, F., Ansah, P.O., Apinjoh, T., Arnaldo, P., Ashley, E., Auburn, S., Awandare, G.A., Ba, H., Baraka, V., Barry, A., Bejon, P., Bertin, G.I., Boni, M.F., Borrmann, S., Bousema, T., Bouyou-Akotet, M., Branch, O., Bull, P.C., Cheah, H., Chindavongsa, K., Chookajorn, T., Chotivanich, K., Claessens, A., Conway, D.J., Corredor, V., Courtier, E., Craig, A., D'Alessandro, U., Dama, S., Day, N., Denis, B., Dhorda, M., Diakite, M., Djimde, A., Dolecek, C., Dondorp, A., Doumbia, S., Drakeley, C., Drury, E., Duffy, P., Echeverry, D.F., Egwang, T.G., Enosse, S.M.M., Erko, B., Fairhurst, R.M., Faiz, A., Fanello, C.A., Fleharty, M., Forbes, M., Fukuda, M., Gamboa, D., Ghansah, A., Golassa, L., Goncalves, S., Harrison, G.L.A., Healy, Sara A., Hendry, J.A., Hernandez-Koutoucheva, A., Hien, T.T., Hill, C.A., Hombhanje, F., Hott, A., Htut, Y., Hussein, M., Imwong, M., Ishengoma, D., Jackson, S.A., Jacob, C.G., Jeans, J., Johnson, K.J., Kamaliddin, C., Kamau, E., Keatley, J., Kochakarn, T., Konate, D.S., Konaté, A., Kone, A., Kwiatkowski, D.P., Kyaw, M.P., Kyle, D., Lawniczak, M., Lee, S.K., Lemnge, M., Lim, P., Lon, C., Yavo, W., and Pluijm, R.W. van der

Abstract

Item does not contain fulltext, We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network. It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented. For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations. We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show examples of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent. We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines. Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website.

Published
2023

2. An open dataset of Plasmodium vivax genome variation in 1,895 worldwide samples.

Author

MalariaGEN, Adam, I, Alam, MS, Alemu, S, Amaratunga, C, Amato, R, Andrianaranjaka, V, Anstey, NM, Aseffa, A, Ashley, E, Assefa, A, Auburn, S, Barber, BE, Barry, A, Batista Pereira, D, Cao, J, Chau, NH, Chotivanich, K, Chu, C, Dondorp, AM, Drury, E, Echeverry, DF, Erko, B, Espino, F, Fairhurst, R, Faiz, A, Fernanda Villegas, M, Gao, Q, Golassa, L, Goncalves, S, Grigg, MJ, Hamedi, Y, Hien, TT, Htut, Y, Johnson, KJ, Karunaweera, N, Khan, W, Krudsood, S, Kwiatkowski, DP, Lacerda, M, Ley, B, Lim, P, Liu, Y, Llanos-Cuentas, A, Lon, C, Lopera-Mesa, T, Marfurt, J, Michon, P, Miotto, O, Mohammed, R, Mueller, I, Namaik-Larp, C, Newton, PN, Nguyen, T-N, Nosten, F, Noviyanti, R, Pava, Z, Pearson, RD, Petros, B, Phyo, AP, Price, RN, Pukrittayakamee, S, Rahim, AG, Randrianarivelojosia, M, Rayner, JC, Rumaseb, A, Siegel, SV, Simpson, VJ, Thriemer, K, Tobon-Castano, A, Trimarsanto, H, Urbano Ferreira, M, Vélez, ID, Wangchuk, S, Wellems, TE, White, NJ, William, T, Yasnot, MF, Yilma, D, MalariaGEN, Adam, I, Alam, MS, Alemu, S, Amaratunga, C, Amato, R, Andrianaranjaka, V, Anstey, NM, Aseffa, A, Ashley, E, Assefa, A, Auburn, S, Barber, BE, Barry, A, Batista Pereira, D, Cao, J, Chau, NH, Chotivanich, K, Chu, C, Dondorp, AM, Drury, E, Echeverry, DF, Erko, B, Espino, F, Fairhurst, R, Faiz, A, Fernanda Villegas, M, Gao, Q, Golassa, L, Goncalves, S, Grigg, MJ, Hamedi, Y, Hien, TT, Htut, Y, Johnson, KJ, Karunaweera, N, Khan, W, Krudsood, S, Kwiatkowski, DP, Lacerda, M, Ley, B, Lim, P, Liu, Y, Llanos-Cuentas, A, Lon, C, Lopera-Mesa, T, Marfurt, J, Michon, P, Miotto, O, Mohammed, R, Mueller, I, Namaik-Larp, C, Newton, PN, Nguyen, T-N, Nosten, F, Noviyanti, R, Pava, Z, Pearson, RD, Petros, B, Phyo, AP, Price, RN, Pukrittayakamee, S, Rahim, AG, Randrianarivelojosia, M, Rayner, JC, Rumaseb, A, Siegel, SV, Simpson, VJ, Thriemer, K, Tobon-Castano, A, Trimarsanto, H, Urbano Ferreira, M, Vélez, ID, Wangchuk, S, Wellems, TE, White, NJ, William, T, Yasnot, MF, and Yilma, D

Abstract

This report describes the MalariaGEN Pv4 dataset, a new release of curated genome variation data on 1,895 samples of Plasmodium vivax collected at 88 worldwide locations between 2001 and 2017. It includes 1,370 new samples contributed by MalariaGEN and VivaxGEN partner studies in addition to previously published samples from these and other sources. We provide genotype calls at over 4.5 million variable positions including over 3 million single nucleotide polymorphisms (SNPs), as well as short indels and tandem duplications. This enlarged dataset highlights major compartments of parasite population structure, with clear differentiation between Africa, Latin America, Oceania, Western Asia and different parts of Southeast Asia. Each sample has been classified for drug resistance to sulfadoxine, pyrimethamine and mefloquine based on known markers at the dhfr, dhps and mdr1 loci. The prevalence of all of these resistance markers was much higher in Southeast Asia and Oceania than elsewhere. This open resource of analysis-ready genome variation data from the MalariaGEN and VivaxGEN networks is driven by our collective goal to advance research into the complex biology of P. vivax and to accelerate genomic surveillance for malaria control and elimination.

Published
2022

3. A molecular barcode and web-based data analysis tool to identify imported Plasmodium vivax malaria.

Author

Trimarsanto, H, Amato, R, Pearson, RD, Sutanto, E, Noviyanti, R, Trianty, L, Marfurt, J, Pava, Z, Echeverry, DF, Lopera-Mesa, TM, Montenegro, LM, Tobón-Castaño, A, Grigg, MJ, Barber, B, William, T, Anstey, NM, Getachew, S, Petros, B, Aseffa, A, Assefa, A, Rahim, AG, Chau, NH, Hien, TT, Alam, MS, Khan, WA, Ley, B, Thriemer, K, Wangchuck, S, Hamedi, Y, Adam, I, Liu, Y, Gao, Q, Sriprawat, K, Ferreira, MU, Laman, M, Barry, A, Mueller, I, Lacerda, MVG, Llanos-Cuentas, A, Krudsood, S, Lon, C, Mohammed, R, Yilma, D, Pereira, DB, Espino, FEJ, Chu, CS, Vélez, ID, Namaik-Larp, C, Villegas, MF, Green, JA, Koh, G, Rayner, JC, Drury, E, Gonçalves, S, Simpson, V, Miotto, O, Miles, A, White, NJ, Nosten, F, Kwiatkowski, DP, Price, RN, Auburn, S, Trimarsanto, H, Amato, R, Pearson, RD, Sutanto, E, Noviyanti, R, Trianty, L, Marfurt, J, Pava, Z, Echeverry, DF, Lopera-Mesa, TM, Montenegro, LM, Tobón-Castaño, A, Grigg, MJ, Barber, B, William, T, Anstey, NM, Getachew, S, Petros, B, Aseffa, A, Assefa, A, Rahim, AG, Chau, NH, Hien, TT, Alam, MS, Khan, WA, Ley, B, Thriemer, K, Wangchuck, S, Hamedi, Y, Adam, I, Liu, Y, Gao, Q, Sriprawat, K, Ferreira, MU, Laman, M, Barry, A, Mueller, I, Lacerda, MVG, Llanos-Cuentas, A, Krudsood, S, Lon, C, Mohammed, R, Yilma, D, Pereira, DB, Espino, FEJ, Chu, CS, Vélez, ID, Namaik-Larp, C, Villegas, MF, Green, JA, Koh, G, Rayner, JC, Drury, E, Gonçalves, S, Simpson, V, Miotto, O, Miles, A, White, NJ, Nosten, F, Kwiatkowski, DP, Price, RN, and Auburn, S

Abstract

Traditionally, patient travel history has been used to distinguish imported from autochthonous malaria cases, but the dormant liver stages of Plasmodium vivax confound this approach. Molecular tools offer an alternative method to identify, and map imported cases. Using machine learning approaches incorporating hierarchical fixation index and decision tree analyses applied to 799 P. vivax genomes from 21 countries, we identified 33-SNP, 50-SNP and 55-SNP barcodes (GEO33, GEO50 and GEO55), with high capacity to predict the infection's country of origin. The Matthews correlation coefficient (MCC) for an existing, commonly applied 38-SNP barcode (BR38) exceeded 0.80 in 62% countries. The GEO panels outperformed BR38, with median MCCs > 0.80 in 90% countries at GEO33, and 95% at GEO50 and GEO55. An online, open-access, likelihood-based classifier framework was established to support data analysis (vivaxGEN-geo). The SNP selection and classifier methods can be readily amended for other use cases to support malaria control programs.

Published
2022

4. Short-course primaquine for the radical cure of Plasmodium vivax malaria: a multicentre, randomised, placebo-controlled non-inferiority trial

Author

Taylor, WRJ, Thriemer, K, von Seidlein, L, Yuentrakul, P, Assawariyathipat, T, Assefa, A, Auburn, S, Chand, K, Chau, NH, Cheah, PY, Dong, LT, Dhorda, M, Degaga, TS, Devine, A, Ekawati, LL, Fahmi, F, Hailu, A, Hasanzai, MA, Hien, TT, Khu, H, Ley, B, Lubell, Y, Marfurt, J, Mohammad, H, Moore, KA, Naddim, MN, Pasaribu, AP, Pasaribu, S, Promnarate, C, Rahim, AG, Sirithiranont, P, Solomon, H, Sudoyo, H, Sutanto, I, Thanh, NV, Tuyet-Trinh, NT, Waithira, N, Woyessa, A, Yamin, FY, Dondorp, A, Simpson, JA, Baird, JK, White, NJ, Day, NP, and Price, RN

Subjects
Antimalarials, Recurrence, parasitic diseases, Chronic Disease, Malaria, Vivax, Humans, Primaquine, Article
Abstract

Summary Background Primaquine is the only widely used drug that prevents Plasmodium vivax malaria relapses, but adherence to the standard 14-day regimen is poor. We aimed to assess the efficacy of a shorter course (7 days) of primaquine for radical cure of vivax malaria. Methods We did a randomised, double-blind, placebo-controlled, non-inferiority trial in eight health-care clinics (two each in Afghanistan, Ethiopia, Indonesia, and Vietnam). Patients (aged ≥6 months) with normal glucose-6-phosphate dehydrogenase (G6PD) and presenting with uncomplicated vivax malaria were enrolled. Patients were given standard blood schizontocidal treatment and randomly assigned (2:2:1) to receive 7 days of supervised primaquine (1·0 mg/kg per day), 14 days of supervised primaquine (0·5 mg/kg per day), or placebo. The primary endpoint was the incidence rate of symptomatic P vivax parasitaemia during the 12-month follow-up period, assessed in the intention-to-treat population. A margin of 0·07 recurrences per person-year was used to establish non-inferiority of the 7-day regimen compared with the 14-day regimen. This trial is registered at ClinicalTrials.gov (NCT01814683). Findings Between July 20, 2014, and Nov 25, 2017, 2336 patients were enrolled. The incidence rate of symptomatic recurrent P vivax malaria was 0·18 (95% CI 0·15 to 0·21) recurrences per person-year for 935 patients in the 7-day primaquine group and 0·16 (0·13 to 0·18) for 937 patients in the 14-day primaquine group, a difference of 0·02 (–0·02 to 0·05, p=0·3405). The incidence rate for 464 patients in the placebo group was 0·96 (95% CI 0·83 to 1·08) recurrences per person-year. Potentially drug-related serious adverse events within 42 days of starting treatment were reported in nine (1·0%) of 935 patients in the 7-day group, one (0·1%) of 937 in the 14-day group and none of 464 in the control arm. Four of the serious adverse events were significant haemolysis (three in the 7-day group and one in the 14-day group). Interpretation In patients with normal G6PD, 7-day primaquine was well tolerated and non-inferior to 14-day primaquine. The short-course regimen might improve adherence and therefore the effectiveness of primaquine for radical cure of P vivax malaria. Funding UK Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust through the Joint Global Health Trials Scheme (MR/K007424/1) and the Bill & Melinda Gates Foundation (OPP1054404).

Published
2019

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

Author

Ahouidi, A., Ali, M, Almagro-Garcia, J., Amambua-Ngwa, A., Amaratunga, C., Amato, R., Amenga-Etego, L., Andagalu, B., Anderson, T.J., Andrianaranjaka, V., Apinjoh, T., Ariani, C., Ashley, E.A., Auburn, S., Awandare, G.A., Ba, H., Baraka, V., Barry, A.E., Bejon, P., Bertin, G.I., Boni, M.F., Borrmann, S., Bousema, T., Branch, O., Bull, P.C., Busby, G.B.J., Chookajorn, T., Chotivanich, K., Claessens, A., Conway, D., Craig, A., D'Alessandro, U., Dama, S., Day, N.P., Denis, B., Diakite, M., Djimdé, A., Dolecek, C., Dondorp, A.M., Drakeley, C., Drury, E., Duffy, P., Echeverry, D.F., Egwang, T.G., Erko, B., Fairhurst, R.M., Faiz, A., Fanello, C.A., Fukuda, M.M., Gamboa, D., Ghansah, A., Golassa, L., Goncalves, S., Hamilton, W.L., Harrison, G.L.A., Hart, L. 't, Henrichs, C., Hien, T.T., Hill, C.A., Hodgson, A., Hubbart, C., Imwong, M., Ishengoma, D.S., Jackson, S.A., Jacob, C.G., Jeffery, B., Jeffreys, A.E., Johnson, K.J., Jyothi, D., Kamaliddin, C., Kamau, E., Kekre, M., Kluczynski, K., Kochakarn, T., Konaté, A., Kwiatkowski, D.P., Kyaw, M.P., Lim, P., Lon, C., Loua, K.M., Maïga-Ascofaré, O., Malangone, C., Manske, M., Marfurt, J., Marsh, K., Mayxay, M., Miles, A., Miotto, O., Mobegi, V., Mokuolu, O.A., Montgomery, J., Mueller, I., Newton, P.N., Nguyen, T., Nguyen, T.N.D., Noedl, H., Nosten, F., Noviyanti, R., Nzila, A., Ochola-Oyier, L.I., and MalariaGEN

Subjects
0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], 030231 tropical medicine, parasitic diseases, Medicine (miscellaneous), General Biochemistry, Genetics and Molecular Biology, 3. Good health
Abstract

Contains fulltext : 238195.pdf (Publisher’s version ) (Open Access) 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 Plasmodium falciparum 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.

Published
2021

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

Author

MalariaGEN, Ahouidi, A, Ali, M, Almagro-Garcia, J, Amambua-Ngwa, A, Amaratunga, C, Amato, R, Amenga-Etego, L, Andagalu, B, Anderson, TJC, Andrianaranjaka, V, Apinjoh, T, Ariani, C, Ashley, EA, Auburn, S, Awandare, GA, Ba, H, Baraka, V, Barry, Alyssa, Bejon, P, Bertin, GI, Boni, MF, Borrmann, S, Bousema, T, Branch, O, Bull, PC, Busby, GBJ, Chookajorn, T, Chotivanich, K, Claessens, A, Conway, D, Craig, A, D'Alessandro, U, Dama, S, Day, NP, Denis, B, Diakite, M, Djimdé, A, Dolecek, C, Dondorp, AM, Drakeley, C, Drury, E, Duffy, P, Echeverry, DF, Egwang, TG, Erko, B, Fairhurst, RM, Faiz, A, Fanello, CA, Fukuda, MM, Gamboa, D, Ghansah, A, Golassa, L, Goncalves, S, Hamilton, WL, Harrison, GLA, Hart, L, Henrichs, C, Hien, TT, Hill, CA, Hodgson, A, Hubbart, C, Imwong, M, Ishengoma, DS, Jackson, SA, Jacob, CG, Jeffery, B, Jeffreys, AE, Johnson, KJ, Jyothi, D, Kamaliddin, C, Kamau, E, Kekre, M, Kluczynski, K, Kochakarn, T, Konaté, A, Kwiatkowski, DP, Kyaw, MP, Lim, P, Lon, C, Loua, KM, Maïga-Ascofaré, O, Malangone, C, Manske, M, Marfurt, J, Marsh, K, Mayxay, M, Miles, A, Miotto, O, Mobegi, V, Mokuolu, OA, Montgomery, J, Mueller, I, Newton, PN, Nguyen, T, Nguyen, T-N, Noedl, H, Nosten, F, Noviyanti, R, Nzila, A, Ochola-Oyier, LI, Ocholla, H, Oduro, A, Omedo, I, Onyamboko, MA, Ouedraogo, J-B, Oyebola, K, Pearson, RD, Peshu, N, Phyo, AP, Plowe, CV, Price, RN, Pukrittayakamee, S, Randrianarivelojosia, M, Rayner, JC, Ringwald, P, Rockett, KA, Rowlands, K, Ruiz, L, Saunders, D, Shayo, A, Siba, P, Simpson, VJ, Stalker, J, Su, X-Z, Sutherland, C, Takala-Harrison, S, Tavul, L, Thathy, V, Tshefu, A, Verra, F, Vinetz, J, Wellems, TE, Wendler, J, White, NJ, Wright, I, Yavo, W, Ye, H, MalariaGEN, Ahouidi, A, Ali, M, Almagro-Garcia, J, Amambua-Ngwa, A, Amaratunga, C, Amato, R, Amenga-Etego, L, Andagalu, B, Anderson, TJC, Andrianaranjaka, V, Apinjoh, T, Ariani, C, Ashley, EA, Auburn, S, Awandare, GA, Ba, H, Baraka, V, Barry, Alyssa, Bejon, P, Bertin, GI, Boni, MF, Borrmann, S, Bousema, T, Branch, O, Bull, PC, Busby, GBJ, Chookajorn, T, Chotivanich, K, Claessens, A, Conway, D, Craig, A, D'Alessandro, U, Dama, S, Day, NP, Denis, B, Diakite, M, Djimdé, A, Dolecek, C, Dondorp, AM, Drakeley, C, Drury, E, Duffy, P, Echeverry, DF, Egwang, TG, Erko, B, Fairhurst, RM, Faiz, A, Fanello, CA, Fukuda, MM, Gamboa, D, Ghansah, A, Golassa, L, Goncalves, S, Hamilton, WL, Harrison, GLA, Hart, L, Henrichs, C, Hien, TT, Hill, CA, Hodgson, A, Hubbart, C, Imwong, M, Ishengoma, DS, Jackson, SA, Jacob, CG, Jeffery, B, Jeffreys, AE, Johnson, KJ, Jyothi, D, Kamaliddin, C, Kamau, E, Kekre, M, Kluczynski, K, Kochakarn, T, Konaté, A, Kwiatkowski, DP, Kyaw, MP, Lim, P, Lon, C, Loua, KM, Maïga-Ascofaré, O, Malangone, C, Manske, M, Marfurt, J, Marsh, K, Mayxay, M, Miles, A, Miotto, O, Mobegi, V, Mokuolu, OA, Montgomery, J, Mueller, I, Newton, PN, Nguyen, T, Nguyen, T-N, Noedl, H, Nosten, F, Noviyanti, R, Nzila, A, Ochola-Oyier, LI, Ocholla, H, Oduro, A, Omedo, I, Onyamboko, MA, Ouedraogo, J-B, Oyebola, K, Pearson, RD, Peshu, N, Phyo, AP, Plowe, CV, Price, RN, Pukrittayakamee, S, Randrianarivelojosia, M, Rayner, JC, Ringwald, P, Rockett, KA, Rowlands, K, Ruiz, L, Saunders, D, Shayo, A, Siba, P, Simpson, VJ, Stalker, J, Su, X-Z, Sutherland, C, Takala-Harrison, S, Tavul, L, Thathy, V, Tshefu, A, Verra, F, Vinetz, J, Wellems, TE, Wendler, J, White, NJ, Wright, I, Yavo, W, and Ye, H

Abstract

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 Plasmodium falciparum 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.

Published
2021

9. Emergence of artemisinin-resistant Plasmodium falciparum with kelch13 C580Y mutations on the island of New Guinea

Author

Miotto, O, Sekihara, M, Tachibana, SI, Yamauchi, M, Pearson, RD, Amato, R, Gonçalves, S, Mehra, S, Noviyanti, R, Marfurt, J, Auburn, S, Price, RN, Mueller, I, Ikeda, M, Mori, T, Hirai, M, Tavul, L, Hetzel, MW, Laman, M, Barry, A, Ringwald, P, Ohashi, J, Hombhanje, F, Kwiatkowski, DP, Mita, T, Miotto, O, Sekihara, M, Tachibana, SI, Yamauchi, M, Pearson, RD, Amato, R, Gonçalves, S, Mehra, S, Noviyanti, R, Marfurt, J, Auburn, S, Price, RN, Mueller, I, Ikeda, M, Mori, T, Hirai, M, Tavul, L, Hetzel, MW, Laman, M, Barry, A, Ringwald, P, Ohashi, J, Hombhanje, F, Kwiatkowski, DP, and Mita, T

Abstract

The rapid and aggressive spread of artemisinin-resistant Plasmodium falciparum carrying the C580Y mutation in the kelch13 gene is a growing threat to malaria elimination in Southeast Asia, but there is no evidence of their spread to other regions. We conducted cross-sectional surveys in 2016 and 2017 at two clinics in Wewak, Papua New Guinea (PNG) where we identified three infections caused by C580Y mutants among 239 genotyped clinical samples. One of these mutants exhibited the highest survival rate (6.8%) among all parasites surveyed in ring-stage survival assays (RSA) for artemisinin. Analyses of kelch13 flanking regions, and comparisons of deep sequencing data from 389 clinical samples from PNG, Indonesian Papua and Western Cambodia, suggested an independent origin of the Wewak C580Y mutation, showing that the mutants possess several distinctive genetic features. Identity by descent (IBD) showed that multiple portions of the mutants’ genomes share a common origin with parasites found in Indonesian Papua, comprising several mutations within genes previously associated with drug resistance, such as mdr1, ferredoxin, atg18 and pnp. These findings suggest that a P. falciparum lineage circulating on the island of New Guinea has gradually acquired a complex ensemble of variants, including kelch13 C580Y, which have affected the parasites’ drug sensitivity. This worrying development reinforces the need for increased surveillance of the evolving parasite populations on the island, to contain the spread of resistance.

Published
2020

10. Implementing parasite genotyping into national surveillance frameworks: feedback from control programmes and researchers in the Asia-Pacific region

Author

Noviyanti, R., Miotto, O., Barry, Alyssa, Marfurt, J., Siegel, S., Thuy-Nhien, N., Quang, H.H., Anggraeni, N.D., Laihad, F., Liu, Y., Sumiwi, M.E., Trimarsanto, H., Coutrier, F., Fadila, N., Ghanchi, N., Johora, F.T., Puspitasari, A.M., Tavul, L., Trianty, L., Utami, R.A.S., Wang, D., Wangchuck, K., Price, R.N., Auburn, S., Noviyanti, R., Miotto, O., Barry, Alyssa, Marfurt, J., Siegel, S., Thuy-Nhien, N., Quang, H.H., Anggraeni, N.D., Laihad, F., Liu, Y., Sumiwi, M.E., Trimarsanto, H., Coutrier, F., Fadila, N., Ghanchi, N., Johora, F.T., Puspitasari, A.M., Tavul, L., Trianty, L., Utami, R.A.S., Wang, D., Wangchuck, K., Price, R.N., and Auburn, S.

Published
2020

11. Implementing parasite genotyping into national surveillance frameworks: feedback from control programmes and researchers in the Asia-Pacific region

Author

Noviyanti, R, Miotto, O, Barry, A, Marfurt, J, Siegel, S, Nguyen, T-N, Huynh, HQ, Anggraeni, ND, Laihad, F, Liu, Y, Sumiwi, ME, Trimarsanto, H, Coutrier, F, Fadila, N, Ghanchi, N, Johora, FT, Puspitasari, AM, Tavul, L, Trianty, L, Utami, RAS, Wang, D, Wangchuck, K, Price, RN, Auburn, S, Noviyanti, R, Miotto, O, Barry, A, Marfurt, J, Siegel, S, Nguyen, T-N, Huynh, HQ, Anggraeni, ND, Laihad, F, Liu, Y, Sumiwi, ME, Trimarsanto, H, Coutrier, F, Fadila, N, Ghanchi, N, Johora, FT, Puspitasari, AM, Tavul, L, Trianty, L, Utami, RAS, Wang, D, Wangchuck, K, Price, RN, and Auburn, S

Abstract

The Asia-Pacific region faces formidable challenges in achieving malaria elimination by the proposed target in 2030. Molecular surveillance of Plasmodium parasites can provide important information on malaria transmission and adaptation, which can inform national malaria control programmes (NMCPs) in decision-making processes. In November 2019 a parasite genotyping workshop was held in Jakarta, Indonesia, to review molecular approaches for parasite surveillance and explore ways in which these tools can be integrated into public health systems and inform policy. The meeting was attended by 70 participants from 8 malaria-endemic countries and partners of the Asia Pacific Malaria Elimination Network. The participants acknowledged the utility of multiple use cases for parasite genotyping including: quantifying the prevalence of drug resistant parasites, predicting risks of treatment failure, identifying major routes and reservoirs of infection, monitoring imported malaria and its contribution to local transmission, characterizing the origins and dynamics of malaria outbreaks, and estimating the frequency of Plasmodium vivax relapses. However, the priority of each use case varies with different endemic settings. Although a one-size-fits-all approach to molecular surveillance is unlikely to be applicable across the Asia-Pacific region, consensus on the spectrum of added-value activities will help support data sharing across national boundaries. Knowledge exchange is needed to establish local expertise in different laboratory-based methodologies and bioinformatics processes. Collaborative research involving local and international teams will help maximize the impact of analytical outputs on the operational needs of NMCPs. Research is also needed to explore the cost-effectiveness of genetic epidemiology for different use cases to help to leverage funding for wide-scale implementation. Engagement between NMCPs and local researchers will be critical throughout this process.

Published
2020

12. Emergence of artemisinin-resistant Plasmodium falciparum with kelch13 C580Y mutations on the island of New Guinea

Author

Billker, O, Miotto, O, Sekihara, M, Tachibana, S-I, Yamauchi, M, Pearson, RD, Amato, R, Goncalves, S, Mehra, S, Noviyanti, R, Marfurt, J, Auburn, S, Price, RN, Mueller, I, Ikeda, M, Mori, T, Hirai, M, Tavul, L, Hetzel, MW, Laman, M, Barry, AE, Ringwald, P, Ohashi, J, Hombhanje, F, Kwiatkowski, DP, Mita, T, Billker, O, Miotto, O, Sekihara, M, Tachibana, S-I, Yamauchi, M, Pearson, RD, Amato, R, Goncalves, S, Mehra, S, Noviyanti, R, Marfurt, J, Auburn, S, Price, RN, Mueller, I, Ikeda, M, Mori, T, Hirai, M, Tavul, L, Hetzel, MW, Laman, M, Barry, AE, Ringwald, P, Ohashi, J, Hombhanje, F, Kwiatkowski, DP, and Mita, T

Abstract

The rapid and aggressive spread of artemisinin-resistant Plasmodium falciparum carrying the C580Y mutation in the kelch13 gene is a growing threat to malaria elimination in Southeast Asia, but there is no evidence of their spread to other regions. We conducted cross-sectional surveys in 2016 and 2017 at two clinics in Wewak, Papua New Guinea (PNG) where we identified three infections caused by C580Y mutants among 239 genotyped clinical samples. One of these mutants exhibited the highest survival rate (6.8%) among all parasites surveyed in ring-stage survival assays (RSA) for artemisinin. Analyses of kelch13 flanking regions, and comparisons of deep sequencing data from 389 clinical samples from PNG, Indonesian Papua and Western Cambodia, suggested an independent origin of the Wewak C580Y mutation, showing that the mutants possess several distinctive genetic features. Identity by descent (IBD) showed that multiple portions of the mutants' genomes share a common origin with parasites found in Indonesian Papua, comprising several mutations within genes previously associated with drug resistance, such as mdr1, ferredoxin, atg18 and pnp. These findings suggest that a P. falciparum lineage circulating on the island of New Guinea has gradually acquired a complex ensemble of variants, including kelch13 C580Y, which have affected the parasites' drug sensitivity. This worrying development reinforces the need for increased surveillance of the evolving parasite populations on the island, to contain the spread of resistance.

Published
2020

13. Genomic analysis of plasmodium vivax in southern Ethiopia reveals selective pressures in multiple parasite mechanisms

Author

Auburn, S, Getachew, S, Pearson, R, Amato, R, Miotto, O, Trimarsanto, H, Zhu, S, Rumaseb, A, Marfurt, J, Noviyanti, R, Grigg, M, Barber, B, William, T, Goncalves, S, Drury, E, Sriprawat, K, Anstey, N, Nosten, F, Petros, B, Aseffa, A, McVean, G, Kwiatkowski, D, and Price, R

Subjects
Male, Adolescent, Genotype, Adaptation, Biological, Infant, Newborn, malaria, Infant, Article, Child, Preschool, parasitic diseases, Prevalence, genomics, Malaria, Vivax, Humans, Animals, Female, Parasites, Ethiopia, Selection, Genetic, Child, Plasmodium vivax, Duffy
Abstract

The Horn of Africa harbors the largest reservoir of Plasmodium vivax in the continent. Most of sub-Saharan Africa has remained relatively vivax-free due to a high prevalence of the human Duffy-negative trait, but the emergence of strains able to invade Duffy-negative reticulocytes poses a major public health threat. We undertook the first population genomic investigation of P. vivax from the region, comparing the genomes of 24 Ethiopian isolates against data from Southeast Asia to identify important local adaptions. The prevalence of the Duffy binding protein amplification in Ethiopia was 79%, potentially reflecting adaptation to Duffy negativity. There was also evidence of selection in a region upstream of the chloroquine resistance transporter, a putative chloroquine-resistance determinant. Strong signals of selection were observed in genes involved in immune evasion and regulation of gene expression, highlighting the need for a multifaceted intervention approach to combat P. vivax in the region.

Published
2019

14. Genomic analysis of a pre-elimination Malaysian Plasmodium vivax population reveals selective pressures and changing transmission dynamics

Author

Auburn, S, Benavente, E, Miotto, O, Pearson, R, Amato, R, Grigg, M, Barber, B, William, T, Handayuni, I, Marfurt, J, Trimarsanto, H, Noviyanti, R, Sriprawat, K, Nosten, F, Campino, S, Clark, T, Anstey, N, Kwiatkowski, D, and Price, R

Subjects
Science, parasitic diseases, virus diseases, lcsh:Q, lcsh:Science, human activities, Article, geographic locations
Abstract

The incidence of Plasmodium vivax infection has declined markedly in Malaysia over the past decade despite evidence of high-grade chloroquine resistance. Here we investigate the genetic changes in a P. vivax population approaching elimination in 51 isolates from Sabah, Malaysia and compare these with data from 104 isolates from Thailand and 104 isolates from Indonesia. Sabah displays extensive population structure, mirroring that previously seen with the emergence of artemisinin-resistant P. falciparum founder populations in Cambodia. Fifty-four percent of the Sabah isolates have identical genomes, consistent with a rapid clonal expansion. Across Sabah, there is a high prevalence of loci known to be associated with antimalarial drug resistance. Measures of differentiation between the three countries reveal several gene regions under putative selection in Sabah. Our findings highlight important factors pertinent to parasite resurgence and molecular cues that can be used to monitor low-endemic populations at the end stages of P. vivax elimination., Plasmodium vivax incidence in Malaysia has declined markedly over the last decade, despite evidence of chloroquine resistance. Here, Auburn et al. compare population structure of P. vivax in Malaysia to regions with intermediate and high transmission and identify genetic regions under putative selection.

Published
2018

15. Passively versus actively detected malaria: similar genetic diversity but different complexity of infection

Author

Pava, Z, Handayuni, I, Trianty, L, Utami, RAS, Tirta, YK, Puspitasari, AM, Burdam, F, Kenangalem, E, Wirjanata, G, Kho, S, Trimarsanto, H, Anstey, N, Poespoprodjo, JR, Noviyanti, R, Price, RN, Marfurt, J, and Auburn, S

Subjects
Male, Adolescent, Genotyping Techniques, Plasmodium falciparum, Genetic Variation, Articles, DNA, Protozoan, Linkage Disequilibrium, Sympatry, Cross-Sectional Studies, Indonesia, Child, Preschool, parasitic diseases, Malaria, Vivax, Humans, Female, Malaria, Falciparum, Child, Plasmodium vivax, Asymptomatic Infections, Microsatellite Repeats
Abstract

The surveillance of malaria is generally undertaken on the assumption that samples passively collected at health facilities are comparable to or representative of the broader Plasmodium reservoir circulating in the community. Further characterization and comparability of the hidden asymptomatic parasite reservoir are needed to inform on the potential impact of sampling bias. This study explores the impact of sampling strategy on molecular surveillance by comparing the genetic make-up of Plasmodium falciparum and Plasmodium vivax isolates collected by passive versus active case detection. Sympatric isolates of P. falciparum and P. vivax were collected from a large community survey and ongoing clinical surveillance studies undertaken in the hypomesoendemic setting of Mimika District (Papua, Indonesia). Plasmodium falciparum isolates were genotyped at nine microsatellite loci and P. vivax at eight loci. Measures of diversity and differentiation were used to compare different patient and parasitological sample groups. The results demonstrated that passively detected cases (symptomatic) had comparable population diversity to those circulating in the community (asymptomatic) in both species. In addition, asymptomatic patent infections were as diverse as subpatent infections. However, a significant difference in multiplicity of infection (MOI) and percentage of polyclonal infections was observed between actively and passively detected P. vivax cases (mean MOI: 1.7 ± 0.7 versus 1.4 ± 1.4, respectively; P = 0.001). The study findings infer that, in hypomesoendemic settings, passive sampling is appropriate for molecular parasite surveillance strategies using the predominant clone in any given infection; however, the findings suggest caution when analyzing complexity of infection. Further evaluation is required in other endemic settings.

Published
2017

16. Chloroquine efficacy for Plasmodium vivax in Myanmar in populations with high genetic diversity and moderate parasite gene flow

Author

Htun, MW, Mon, NCN, Aye, KM, Hlaing, CM, Kyaw, MP, Handayuni, I, Trimarsanto, H, Bustos, D, Ringwald, P, Price, RN, Auburn, S, and Thriemer, K

Subjects
Adult, Gene Flow, Male, Plasmodium, Genotyping, lcsh:Arctic medicine. Tropical medicine, pvmdr1, Adolescent, DNA Copy Number Variations, Genotype, Efficacy, lcsh:RC955-962, Resistance, Protozoan Proteins, Myanmar, Vivax, lcsh:Infectious and parasitic diseases, Antimalarials, Young Adult, parasitic diseases, Malaria, Vivax, Humans, Transmission, lcsh:RC109-216, Child, Aged, Aged, 80 and over, Diversity, Copy number, Research, Genetic Variation, Chloroquine, Middle Aged, Malaria, Cross-Sectional Studies, Female, Multidrug Resistance-Associated Proteins, Plasmodium vivax, Microsatellite Repeats
Abstract

BACKGROUND:Plasmodium vivax malaria remains a major public health burden in Myanmar. Resistance to chloroquine (CQ), the first-line treatment for P. vivax, has been reported in the country and has potential to undermine local control efforts. METHODS: Patients over 6 years of age with uncomplicated P. vivax mono-infection were enrolled into clinical efficacy studies in Myawaddy in 2014 and Kawthoung in 2012. Study participants received a standard dose of CQ (25 mg/kg over 3 days) followed by weekly review until day 28. Pvmdr1 copy number (CN) and microsatellite diversity were assessed on samples from the patients enrolled in the clinical study and additional cross-sectional surveys undertaken in Myawaddy and Shwegyin in 2012. RESULTS: A total of 85 patients were enrolled in the CQ clinical studies, 25 in Myawaddy and 60 in Kawthoung. One patient in Myawaddy (1.2%) had an early treatment failure and two patients (2.3%) in Kawthoung presented with late treatment failures on day 28. The day 28 efficacy was 92.0% (95% CI 71.6-97.9) in Myawaddy and 98.3% (95% CI 88.7-99.8) in Kawthoung. By day 2, 92.2% (23/25) in Myawaddy and 85.0% (51/60) in Kawthoung were aparasitaemic. Genotyping and pvmdr1 CN assessment was undertaken on 43, 52 and 46 clinical isolates from Myawaddy, Kawthoung and Shwegyin respectively. Pvmdr1 amplification was observed in 3.2% (1/31) of isolates in Myawaddy, 0% (0/49) in Kawthoung and 2.5% (1/40) in Shwegyin. Diversity was high in all sites (HE 0.855-0.876), with low inter-population differentiation (FST 0.016-0.026, P CONCLUSIONS: Treatment failures after chloroquine were observed following chloroquine monotherapy, with pvmdr1 amplification present in both Myawaddy and Shwegyin. The results emphasize the importance of ongoing P. vivax drug resistance surveillance in Myanmar, particularly given the potential connectivity between parasite population at different sites.

Published
2017

17. VivaxGEN: An open access platform for comparative analysis of short tandem repeat genotyping data in Plasmodium vivax Populations

Author

Trimarsanto, H, Benavente, E, Noviyanti, R, Utami, R, Utami, S, Trianty, L, Pava, Z, Getachew, S, Kim, J, Goo, Y, Wangchuck, S, Liu, Y, Gao, Q, Dowd, S, Cheng, Q, Clark, T, Price, R, and Auburn, S

Abstract

Background The control and elimination of Plasmodium vivax will require a better understanding of its transmission dynamics, through the application of genotyping and population genetics analyses. This paper describes VivaxGEN (http://vivaxgen.menzies.edu.au), a web-based platform that has been developed to support P. vivax short tandem repeat data sharing and comparative analyses. Results The VivaxGEN platform provides a repository for raw data generated by capillary electrophoresis (FSA files), with fragment analysis and standardized allele calling tools. The query system of the platform enables users to filter, select and differentiate samples and alleles based on their specified criteria. Key population genetic analyses are supported including measures of population differentiation (FST), expected heterozygosity (HE), linkage disequilibrium (IAS), neighbor-joining analysis and Principal Coordinate Analysis. Datasets can also be formatted and exported for application in commonly used population genetic software including GENEPOP, Arlequin and STRUCTURE. To date, data from 10 countries, including 5 publicly available data sets have been shared with VivaxGEN. Conclusions VivaxGEN is well placed to facilitate regional overviews of P. vivax transmission dynamics in different endemic settings and capable to be adapted for similar genetic studies of P. falciparum and other organisms.

Published
2017

18. Challenges for achieving safe and effective radical cure of P. vivax – a round table discussion of the APMEN Vivax Working Group

Author

Thriemer, K, Ley, B, Bobogare, A, Dysoley, L, Alam, M, Pasaribu, A, Sattabongkot, J, Jambert, E, Domingo, G, Commons, R, Auburn, S, Marfurt, J, Devine, A, Akturazzaman, M, Sohel, N, Namgay, R, Drukpa, T, Sharma, S, Sarawati, E, Samad, I, Theodora, M, Nambanya, S, Ounekham, S, Mudin, R, Da Thakur, G, Makita, L, Deray, R, Lee, S, Boaz, L, Danansuriya, M, Mudiyanselage, S, Chinanonwait, N, Kitchakarn, S, Nausien, J, Naket, E, Duc, T, Manh, H, Hong, Y, Cheng, Q, Richards, J, Kusriastuti, R, Satyagraha, A, Noviyanti, R, Ding, X, Khan, W, Swe, C, Guoding, Z, Qi, G, Kaneko, A, Miotto, O, Nguitragool, W, Roobsoong, W, Battle, K, Howes, R, Roca-Feltrer, A, Duparc, S, Bhowmick, I, Kenangalem, E, Bibit, J, Berry, A, Sintasath, D, Abeyasinghe, R, Sibley, C, McCarthy, J, von Seidlein, L, Baird, K, and Price, R

Subjects
parasitic diseases
Abstract

The delivery of safe and effective radical cure for Plasmodium vivax is one of the greatest challenges for achieving malaria elimination from the Asia-Pacific by 2030. During the annual meeting of the Asia Pacific Malaria Elimination Network (APMEN) Vivax Working Group in October 2016, a round table discussion was held to discuss the programmatic issues hindering the widespread use of primaquine (PQ) radical cure. Participants included 73 representatives from 16 partner countries and 33 institutional partners and other research institutes. In this review the key discussion points are presented and grouped into five themes: (i) current barriers for glucose-6-phosphate deficiency (G6PD) testing prior to PQ radical cure, (ii) necessary properties of G6PD tests for wide scale deployment, (iii) the promotion of G6PD testing, (iv) improving adherence to PQ regimens and (v) the challenges for future tafenoquine (TQ) roll out. Robust point of care (PoC) G6PD tests are needed, which are suitable and cost-effective for clinical settings with limited infrastructure. An affordable and competitive test price is needed, accompanied by sustainable funding for the product with appropriate training of healthcare staff, and robust quality control and assurance processes. In the absence of quantitative PoC G6PD tests, G6PD status can be gauged with qualitative diagnostics, however none of the available tests is currently sensitive enough to guide TQ treatment. TQ introduction will require overcoming additional challenges including the management of severely and intermediately G6PD deficient individuals. Robust strategies are needed to ensure that effective treatment practices can be deployed widely, and these should highlight the caveats as well as the benefits of radical cure for both the patients and the community. Widespread access to quality controlled G6PD testing will be critical.

Published
2017

19. Challenges for achieving safe and effective radical cure of Plasmodium vivax: a round table discussion of the APMEN Vivax Working Group

Author

Thriemer, K., Ley, B., Bobogare, A., Dysoley, L., Alam, M.S., Pasaribu, A.P., Sattabongkot, J., Jambert, E., Domingo, G.J., Commons, R., Auburn, S., Marfurt, J., Devine, A., Aktaruzzaman, M.M., Sohel, N., Namgay, R., Drukpa, T., Sharma, S.N., Sarawati, E., Samad, I., Theodora, M., Nambanya, S., Ounekham, S., Mudin, R.N.B., Da Thakur, G., Makita, L.S., Deray, R., Lee, S.E., Boaz, L., Danansuriya, M.N., Mudiyanselage, S.D., Chinanonwait, N., Kitchakarn, S., Nausien, J., Naket, E., Duc, T.N., Do Manh, H., Hong, Y.S., Cheng, Q., Richards, J.S., Kusriastuti, R., Satyagraha, A., Noviyanti, R., Ding, X.C., Khan, W.A., Swe Phru, C., Guoding, Z., Qi, G., Kaneko, A., Miotto, O., Nguitragool, W., Roobsoong, W., Battle, K., Howes, R.E., Roca-Feltrer, A., Duparc, S., Bhowmick, I.P., Kenangalem, E., Bibit, J.A., Barry, Alyssa, Sintasath, D., Abeyasinghe, R., Sibley, C.H., McCarthy, J., Von Seidlein, L., Baird, J.K., Price, R.N., Thriemer, K., Ley, B., Bobogare, A., Dysoley, L., Alam, M.S., Pasaribu, A.P., Sattabongkot, J., Jambert, E., Domingo, G.J., Commons, R., Auburn, S., Marfurt, J., Devine, A., Aktaruzzaman, M.M., Sohel, N., Namgay, R., Drukpa, T., Sharma, S.N., Sarawati, E., Samad, I., Theodora, M., Nambanya, S., Ounekham, S., Mudin, R.N.B., Da Thakur, G., Makita, L.S., Deray, R., Lee, S.E., Boaz, L., Danansuriya, M.N., Mudiyanselage, S.D., Chinanonwait, N., Kitchakarn, S., Nausien, J., Naket, E., Duc, T.N., Do Manh, H., Hong, Y.S., Cheng, Q., Richards, J.S., Kusriastuti, R., Satyagraha, A., Noviyanti, R., Ding, X.C., Khan, W.A., Swe Phru, C., Guoding, Z., Qi, G., Kaneko, A., Miotto, O., Nguitragool, W., Roobsoong, W., Battle, K., Howes, R.E., Roca-Feltrer, A., Duparc, S., Bhowmick, I.P., Kenangalem, E., Bibit, J.A., Barry, Alyssa, Sintasath, D., Abeyasinghe, R., Sibley, C.H., McCarthy, J., Von Seidlein, L., Baird, J.K., and Price, R.N.

Published
2017

20. Plasmodium malariae and P. ovale genomes provide insights into malaria parasite evolution

Author

Rutledge, GG, Bohme, U, Sanders, M, Rrid, AJ, Cotton, JA, Maiga-Ascofare, O, Djimde, AA, Apinjoh, TO, Amenga-Etego, L, Manske, M, Barnwell, JW, Renaud, F, Ollomo, B, Prugnolle, F, Anstey, NM, Auburn, S, Price, RN, McCarthy, JS, Kwiatkowski, DP, Newbold, CI, Berriman, M, Otto, TD, Rutledge, GG, Bohme, U, Sanders, M, Rrid, AJ, Cotton, JA, Maiga-Ascofare, O, Djimde, AA, Apinjoh, TO, Amenga-Etego, L, Manske, M, Barnwell, JW, Renaud, F, Ollomo, B, Prugnolle, F, Anstey, NM, Auburn, S, Price, RN, McCarthy, JS, Kwiatkowski, DP, Newbold, CI, Berriman, M, and Otto, TD

Abstract

Elucidation of the evolutionary history and interrelatedness of Plasmodium species that infect humans has been hampered by a lack of genetic information for three human-infective species: P. malariae and two P. ovale species (P. o. curtisi and P. o. wallikeri). These species are prevalent across most regions in which malaria is endemic and are often undetectable by light microscopy, rendering their study in human populations difficult. The exact evolutionary relationship of these species to the other human-infective species has been contested. Using a new reference genome for P. malariae and a manually curated draft P. o. curtisi genome, we are now able to accurately place these species within the Plasmodium phylogeny. Sequencing of a P. malariae relative that infects chimpanzees reveals similar signatures of selection in the P. malariae lineage to another Plasmodium lineage shown to be capable of colonization of both human and chimpanzee hosts. Molecular dating suggests that these host adaptations occurred over similar evolutionary timescales. In addition to the core genome that is conserved between species, differences in gene content can be linked to their specific biology. The genome suggests that P. malariae expresses a family of heterodimeric proteins on its surface that have structural similarities to a protein crucial for invasion of red blood cells. The data presented here provide insight into the evolution of the Plasmodium genus as a whole.

Published
2017

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

Author

Manske, M, Miotto, O, Campino, S, Auburn, S, Almagro-Garcia, J, Maslen, G, O'Brien, J, Djimde, A, Doumbo, O, Zongo, I, Ouedraogo, JB, Michon, P, Mueller, I, Siba, P, Nzila, A, Borrmann, S, Kiara, SM, Marsh, K, Jiang, H, Su, XZ, Amaratunga, C, Fairhurst, R, Socheat, D, Nosten, F, Imwong, M, White, NJ, Sanders, M, Anastasi, E, Alcock, D, Drury, E, Oyola, S, Quail, MA, Turner, DJ, Ruano-Rubio, V, Jyothi, D, Amenga-Etego, L, Hubbart, C, Jeffreys, A, Rowlands, K, Sutherland, C, Roper, C, Mangano, V, Modiano, D, Tan, JC, Ferdig, MT, Amambua-Ngwa, A, Conway, DJ, Takala-Harrison, S, Plowe, CV, Rayner, JC, Rockett, KA, Clark, TG, Newbold, CI, Berriman, M, MacInnis, B, and Kwiatkowski, DP

Subjects
Genotype, 030231 tropical medicine, Population, Plasmodium falciparum, Genomics, Biology, Polymorphism, Single Nucleotide, Deep sequencing, Article, 03 medical and health sciences, 0302 clinical medicine, parasitic diseases, Humans, Genetic variability, Malaria, Falciparum, education, Genotyping, Alleles, Phylogeny, 030304 developmental biology, Genetics, Whole genome sequencing, 0303 health sciences, Genetic diversity, education.field_of_study, Principal Component Analysis, Multidisciplinary, High-Throughput Nucleotide Sequencing, Biodiversity, biology.organism_classification, 3. Good health, Genome, Protozoan
Abstract

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 genomewide 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. The genetic diversity and evolutionary plasticity of P. falciparum are major obstacles for malaria elimination. New forms of resistance against antimalarial drugs are continually emerging 1,2 , and new forms of antigenic variation are a critical point of vulnerability for future malaria vaccines. Effective tools are needed to detect evolutionary changes in the parasite population and to monitor the spread of genetic variants that affect malaria control. Here we describe the use of deep sequencing to analyse P. falciparum diversity, using blood samples from patients with malaria. The P. falciparum genome has several unusual features that greatly complicate sequence analysis, such as extreme AT bias, large tracts of nonunique sequence and several large families of intensely polymorphic genes 3 . Our aim was therefore not to determine the entire genome sequence of individual field samples—which would be prohibitively expensive with current technologies—but to define an initial set of single nucleotide polymorphisms (SNPs) distributed across the P. falciparum genome, whose genotype can be ascertained with confidence in parasitized blood samples by deep sequencing. An additional complication in the analysis of P. falciparum genome variation is that the billions of haploid parasites that infect a single individual can be a complex mixture of genetic types. Previous studies 4–8 have largely focused on laboratory-adapted parasite clones, but the within-host diversity of natural infections is of fundamental biological interest. Parasites in the blood replicate asexually, but when they are taken up in the blood meal of an Anopheles mosquito they undergo sexual mating. If the parasites in the blood are of diverse genetic types, this process of sexual mating can generate novel recombinant forms. Deep sequencing provides new ways of investigating within-host diversity and the role of sexual recombination in parasite evolution.

Published
2016

22. 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

23. Genomic epidemiology of artemisinin resistant malaria.

Author

Amato, A., 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, A., 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., et al., Amato, A., 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, A., 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., and et al.

Abstract

Contains fulltext : 172626.pdf (publisher's version ) (Open Access)

Published
2016

24. 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

25. 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

26. Genomic analysis of local variation and recent evolution in Plasmodium vivax

Author

Pearson, RD, Amato, R, Auburn, S, Miotto, O, Almagro-Garcia, J, Amaratunga, C, Suon, S, Mao, S, Noviyanti, R, Trimarsanto, H, Marfurt, J, Anstey, NM, William, T, Boni, MF, Dolecek, C, Hien, TT, White, NJ, Michon, P, Siba, P, Tavul, L, Harrison, G, Barry, A, Mueller, I, Ferreira, MU, Karunaweera, N, Randrianarivelojosia, M, Gao, Q, Hubbart, C, Hart, L, Jeffery, B, Drury, E, Mead, D, Kekre, M, Campino, S, Manske, M, Cornelius, VJ, MacInnis, B, Rockett, KA, Miles, A, Rayner, JC, Fairhurst, RM, Nosten, F, Price, RN, Kwiatkowski, DP, Pearson, RD, Amato, R, Auburn, S, Miotto, O, Almagro-Garcia, J, Amaratunga, C, Suon, S, Mao, S, Noviyanti, R, Trimarsanto, H, Marfurt, J, Anstey, NM, William, T, Boni, MF, Dolecek, C, Hien, TT, White, NJ, Michon, P, Siba, P, Tavul, L, Harrison, G, Barry, A, Mueller, I, Ferreira, MU, Karunaweera, N, Randrianarivelojosia, M, Gao, Q, Hubbart, C, Hart, L, Jeffery, B, Drury, E, Mead, D, Kekre, M, Campino, S, Manske, M, Cornelius, VJ, MacInnis, B, Rockett, KA, Miles, A, Rayner, JC, Fairhurst, RM, Nosten, F, Price, RN, and Kwiatkowski, DP

Abstract

The widespread distribution and relapsing nature of Plasmodium vivax infection present major challenges for the elimination of malaria. To characterize the genetic diversity of this parasite in individual infections and across the population, we performed deep genome sequencing of >200 clinical samples collected across the Asia-Pacific region and analyzed data on >300,000 SNPs and nine regions of the genome with large copy number variations. Individual infections showed complex patterns of genetic structure, with variation not only in the number of dominant clones but also in their level of relatedness and inbreeding. At the population level, we observed strong signals of recent evolutionary selection both in known drug resistance genes and at new loci, and these varied markedly between geographical locations. These findings demonstrate a dynamic landscape of local evolutionary adaptation in the parasite population and provide a foundation for genomic surveillance to guide effective strategies for control and elimination of P. vivax.

Published
2016

27. Submicroscopic and Asymptomatic Plas-modium Parasitaemia Associated with Significant Risk of Anaemia in Papua, Indonesia

Author

Tsuboi, T, Pava, Z, Burdam, FH, Handayuni, I, Trianty, L, Utami, RAS, Tirta, YK, Kenangalem, E, Lampah, D, Kusuma, A, Wirjanata, G, Kho, S, Simpson, JA, Auburn, S, Douglas, NM, Noviyanti, R, Anstey, NM, Poespoprodjo, JR, Marfurt, J, Price, RN, Tsuboi, T, Pava, Z, Burdam, FH, Handayuni, I, Trianty, L, Utami, RAS, Tirta, YK, Kenangalem, E, Lampah, D, Kusuma, A, Wirjanata, G, Kho, S, Simpson, JA, Auburn, S, Douglas, NM, Noviyanti, R, Anstey, NM, Poespoprodjo, JR, Marfurt, J, and Price, RN

Abstract

Submicroscopic Plasmodium infections are an important parasite reservoir, but their clinical relevance is poorly defined. A cross-sectional household survey was conducted in southern Papua, Indonesia, using cluster random sampling. Data were recorded using a standardized questionnaire. Blood samples were collected for haemoglobin measurement. Plasmodium parasitaemia was determined by blood film microscopy and PCR. Between April and July 2013, 800 households and 2,830 individuals were surveyed. Peripheral parasitaemia was detected in 37.7% (968/2,567) of individuals, 36.8% (357) of whom were identified by blood film examination. Overall the prevalence of P. falciparum parasitaemia was 15.4% (396/2567) and that of P. vivax 18.3% (471/2567). In parasitaemic individuals, submicroscopic infection was significantly more likely in adults (adjusted odds ratio (AOR): 3.82 [95%CI: 2.49-5.86], p<0.001) compared to children, females (AOR = 1.41 [1.07-1.86], p = 0.013), individuals not sleeping under a bednet (AOR = 1.4 [1.0-1.8], p = 0.035), and being afebrile (AOR = 3.2 [1.49-6.93], p = 0.003). The risk of anaemia (according to WHO guidelines) was 32.8% and significantly increased in those with asymptomatic parasitaemia (AOR 2.9 [95% 2.1-4.0], p = 0.007), and submicroscopic P. falciparum infections (AOR 2.5 [95% 1.7-3.6], p = 0.002). Asymptomatic and submicroscopic infections in this area co-endemic for P. falciparum and P. vivax constitute two thirds of detectable parasitaemia and are associated with a high risk of anaemia. Novel public health strategies are needed to detect and eliminate these parasite reservoirs, for the benefit both of the patient and the community.

Published
2016

28. Targeting vivax malaria in the Asia Pacific: The Asia Pacific Malaria Elimination Network Vivax Working Group

Author

Anstey, NM, Auburn, S, Baird, JK, Battle, KE, Bobogare, A, Chancellor, A, Chasombat, S, Cheng, Q, Domingo, GJ, Drakeley, CJ, Drukpa, T, Dysoley, L, Esperanza Espino, F, Gething, PW, Ghimire, P, Gosling, RD, Grewal-Daumerie, P, Hay, SI, Howes, RE, Hwang, J, Karim, J, Khan, WA, Kim, J-Y, Ley, B, Mannion, K, McCarthy, J, Keong, WM, Mueller, I, Namgay, R, Price, RN, Qi, G, Rebueno, M, Reeder, J, Richards, J, Sattabongkot-Prachumsri, J, Shanks, GD, Sibley, CH, Surya, A, Taleo, G, Ngo, DT, Thongpaseuth, V, Thriemer, K, Trimarsanto, H, Vestergaard, LS, von Seidelein, L, Whittaker, M, Anstey, NM, Auburn, S, Baird, JK, Battle, KE, Bobogare, A, Chancellor, A, Chasombat, S, Cheng, Q, Domingo, GJ, Drakeley, CJ, Drukpa, T, Dysoley, L, Esperanza Espino, F, Gething, PW, Ghimire, P, Gosling, RD, Grewal-Daumerie, P, Hay, SI, Howes, RE, Hwang, J, Karim, J, Khan, WA, Kim, J-Y, Ley, B, Mannion, K, McCarthy, J, Keong, WM, Mueller, I, Namgay, R, Price, RN, Qi, G, Rebueno, M, Reeder, J, Richards, J, Sattabongkot-Prachumsri, J, Shanks, GD, Sibley, CH, Surya, A, Taleo, G, Ngo, DT, Thongpaseuth, V, Thriemer, K, Trimarsanto, H, Vestergaard, LS, von Seidelein, L, and Whittaker, M

Abstract

The Asia Pacific Malaria Elimination Network (APMEN) is a collaboration of 18 country partners committed to eliminating malaria from within their borders. Over the past 5 years, APMEN has helped to build the knowledge, tools and in-country technical expertise required to attain this goal. At its inaugural meeting in Brisbane in 2009, Plasmodium vivax infections were identified across the region as a common threat to this ambitious programme; the APMEN Vivax Working Group was established to tackle specifically this issue. The Working Group developed a four-stage strategy to identify knowledge gaps, build regional consensus on shared priorities, generate evidence and change practice to optimize malaria elimination activities. This case study describes the issues faced and the solutions found in developing this robust strategic partnership between national programmes and research partners within the Working Group. The success of the approach adopted by the group may facilitate similar applications in other regions seeking to deploy evidence-based policy and practice.

Published
2015

30. 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

32. Review of key knowledge gaps in glucose-6-phosphate dehydrogenase deficiency detection with regard to the safe clinical deployment of 8-aminoquinoline treatment regimens: a workshop report

Author

von Seidlein, L, Auburn, S, Espino, F, Shanks, D, Cheng, Q, McCarthy, J, Baird, K, Moyes, C, Howes, R, Menard, D, Bancone, G, Winasti-Satyahraha, A, Vestergaard, LS, Green, J, Domingo, G, Yeung, S, Price, R, von Seidlein, L, Auburn, S, Espino, F, Shanks, D, Cheng, Q, McCarthy, J, Baird, K, Moyes, C, Howes, R, Menard, D, Bancone, G, Winasti-Satyahraha, A, Vestergaard, LS, Green, J, Domingo, G, Yeung, S, and Price, R

Abstract

The diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency is a crucial aspect in the current phases of malaria control and elimination, which will require the wider use of 8-aminoquinolines for both reducing Plasmodium falciparum transmission and achieving the radical cure of Plasmodium vivax. 8-aminoquinolines, such as primaquine, can induce severe haemolysis in G6PD-deficient individuals, potentially creating significant morbidity and undermining confidence in 8-aminoquinoline prescription. On the other hand, erring on the side of safety and excluding large numbers of people with unconfirmed G6PD deficiency from treatment with 8-aminoquinolines will diminish the impact of these drugs. Estimating the remaining G6PD enzyme activity is the most direct, accessible, and reliable assessment of the phenotype and remains the gold standard for the diagnosis of patients who could be harmed by the administration of primaquine. Genotyping seems an unambiguous technique, but its use is limited by cost and the large range of recognized G6PD genotypes. A number of enzyme activity assays diagnose G6PD deficiency, but they require a cold chain, specialized equipment, and laboratory skills. These assays are impractical for care delivery where most patients with malaria live. Improvements to the diagnosis of G6PD deficiency are required for the broader and safer use of 8-aminoquinolines to kill hypnozoites, while lower doses of primaquine may be safely used to kill gametocytes without testing. The discussions and conclusions of a workshop conducted in Incheon, Korea in May 2012 to review key knowledge gaps in G6PD deficiency are reported here.

Published
2013

33. Engagement in video and audio narratives: contrasting self-report and physiological measures

Author

Daniel C. Richardson, Nicole K. Griffin, Lara Zaki, Auburn Stephenson, Jiachen Yan, Thomas Curry, Richard Noble, John Hogan, Jeremy I. Skipper, and Joseph T. Devlin

Subjects
Medicine, Science
Abstract

Abstract Stories play a fundamental role in human culture. They provide a mechanism for sharing cultural identity, imparting knowledge, revealing beliefs, reinforcing social bonds and providing entertainment that is central to all human societies. Here we investigated the extent to which the delivery medium of a story (audio or visual) affected self-reported and physiologically measured engagement with the narrative. Although participants self-reported greater involvement for watching video relative to listening to auditory scenes, stronger physiological responses were recorded for auditory stories. Sensors placed at their wrists showed higher and more variable heart rates, greater electrodermal activity, and even higher body temperatures. We interpret these findings as evidence that the stories were more cognitively and emotionally engaging at a physiological level when presented in an auditory format. This may be because listening to a story, rather than watching a video, is a more active process of co-creation, and that this imaginative process in the listener’s mind is detectable on the skin at their wrist.

Published
2020
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34. Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing

Author

Manske, M, Miotto, O, Campino, S, Auburn, S, Almagro-Garcia, J, Maslen, G, O'Brien, J, Djimde, A, Doumbo, O, Zongo, I, Ouedraogo, J-B, Michon, P, Mueller, I, Siba, P, Nzila, A, Borrmann, S, Kiara, SM, Marsh, K, Jiang, H, Su, X-Z, Amaratunga, C, Fairhurst, R, Socheat, D, Nosten, F, Imwong, M, White, NJ, Sanders, M, Anastasi, E, Alcock, D, Drury, E, Oyola, S, Quail, MA, Turner, DJ, Ruano-Rubio, V, Jyothi, D, Amenga-Etego, L, Hubbart, C, Jeffreys, A, Rowlands, K, Sutherland, C, Roper, C, Mangano, V, Modiano, D, Tan, JC, Ferdig, MT, Amambua-Ngwa, A, Conway, DJ, Takala-Harrison, S, Plowe, CV, Rayner, JC, Rockett, KA, Clark, TG, Newbold, CI, Berriman, M, MacInnis, B, Kwiatkowski, DP, Manske, M, Miotto, O, Campino, S, Auburn, S, Almagro-Garcia, J, Maslen, G, O'Brien, J, Djimde, A, Doumbo, O, Zongo, I, Ouedraogo, J-B, Michon, P, Mueller, I, Siba, P, Nzila, A, Borrmann, S, Kiara, SM, Marsh, K, Jiang, H, Su, X-Z, Amaratunga, C, Fairhurst, R, Socheat, D, Nosten, F, Imwong, M, White, NJ, Sanders, M, Anastasi, E, Alcock, D, Drury, E, Oyola, S, Quail, MA, Turner, DJ, Ruano-Rubio, V, Jyothi, D, Amenga-Etego, L, Hubbart, C, Jeffreys, A, Rowlands, K, Sutherland, C, Roper, C, Mangano, V, Modiano, D, Tan, JC, Ferdig, MT, Amambua-Ngwa, A, Conway, DJ, Takala-Harrison, S, Plowe, CV, Rayner, JC, Rockett, KA, Clark, TG, Newbold, CI, Berriman, M, MacInnis, B, and Kwiatkowski, DP

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.

Published
2012

35. Population Genetic Analysis of Plasmodium falciparum Parasites Using a Customized Illumina GoldenGate Genotyping Assay

Author

Fitzgerald, JR, Campino, S, Auburn, S, Kivinen, K, Zongo, I, Ouedraogo, J-B, Mangano, V, Djimde, A, Doumbo, OK, Kiara, SM, Nzila, A, Borrmann, S, Marsh, K, Michon, P, Mueller, I, Siba, P, Jiang, H, Su, X-Z, Amaratunga, C, Socheat, D, Fairhurst, RM, Imwong, M, Anderson, T, Nosten, F, White, NJ, Gwilliam, R, Deloukas, P, MacInnis, B, Newbold, CI, Rockett, K, Clark, TG, Kwiatkowski, DP, Fitzgerald, JR, Campino, S, Auburn, S, Kivinen, K, Zongo, I, Ouedraogo, J-B, Mangano, V, Djimde, A, Doumbo, OK, Kiara, SM, Nzila, A, Borrmann, S, Marsh, K, Michon, P, Mueller, I, Siba, P, Jiang, H, Su, X-Z, Amaratunga, C, Socheat, D, Fairhurst, RM, Imwong, M, Anderson, T, Nosten, F, White, NJ, Gwilliam, R, Deloukas, P, MacInnis, B, Newbold, CI, Rockett, K, Clark, TG, and Kwiatkowski, DP

Abstract

The diversity in the Plasmodium falciparum genome can be used to explore parasite population dynamics, with practical applications to malaria control. The ability to identify the geographic origin and trace the migratory patterns of parasites with clinically important phenotypes such as drug resistance is particularly relevant. With increasing single-nucleotide polymorphism (SNP) discovery from ongoing Plasmodium genome sequencing projects, a demand for high SNP and sample throughput genotyping platforms for large-scale population genetic studies is required. Low parasitaemias and multiple clone infections present a number of challenges to genotyping P. falciparum. We addressed some of these issues using a custom 384-SNP Illumina GoldenGate assay on P. falciparum DNA from laboratory clones (long-term cultured adapted parasite clones), short-term cultured parasite isolates and clinical (non-cultured isolates) samples from East and West Africa, Southeast Asia and Oceania. Eighty percent of the SNPs (n = 306) produced reliable genotype calls on samples containing as little as 2 ng of total genomic DNA and on whole genome amplified DNA. Analysis of artificial mixtures of laboratory clones demonstrated high genotype calling specificity and moderate sensitivity to call minor frequency alleles. Clear resolution of geographically distinct populations was demonstrated using Principal Components Analysis (PCA), and global patterns of population genetic diversity were consistent with previous reports. These results validate the utility of the platform in performing population genetic studies of P. falciparum.

Published
2011

37. Tumor necrosis factor and lymphotoxin-alpha polymorphisms and severe malaria in African populations.

Author

Clark TG, Diakite M, Auburn S, Campino S, Fry AE, Green A, Richardson A, Small K, Teo YY, Wilson J, Jallow M, Sisay-Joof F, Pinder M, Griffiths MJ, Peshu N, Williams TN, Marsh K, Molyneux ME, Taylor TE, and Rockett KA

Abstract

The tumor necrosis factor gene (TNF) and lymphotoxin-alpha gene (LTA) have long attracted attention as candidate genes for susceptibility traits for malaria, and several of their polymorphisms have been found to be associated with severe malaria (SM) phenotypes. In a large study involving >10,000 individuals and encompassing 3 African populations, we found evidence to support the reported associations between the TNF -238 polymorphism and SM in The Gambia. However, no TNF/LTA polymorphisms were found to be associated with SM in cohorts in Kenya and Malawi. It has been suggested that the causal polymorphisms regulating the TNF and LTA responses may be located some distance from the genes. Therefore, more-detailed mapping of variants across TNF/LTA genes and their flanking regions in the Gambian and allied populations may need to be undertaken to find any causal polymorphisms. [ABSTRACT FROM AUTHOR]

Published
2009
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38. 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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39. TLR9 polymorphisms in African populations: no association with severe malaria, but evidence of cis-variants acting on gene expression

Author

Pinder Margaret, Sisay-Joof Fatou, Jallow Muminatou, Hull Jeremy, Richardson Anna, Diakite Mahamadou, Fry Andrew, Auburn Sarah, Forton Julian, Campino Susana, Molyneux Malcolm E, Taylor Terrie E, Rockett Kirk, Clark Taane G, and Kwiatkowski Dominic P

Subjects
Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background During malaria infection the Toll-like receptor 9 (TLR9) is activated through induction with plasmodium DNA or another malaria motif not yet identified. Although TLR9 activation by malaria parasites is well reported, the implication to the susceptibility to severe malaria is not clear. The aim of this study was to assess the contribution of genetic variation at TLR9 to severe malaria. Methods This study explores the contribution of TLR9 genetic variants to severe malaria using two approaches. First, an association study of four common single nucleotide polymorphisms was performed on both family- and population-based studies from Malawian and Gambian populations (n>6000 individual). Subsequently, it was assessed whether TLR9 expression is affected by cis-acting variants and if these variants could be mapped. For this work, an allele specific expression (ASE) assay on a panel of HapMap cell lines was carried out. Results No convincing association was found with polymorphisms in TLR9 for malaria severity, in either Gambian or Malawian populations, using both case-control and family based study designs. Using an allele specific expression assay it was observed that TLR9 expression is affected by cis-acting variants, these results were replicated in a second experiment using biological replicates. Conclusion By using the largest cohorts analysed to date, as well as a standardized phenotype definition and study design, no association of TLR9 genetic variants with severe malaria was found. This analysis considered all common variants in the region, but it is remains possible that there are rare variants with association signals. This report also shows that TLR9 expression is potentially modulated through cis-regulatory variants, which may lead to differential inflammatory responses to infection between individuals.

Published
2009
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40. Admixture into and within sub-Saharan Africa

Author

Angeliki Kerasidou, J O'Brien, Aaron Vanderwal, Christina Hubbart, Alistair Miles, Catherine L. Moyes, A Nyika, Abier Elzein, J Shelton, Spencer Cca., Anthony Enimil, A Diss, C Hughes, Lucas Amenga-Etego, E Somaskantharajah, Ogobara K. Doumbo, Jacob Almagro Garcia, Valentina D. Mangano, E Drury, Edith Bougama, Angie Green, Busby Gbj., Geraldine M. Clarke, Dominic P. Kwiatkowski, Jiannis Ragoussis, Alphaxard Manjurano, Bronwyn MacInnis, Tobias O. Apinjoh, D Mead, Gareth Maslen, George B.J. Busby, Kirk A. Rockett, Dushyanth Jyothi, C Potter, C Malangone, Muminatou Jallow, I Ragoussis, Ellen M. Leffler, J Rogers, J Stalker, Quang Si Le, J Rodford, D Barnwell, Alieu Mendy, J deVries, Anna E. Jeffreys, Carolyne M. Ndila, E Hilton, Vysaul Nyirongo, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], The Wellcome Trust Sanger Institute [Cambridge], Medical Research Council Unit The Gambia (MRC), Centre National de Recherche et de Formation sur le Paludisme [Ouagadougou, Burkina Faso] (CNRFP), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Navrongo Health Research Centre [Navrongo, Ghana] (NHRC), Komfo Anokye Teaching Hospital, University of Buéa, KEMRI-Wellcome Trust Research Programme (KWTRP), London School of Hygiene and Tropical Medicine (LSHTM), University of Malawi, University of Bamako [Mali], Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP), Wellcome Trust, Medical Research Council, Foundation for the National Institutes of Health, Malaria Genomics Epidemiology Network : Vanderwal A, Elzein A, Nyika A, Mendy A, Miles A, Diss A, Kerasidou A, Green A, Jeffreys AE, MacInnis B, Hughes C, Moyes C, Spencer CC, Hubbart C, Malangone C, Potter C, Mead D, Barnwell D, Kwiatkowski DP, Jyothi D, Drury E, Somaskantharajah E, Hilton E, Leffler E, Maslen G, Band G, Busby G, Clarke GM, Ragoussis I, Garcia JA, Rogers J, deVries J, Shelton J, Ragoussis J, Stalker J, Rodford J, O'Brien J, Evans J, Rowlands K, Cook K, Fitzpatrick K, Kivinen K, Small K, Johnson KJ, Rockett KA, Hart L, Manske M, McCreight M, Stevens M, Pirinen M, Hennsman M, Parker M, SanJoaquin M, Seplúveda N, Cook O, Miotto O, Deloukas P, Craik R, Wrigley R, Watson R, Pearson R, Hutton R, Oyola S, Auburn S, Shah S, Le SQ, Molloy S, Bull S, Campino S, Clark TG, Ruano-Rubio V, Cornelius V, Teo YY, Corran P, Silva ND, Risley P, Doyle A, Evans J, Horstmann R, Plowe C, Duffy P, Carucci D, Gottleib M, Tall A, Ly AB, Dolo A, Sakuntabhai A, Puijalon O, Bah A, Camara A, Sadiq A, Khan AA, Jobarteh A, Mendy A, Ebonyi A, Danso B, Taal B, Casals-Pascual C, Conway DJ, Onykwelu E, Sisay-Joof F, Sirugo G, Kanyi H, Njie H, Obu H, Saine H, Sambou I, Abubakar I, Njie J, Fullah J, Jaiteh J, Bojang KA, Jammeh K, Sabally-Ceesay K, Manneh L, Camara L, Yamoah L, Njie M, Njie M, Pinder M, Jallow M, Aiyegbo M, Jasseh M, Keita ML, Saidy-Khan M, Jallow M, Ceesay N, Rasheed O, Ceesay PL, Esangbedo P, Cole-Ceesay R, Olaosebikan R, Correa S, Njie S, Usen S, Dibba Y, Barry A, Djimdé A, Sall AH, Abathina A, Niangaly A, Dembele A, Poudiougou B, Diarra E, Bamba K, Thera MA, Doumbo O, Toure O, Konate S, Sissoko S, Diakite M, Konate AT, Modiano D, Bougouma EC, Bancone G, Ouedraogo IN, Simpore J, Sirima SB, Mangano VD, Troye-Blomberg M, Oduro AR, Hodgson AV, Ghansah A, Nkrumah F, Atuguba F, Koram KA, Amenga-Etego LN, Wilson MD, Ansah NA, Mensah N, Ansah PA, Anyorigiya T, Asoala V, Rogers WO, Akoto AO, Ofori AO, Enimil A, Ansong D, Sambian D, Asafo-Agyei E, Sylverken J, Antwi S, Agbenyega T, Orimadegun AE, Amodu FA, Oni O, Omotade OO, Amodu O, Olaniyan S, Ndi A, Yafi C, Achidi EA, Mbunwe E, Anchang-Kimbi J, Mugri R, Besingi R, Apinjoh TO, Titanji V, Elhassan A, Hussein A, Mohamed H, Elhassan I, Ibrahim M, Kokwaro G, Oluoch T, Macharia A, Ndila CM, Newton C, Opi DH, Kamuya D, Bauni E, Marsh K, Peshu N, Molyneux S, Uyoga S, Williams TN, Marsh V, Manjurano A, Nadjm B, Maxwell C, Drakeley C, Riley E, Mtei F, Mtove G, Wangai H, Reyburn H, Joseph S, Ishengoma D, Lemnge M, Mutabingwa T, Makani J, Cox S, Phiri A, Munthali A, Kachala D, Njiragoma L, Molyneux ME, Moore M, Ntunthama N, Pensulo P, Taylor T, Nyirongo V, Carter R, Fernando D, Karunaweera N, Dewasurendra R, Suriyaphol P, Singhasivanon P, Simmons CP, Thai CQ, Sinh DX, Farrar J, Chuong LV, Phu NH, Hieu NT, Hoang Mai NT, Ngoc Quyen NT, Day N, Dunstan SJ, O'Riordan SE, Hong Chau TT, Hien TT, Allen A, Lin E, Karunajeewa H, Mueller I, Reeder J, Manning L, Laman M, Michon P, Siba P, Allen S, Davis TM., Commission of the European Communities, and Wellcome Trust

Subjects
0301 basic medicine, Population genetics, Gene flow, 0302 clinical medicine, MESH: Genetic Variation, Biology (General), African Continental Ancestry Group, media_common, Genetics, 0303 health sciences, education.field_of_study, Human migration, General Neuroscience, 030305 genetics & heredity, General Medicine, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Geography, Genomics and Evolutionary Biology, MESH: Human Migration, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Medicine, admixture, gene-flow, Research Article, Gene Flow, QH301-705.5, Science, media_common.quotation_subject, Human Migration, Population, Black People, Genomics, Biology, africa, chromosome painting, evolutionary biology, genomics, human, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Genetic variation, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, MESH: Africa South of the Sahara, Allele, education, Africa South of the Sahara, MESH: Gene Flow, MESH: Genome, Human, 030304 developmental biology, Genetic diversity, MESH: Humans, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], General Immunology and Microbiology, business.industry, Genome, Human, Haplotype, Genetic Variation, MESH: Haplotypes, 030104 developmental biology, Genetic epidemiology, Haplotypes, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Agriculture, Evolutionary biology, Africa, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: African Continental Ancestry Group, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, 030217 neurology & neurosurgery, Demography, Diversity (politics)
Abstract

Similarity between two individuals in the combination of genetic markers along their chromosomes indicates shared ancestry and can be used to identify historical connections between different population groups due to admixture. We use a genome-wide, haplotype-based, analysis to characterise the structure of genetic diversity and gene-flow in a collection of 48 sub-Saharan African groups. We show that coastal populations experienced an influx of Eurasian haplotypes over the last 7000 years, and that Eastern and Southern Niger-Congo speaking groups share ancestry with Central West Africans as a result of recent population expansions. In fact, most sub-Saharan populations share ancestry with groups from outside of their current geographic region as a result of gene-flow within the last 4000 years. Our in-depth analysis provides insight into haplotype sharing across different ethno-linguistic groups and the recent movement of alleles into new environments, both of which are relevant to studies of genetic epidemiology. DOI: http://dx.doi.org/10.7554/eLife.15266.001, eLife digest Our genomes contain a record of historical events. This is because when groups of people are separated for generations, the DNA sequence in the two groups’ genomes will change in different ways. Looking at the differences in the genomes of people from the same population can help researchers to understand and reconstruct the historical interactions that brought their ancestors together. The mixing of two populations that were previously separate is known as admixture. Africa as a continent has few written records of its history. This means that it is somewhat unknown which important movements of people in the past generated the populations found in modern-day Africa. Busby et al. have now attempted to use DNA to look into this and reconstruct the last 4000 years of genetic history in African populations. As has been shown in other regions of the world, the new analysis showed that all African populations are the result of historical admixture events. However, Busby et al. could characterize these events to unprecedented level of detail. For example, multiple ethnic groups from The Gambia and Mali all show signs of sharing the same set of ancestors from West Africa, Europe and Asia who mixed around 2000 years ago. Evidence of a migration of people from Central West Africa, known as the Bantu expansion, could also be detected, and was shown to carry genes to the south and east. An important next step will be to now look at the consequences of the observed gene-flow, and ask if it has contributed to spreading beneficial, or detrimental, mutations around Africa. DOI: http://dx.doi.org/10.7554/eLife.15266.002

Published
2016

41. Lineage-informative microhaplotypes for recurrence classification and spatio-temporal surveillance of Plasmodium vivax malaria parasites.

Author

Siegel SV, Trimarsanto H, Amato R, Murie K, Taylor AR, Sutanto E, Kleinecke M, Whitton G, Watson JA, Imwong M, Assefa A, Rahim AG, Nguyen HC, Tran TH, Green JA, Koh GCKW, White NJ, Day N, Kwiatkowski DP, Rayner JC, Price RN, and Auburn S

Subjects
Humans, Haplotypes genetics, Polymorphism, Single Nucleotide, Genome, Protozoan genetics, Genotype, Plasmodium vivax genetics, Malaria, Vivax parasitology, Malaria, Vivax epidemiology, Recurrence
Abstract

Challenges in classifying recurrent Plasmodium vivax infections constrain surveillance of antimalarial efficacy and transmission. Recurrent infections may arise from activation of dormant liver stages (relapse), blood-stage treatment failure (recrudescence) or reinfection. Molecular inference of familial relatedness (identity-by-descent or IBD) can help resolve the probable origin of recurrences. As whole genome sequencing of P. vivax remains challenging, targeted genotyping methods are needed for scalability. We describe a P. vivax marker discovery framework to identify and select panels of microhaplotypes (multi-allelic markers within small, amplifiable segments of the genome) that can accurately capture IBD. We evaluate panels of 50-250 microhaplotypes discovered in a global set of 615 P. vivax genomes. A candidate global 100-microhaplotype panel exhibits high marker diversity in the Asia-Pacific, Latin America and horn of Africa (median H E  = 0.70-0.81) and identifies 89% of the polyclonal infections detected with genome-wide datasets. Data simulations reveal lower error in estimating pairwise IBD using microhaplotypes relative to traditional biallelic SNP barcodes. The candidate global panel also exhibits high accuracy in predicting geographic origin and captures local infection outbreak and bottlenecking events. Our framework is open-source enabling customised microhaplotype discovery and selection, with potential for porting to other species or data resources., (© 2024. The Author(s).)

Published
2024
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42. Chloroquine has shown high therapeutic efficacy against uncomplicated Plasmodium vivax malaria in southern Ethiopia: seven decades after its introduction.

Author

Mare AK, Mohammed H, Sime H, Hailgiorgis H, Gubae K, Gidey B, Haile M, Assefa G, Bekele W, Auburn S, Price R, Parr JB, Juliano JJ, Tasew G, Abay SM, and Assefa A

Subjects
Ethiopia, Humans, Male, Adult, Female, Adolescent, Young Adult, Child, Middle Aged, Child, Preschool, Plasmodium vivax drug effects, Treatment Outcome, Aged, Parasitemia drug therapy, Malaria, Vivax drug therapy, Chloroquine therapeutic use, Antimalarials therapeutic use
Abstract

Background: Plasmodium vivax malaria is a leading cause of morbidity in Ethiopia. The first-line treatment for P. vivax is chloroquine (CQ) and primaquine (PQ), but there have been local reports of CQ resistance. A clinical study was conducted to determine the efficacy of CQ for the treatment of P. vivax malaria in southern Ethiopia., Methods: In 2021, patients with P. vivax mono-infection and uncomplicated malaria were enrolled and treated with 25 mg/kg CQ for 3 consecutive days. Patients were followed for 28 days according to WHO guidelines. The data were analysed using per-protocol (PP) and Kaplan‒Meier (K‒M) analyses to estimate the risk of recurrent P. vivax parasitaemia on day 28., Results: A total of 88 patients were enrolled, 78 (88.6%) of whom completed the 28 days of follow-up. Overall, 76 (97.4%) patients had adequate clinical and parasitological responses, and two patients had late parasitological failures. The initial therapeutic response was rapid, with 100% clearance of asexual parasitaemia within 48 h., Conclusion: Despite previous reports of declining chloroquine efficacy against P. vivax, CQ retains high therapeutic efficacy in southern Ethiopia, supporting the current national treatment guidelines. Ongoing clinical monitoring of CQ efficacy supported by advanced molecular methods is warranted to inform national surveillance and ensure optimal treatment guidelines., (© 2024. The Author(s).)

Published
2024
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43. Imported malaria into Australia: surveillance insights and opportunities.

Author

Sohail A, Barry A, Auburn S, Cheng Q, Lau CL, Lee R, Price RN, Furuya-Kanamori L, Bareng P, McGuinness SL, and Leder K

Subjects
Young Adult, Male, Humans, Female, Travel, Plasmodium falciparum, Australia epidemiology, Malaria diagnosis, Malaria drug therapy, Malaria epidemiology, Malaria, Vivax
Abstract

Background: Malaria continues to pose a significant burden in endemic countries, many of which lack access to molecular surveillance. Insights from malaria cases in travellers returning to non-endemic areas can provide valuable data to inform endemic country programmes. To evaluate the potential for novel global insights into malaria, we examined epidemiological and molecular data from imported malaria cases to Australia., Methods: We analysed malaria cases reported in Australia from 2012 to 2022 using National Notifiable Disease Surveillance System data. Molecular data on imported malaria cases were obtained from literature searches., Results: Between 2012 and 2022, 3204 malaria cases were reported in Australia. Most cases (69%) were male and 44% occurred in young adults aged 20-39 years. Incidence rates initially declined between 2012 and 2015, then increased until 2019. During 2012-2019, the incidence in travellers ranged from 1.34 to 7.71 per 100 000 trips. Cases were primarily acquired in Sub-Saharan Africa (n = 1433; 45%), Oceania (n = 569; 18%) and Southern and Central Asia (n = 367; 12%). The most common countries of acquisition were Papua New Guinea (n = 474) and India (n = 277). Plasmodium falciparum accounted for 58% (1871/3204) of cases and was predominantly acquired in Sub-Saharan Africa, and Plasmodium vivax accounted for 32% (1016/3204), predominantly from Oceania and Asia. Molecular studies of imported malaria cases to Australia identified genetic mutations and deletions associated with drug resistance and false-negative rapid diagnostic test results, and led to the establishment of reference genomes for P. vivax and Plasmodium malariae., Conclusions: Our analysis highlights the continuing burden of imported malaria into Australia. Molecular studies have offered valuable insights into drug resistance and diagnostic limitations, and established reference genomes. Integrating molecular data into national surveillance systems could provide important infectious disease intelligence to optimize treatment guidelines for returning travellers and support endemic country surveillance programmes., (© International Society of Travel Medicine 2023. Published by Oxford University Press.)

Published
2024
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44. Molecular markers for malaria genetic epidemiology: progress and pitfalls.

Author

Ruybal-Pesántez S, McCann K, Vibin J, Siegel S, Auburn S, and Barry AE

Subjects
Humans, Molecular Epidemiology, Biomarkers, Malaria epidemiology, Malaria, Falciparum parasitology
Abstract

Over recent years, progress in molecular markers for genotyping malaria parasites has enabled informative studies of epidemiology and transmission dynamics. Results have highlighted the value of these tools for surveillance to support malaria control and elimination strategies. There are many different types and panels of markers available for malaria parasite genotyping, and for end users, the nuances of these markers with respect to 'use case', resolution, and accuracy, are not well defined. This review clarifies issues surrounding different molecular markers and their application to malaria control and elimination. We describe available marker panels, use cases, implications for different transmission settings, limitations, access, cost, and data accuracy. The information provided can be used as a guide for molecular epidemiology and surveillance of malaria., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Published
2024
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45. Genomic analysis of Plasmodium vivax describes patterns of connectivity and putative drivers of adaptation in Ethiopia.

Author

Kebede AM, Sutanto E, Trimarsanto H, Benavente ED, Barnes M, Pearson RD, Siegel SV, Erko B, Assefa A, Getachew S, Aseffa A, Petros B, Lo E, Mohammed R, Yilma D, Rumaseb A, Nosten F, Noviyanti R, Rayner JC, Kwiatkowski DP, Price RN, Golassa L, and Auburn S

Subjects
Humans, Plasmodium vivax, Ethiopia epidemiology, Chloroquine pharmacology, Chloroquine therapeutic use, Genomics, Protozoan Proteins genetics, Protozoan Proteins metabolism, Drug Resistance genetics, Plasmodium falciparum metabolism, Malaria, Vivax parasitology, Malaria, Falciparum parasitology, Antimalarials pharmacology, Antimalarials therapeutic use
Abstract

Ethiopia has the greatest burden of Plasmodium vivax in Africa, but little is known about the epidemiological landscape of parasites across the country. We analysed the genomic diversity of 137 P. vivax isolates collected nine Ethiopian districts from 2012 to 2016. Signatures of selection were detected by cross-country comparisons with isolates from Thailand (n = 104) and Indonesia (n = 111), representing regions with low and high chloroquine resistance respectively. 26% (35/137) of Ethiopian infections were polyclonal, and 48.5% (17/35) of these comprised highly related clones (within-host identity-by-descent > 25%), indicating frequent co-transmission and superinfection. Parasite gene flow between districts could not be explained entirely by geographic distance, with economic and cultural factors hypothesised to have an impact on connectivity. Amplification of the duffy binding protein gene (pvdbp1) was prevalent across all districts (16-75%). Cross-population haplotype homozygosity revealed positive selection in a region proximal to the putative chloroquine resistance transporter gene (pvcrt-o). An S25P variant in amino acid transporter 1 (pvaat1), whose homologue has recently been implicated in P. falciparum chloroquine resistance evolution, was prevalent in Ethiopia (96%) but not Thailand or Indonesia (35-53%). The genomic architecture in Ethiopia highlights circulating variants of potential public health concern in an endemic setting with evidence of stable transmission., (© 2023. The Author(s).)

Published
2023
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46. Genomics of Plasmodium vivax in Colombia reveals evidence of local bottle-necking and inter-country connectivity in the Americas.

Author

Sutanto E, Pava Z, Echeverry DF, Lopera-Mesa TM, Montenegro LM, Yasnot-Acosta MF, Benavente ED, Pearson RD, Herrera S, Arévalo-Herrera M, Trimarsanto H, Rumaseb A, Noviyanti R, Kwiatkowski DP, Price RN, and Auburn S

Subjects
Humans, Plasmodium vivax genetics, Colombia epidemiology, Protozoan Proteins genetics, Drug Resistance genetics, Genomics, Antimalarials pharmacology, Malaria, Vivax epidemiology, Malaria, Vivax drug therapy, Malaria, Falciparum
Abstract

Colombia aims to eliminate malaria by 2030 but remains one of the highest burden countries in the Americas. Plasmodium vivax contributes half of all malaria cases, with its control challenged by relapsing parasitaemia, drug resistance and cross-border spread. Using 64 Colombian P. vivax genomes collected between 2013 and 2017, we explored diversity and selection in two major foci of transmission: Chocó and Córdoba. Open-access data from other countries were used for comparative assessment of drug resistance candidates and to assess cross-border spread. Across Colombia, polyclonal infections were infrequent (12%), and infection connectivity was relatively high (median IBD = 5%), consistent with low endemicity. Chocó exhibited a higher frequency of polyclonal infections (23%) than Córdoba (7%), although the difference was not significant (P = 0.300). Most Colombian infections carried double pvdhfr (95%) and single pvdhps (71%) mutants, but other drug resistance mutations were less prevalent (< 10%). There was no evidence of selection at the pvaat1 gene, whose P. falciparum orthologue has recently been implicated in chloroquine resistance. Global population comparisons identified other putative adaptations. Within the Americas, low-level connectivity was observed between Colombia and Peru, highlighting potential for cross-border spread. Our findings demonstrate the potential of molecular data to inform on infection spread and adaptation., (© 2023. The Author(s).)

Published
2023
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48. No Association between the Plasmodium vivax crt-o MS334 or In9 pvcrt Polymorphisms and Chloroquine Failure in a Pre-Elimination Clinical Cohort from Malaysia with a Large Clonal Expansion.

Author

Rumaseb A, Moraes Barros RR, Sá JM, Juliano JJ, William T, Braima KA, Barber BE, Anstey NM, Price RN, Grigg MJ, Marfurt J, and Auburn S

Subjects
Humans, Chloroquine pharmacology, Chloroquine therapeutic use, Plasmodium vivax genetics, Malaysia, Drug Resistance genetics, Alleles, Protozoan Proteins genetics, Protozoan Proteins therapeutic use, Antimalarials pharmacology, Antimalarials therapeutic use, Malaria, Vivax epidemiology
Abstract

Increasing reports of resistance to a frontline malaria blood-stage treatment, chloroquine (CQ), raises concerns for the elimination of Plasmodium vivax. The absence of an effective molecular marker of CQ resistance in P. vivax greatly constrains surveillance of this emerging threat. A recent genetic cross between CQ sensitive (CQS) and CQ resistant (CQR) NIH-1993 strains of P. vivax linked a moderate CQR phenotype with two candidate markers in P. vivax CQ resistance transporter gene ( pvcrt-o ): MS334 and In9 pvcrt . Longer TGAAGH motif lengths at MS334 were associated with CQ resistance, as were shorter motifs at the In9 pvcrt locus. In this study, high-grade CQR clinical isolates of P. vivax from a low endemic setting in Malaysia were used to investigate the association between the MS334 and In9 pvcrt variants and treatment efficacy. Among a total of 49 independent monoclonal P. vivax isolates assessed, high-quality MS334 and In9 pvcrt sequences could be derived from 30 (61%) and 23 (47%), respectively. Five MS334 and six In9 pvcrt alleles were observed, with allele frequencies ranging from 2 to 76% and 3 to 71%, respectively. None of the clinical isolates had the same variant as the NIH-1993 CQR strain, and none of the variants were associated with CQ treatment failure (all P >  0.05). Multi-locus genotypes (MLGs) at 9 neutral microsatellites revealed a predominant P. vivax strain (MLG6) accounting for 52% of Day 0 infections. The MLG6 strain comprised equal proportions of CQS and CQR infections. Our study reveals complexity in the genetic basis of CQ resistance in the Malaysian P. vivax pre-elimination setting and suggests that the proposed pvcrt-o MS334 and In9 pvcrt markers are not reliable markers of CQ treatment efficacy in this setting. Further studies are needed in other endemic settings, applying hypothesis-free genome-wide approaches, and functional approaches to understand the biological impact of the TGAAGH repeats linked to CQ response in a cross are warranted to comprehend and track CQR P. vivax.

Published
2023
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49. Analysis of the relapse of imported Plasmodium vivax and Plasmodium ovale in five provinces of China.

Author

Yan H, Wei S, Sui Y, Lu S, Zhang W, Feng X, Liu Y, Zhang T, Ruan W, Xia J, Lin W, Ley B, Auburn S, Li S, Li J, and Wang D

Subjects
Humans, Plasmodium vivax, Case-Control Studies, Retrospective Studies, China epidemiology, Recurrence, Chronic Disease, Plasmodium ovale, Malaria prevention & control, Malaria, Vivax epidemiology, Malaria, Vivax drug therapy
Abstract

Background: The global battle against malaria is facing formidable challenges, particularly in controlling Plasmodium vivax and Plasmodium ovale, whose cases have not been reduced as effectively as Plasmodium falciparum because of their relapse. This study investigates the current situation and underlying factors contributing to relapse or recrudescence of imported cases of P. vivax and P. ovale, and seeks to provide a reference for reducing relapse or recrudescence in malaria-free areas and offers a scientific basis for designing strategies to prevent imported re-transmission., Methods: This study analysed imported P. vivax and P. ovale in Anhui, Zhejiang, Henan, Hubei, and Guangxi provinces during 2014-2021 by retrospective analysis. A case-control study was conducted on patients who experienced relapse or recrudescence., Results: From 2014 to 2021, 306 cases of P.vivax and 896 cases of P.ovale were included in the study, while 75 cases had relapse or recrudescence, including 49 cases of P. ovale (65.33%) and 26 cases of P. vivax (34.67%). Within less than 5 weeks after returning to the country, 122 cases of P. vivax (39.87%, 122/306) and 265 cases of P. ovale (29.58%, 265/896) occurred. Within less than 53 weeks, the ratio of P. vivax was 94.77% (290/306), and that of P. ovale was 89.96% (806/896). Among the cases experiencing relapse or recrudescence, only 1 case of P. vivax (1/26 3.85%) and 3 cases of P. ovale (3/49 6.12%) occurred within less than 5 weeks after the first onset, whereas 21 cases of P. vivax (21/26 80.77%) and 42 cases of P. ovale (42/49 85.71%) occurred within less than 53 weeks after the first onset. The difference in relapse or recrudescence due to different drugs and medication regimens and medical activities at various levels of medical institutions was statistically significant., Conclusion: In areas where malaria has been eliminated, routine health screening in a scientific time frame for people returning from at-risk areas can effectively improve the efficiency of preventing re-transmission, thereby reducing prevention costs and disease burden. Preventing patients from self-treating and strengthening medication regulations in health facilities are key measures to reduce relapse or recrudescence., (© 2023. The Author(s).)

Published
2023
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50. Increasing incidence of Plasmodium ovale and persistent reporting of Plasmodium vivax in imported malaria cases: an analysis of 9-year surveillance data in four areas of China.

Author

Wang X, Xu W, Luo F, Lin K, Zhang T, Yao L, Zhang X, Zhang J, Auburn S, Wang D, and Ruan W

Subjects
Humans, Young Adult, Adult, Middle Aged, Plasmodium vivax, Incidence, China epidemiology, Plasmodium ovale, Malaria epidemiology, Malaria prevention & control
Abstract

Background: This study aimed at exploring the epidemiological pattern of imported malaria in China before malaria elimination in 2021, to provide evidence-based data for preventing malaria re-establishment in China., Methods: Nine-year surveillance data on imported malaria in four provincial-level administrative divisions (PLADs) (Anhui, Chongqing, Guangxi, and Zhejiang) between 2011 and 2019 were thoroughly collected and analyzed., Results: A quite stable trend in imported malaria cases between 2011 and 2019 was observed. In total, 6,064 imported patients were included. Plasmodium falciparum was the most frequently reported species (4,575, 75.6%). Cases of malaria were most frequently imported from Western Africa (54.4%). We identified an increasing trend in P. ovale and a persistence of P. vivax infections among the cases of malaria imported from Western Africa. Most patients (97.5%) were 20-50 years old. Among imported malaria infections, the main purposes for traveling abroad were labor export (4,914/6,064, 81.0%) and business trips (649, 10.7%). Most patients (2,008/6,064, 33.1%) first visited county-level medical institutions when they sought medical help in China. More patients were diagnosed within 3 days after visiting Centers for Disease Control and Prevention (CDCs) or entry-exit quarantine facilities (EQFs) (1,147/1609, 71.3%) than after visiting medical institutions (2,182/3993, 54.6%)., Conclusion: Imported malaria still poses a threat to the malaria-free status of China. County-level institutions are the primary targets in China to improve the sensitivity of the surveillance system and prevent the re-establishment of malaria. Health education should focus on exported labors, especially to Western and Central Africa. Increasing trend in P. ovale and persistence of P. vivax infections indicated their underestimations in Western Africa. Efficient diagnostic tools and sensitive monitoring systems are required to identify Plasmodium species in Africa., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Xu, Luo, Lin, Zhang, Yao, Zhang, Zhang, Auburn, Wang and Ruan.)

Published
2023
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