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2. Need for optimized dosages in the design of comparative clinical trials of anti-malarial drugs

Author

Krishna, S and Kremsner, PG

Subjects
Antimalarials, Drug Combinations, Fluorenes, Treatment Outcome, Infectious Diseases, Quinine, Ethanolamines, Humans, Parasitology, Malaria, Falciparum, Artemisinins, Malaria
Abstract

We read with interest the publication on malaria treatment by Obonyo et al. (Malaria J 21:30, 2022). This commentary questions the methodology, especially the chosen time points of treatment outcome measures.

Published
2022

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

Author

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

Abstract

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

Published
2022

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

Author

Mansoor, R, Commons, RJ, Douglas, NM, Abuaku, B, Achan, J, Adam, I, Adjei, GO, Adjuik, M, Alemayehu, BH, Allan, R, Allen, EN, Anvikar, AR, Arinaitwe, E, Ashley, EA, Ashurst, H, Asih, PBS, Bakyaita, N, Barennes, H, Barnes, K, Basco, L, Bassat, Q, Baudin, E, Bell, DJ, Bethell, D, Bjorkman, A, Boulton, C, Bousema, T, Brasseur, P, Bukirwa, H, Burrow, R, Carrara, V, Cot, M, D'Alessandro, U, Das, D, Das, S, Davis, TME, Desai, M, Djimde, AA, Dondorp, AM, Dorsey, G, Drakeley, CJ, Duparc, S, Espie, E, Etard, J-F, Falade, C, Faucher, JF, Filler, S, Fogg, C, Fukuda, M, Gaye, O, Genton, B, Rahim, AG, Gilayeneh, J, Gonzalez, R, Grais, RF, Grandesso, F, Greenwood, B, Grivoyannis, A, Hatz, C, Hodel, EM, Humphreys, GS, Hwang, J, Ishengoma, D, Juma, E, Kachur, SP, Kager, PA, Kamugisha, E, Kamya, MR, Karema, C, Kayentao, K, Kazienga, A, Kiechel, J-R, Kofoed, P-E, Koram, K, Kremsner, PG, Lalloo, DG, Laman, M, Lee, SJ, Lell, B, Maiga, AW, Martensson, A, Mayxay, M, Mbacham, W, McGready, R, Menan, H, Menard, D, Mockenhaupt, F, Moore, BR, Muller, O, Nahum, A, Ndiaye, J-L, Newton, PN, Ngasala, BE, Nikiema, F, Nji, AM, Noedl, H, Nosten, F, Ogutu, BR, Ojurongbe, O, Osorio, L, Ouedraogo, J-B, Owusu-Agyei, S, Pareek, A, Penali, LK, Piola, P, Plucinski, M, Premji, Z, Ramharter, M, Richmond, CL, Rombo, L, Rosenthal, PJ, Salman, S, Same-Ekobo, A, Sibley, C, Sirima, SB, Smithuis, FM, Some, FA, Staedke, SG, Starzengruber, P, Strub-Wourgaft, N, Sutanto, I, Swarthout, TD, Syafruddin, D, Talisuna, AO, Taylor, WR, Temu, EA, Thwing, J, Tinto, H, Tjitra, E, Toure, OA, Tran, TH, Ursing, J, Valea, I, Valentini, G, van Vugt, M, von Seidlein, L, Ward, SA, Were, V, White, NJ, Woodrow, CJ, Yavo, W, Yeka, A, Zongo, I, Simpson, JA, Guerin, PJ, Stepniewska, K, Price, RN, Roper, C, Mansoor, R, Commons, RJ, Douglas, NM, Abuaku, B, Achan, J, Adam, I, Adjei, GO, Adjuik, M, Alemayehu, BH, Allan, R, Allen, EN, Anvikar, AR, Arinaitwe, E, Ashley, EA, Ashurst, H, Asih, PBS, Bakyaita, N, Barennes, H, Barnes, K, Basco, L, Bassat, Q, Baudin, E, Bell, DJ, Bethell, D, Bjorkman, A, Boulton, C, Bousema, T, Brasseur, P, Bukirwa, H, Burrow, R, Carrara, V, Cot, M, D'Alessandro, U, Das, D, Das, S, Davis, TME, Desai, M, Djimde, AA, Dondorp, AM, Dorsey, G, Drakeley, CJ, Duparc, S, Espie, E, Etard, J-F, Falade, C, Faucher, JF, Filler, S, Fogg, C, Fukuda, M, Gaye, O, Genton, B, Rahim, AG, Gilayeneh, J, Gonzalez, R, Grais, RF, Grandesso, F, Greenwood, B, Grivoyannis, A, Hatz, C, Hodel, EM, Humphreys, GS, Hwang, J, Ishengoma, D, Juma, E, Kachur, SP, Kager, PA, Kamugisha, E, Kamya, MR, Karema, C, Kayentao, K, Kazienga, A, Kiechel, J-R, Kofoed, P-E, Koram, K, Kremsner, PG, Lalloo, DG, Laman, M, Lee, SJ, Lell, B, Maiga, AW, Martensson, A, Mayxay, M, Mbacham, W, McGready, R, Menan, H, Menard, D, Mockenhaupt, F, Moore, BR, Muller, O, Nahum, A, Ndiaye, J-L, Newton, PN, Ngasala, BE, Nikiema, F, Nji, AM, Noedl, H, Nosten, F, Ogutu, BR, Ojurongbe, O, Osorio, L, Ouedraogo, J-B, Owusu-Agyei, S, Pareek, A, Penali, LK, Piola, P, Plucinski, M, Premji, Z, Ramharter, M, Richmond, CL, Rombo, L, Rosenthal, PJ, Salman, S, Same-Ekobo, A, Sibley, C, Sirima, SB, Smithuis, FM, Some, FA, Staedke, SG, Starzengruber, P, Strub-Wourgaft, N, Sutanto, I, Swarthout, TD, Syafruddin, D, Talisuna, AO, Taylor, WR, Temu, EA, Thwing, J, Tinto, H, Tjitra, E, Toure, OA, Tran, TH, Ursing, J, Valea, I, Valentini, G, van Vugt, M, von Seidlein, L, Ward, SA, Were, V, White, NJ, Woodrow, CJ, Yavo, W, Yeka, A, Zongo, I, Simpson, JA, Guerin, PJ, Stepniewska, K, Price, RN, and Roper, C

Abstract

BACKGROUND: Plasmodium falciparum malaria is associated with anaemia-related morbidity, attributable to host, parasite and drug factors. We quantified the haematological response following treatment of uncomplicated P. falciparum malaria to identify the factors associated with malarial anaemia. METHODS: Individual patient data from eligible antimalarial efficacy studies of uncomplicated P. falciparum malaria, available through the WorldWide Antimalarial Resistance Network data repository prior to August 2015, were pooled using standardised methodology. The haematological response over time was quantified using a multivariable linear mixed effects model with nonlinear terms for time, and the model was then used to estimate the mean haemoglobin at day of nadir and day 7. Multivariable logistic regression quantified risk factors for moderately severe anaemia (haemoglobin < 7 g/dL) at day 0, day 3 and day 7 as well as a fractional fall ≥ 25% at day 3 and day 7. RESULTS: A total of 70,226 patients, recruited into 200 studies between 1991 and 2013, were included in the analysis: 50,859 (72.4%) enrolled in Africa, 18,451 (26.3%) in Asia and 916 (1.3%) in South America. The median haemoglobin concentration at presentation was 9.9 g/dL (range 5.0-19.7 g/dL) in Africa, 11.6 g/dL (range 5.0-20.0 g/dL) in Asia and 12.3 g/dL (range 6.9-17.9 g/dL) in South America. Moderately severe anaemia (Hb < 7g/dl) was present in 8.4% (4284/50,859) of patients from Africa, 3.3% (606/18,451) from Asia and 0.1% (1/916) from South America. The nadir haemoglobin occurred on day 2 post treatment with a mean fall from baseline of 0.57 g/dL in Africa and 1.13 g/dL in Asia. Independent risk factors for moderately severe anaemia on day 7, in both Africa and Asia, included moderately severe anaemia at baseline (adjusted odds ratio (AOR) = 16.10 and AOR = 23.00, respectively), young age (age < 1 compared to ≥ 12 years AOR = 12.81 and AOR = 6.79, respectively), high parasitaemia (AOR = 1.78 and AOR = 1.

Published
2022

5. Non-communicable disease co-morbidity and associated factors in tuberculosis patients: A cross-sectional study in Gabon

Author

Global Health, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Adegbite, BR, Edoa, JR, Agbo Achimi Abdul, JBP, Epola, M, Mevyann, C, Dejon-Agobé, JC, Zinsou, JF, Honkpehedji, YJ, Mpagama, SG, Alabi, AS, Kremsner, PG, Klipstein-Grobusch, K, Adegnika, AA, Grobusch, MP, Global Health, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Adegbite, BR, Edoa, JR, Agbo Achimi Abdul, JBP, Epola, M, Mevyann, C, Dejon-Agobé, JC, Zinsou, JF, Honkpehedji, YJ, Mpagama, SG, Alabi, AS, Kremsner, PG, Klipstein-Grobusch, K, Adegnika, AA, and Grobusch, MP

Published
2022

6. A call to caution when hydroxychloroquine is given to elderly COVID-19 patients

Author

Gabor, JJ, Kreidenweiss, A, Weber, S, Salama, M, Sulyok, M, Sulyok, Z, Koehne, E, Esen, M, Kreuels, B, Shamsrizi, P, Biecker, E, Mordmüller, B, Berg, CP, Fusco, S, Köhler, C, Kubicka, S, Leitlein, J, Addo, M, Ramharter, M, Schwab, M, Bissinger, AL, Velavan, TP, Krishna, S, and Kremsner, PG

Abstract

INTRODUCTION: Hydroxychloroquine use in COVID-19 patients was widespread and uncontrolled until recently. Patients vulnerable to severe COVID-19 are at risk for hydroxychloroquine interactions with comorbidities and co-medications contributing to detrimental, including fatal adverse treatment effects. METHODS: This is a retrospective survey of health conditions and co-medications of COVID-19 patients who were pre-screened for enrolment into a randomized, double-blind, placebo-controlled hydroxychloroquine multicenter trial. RESULTS: Our survey involved 305 patients (median age 71 (IQR: 59-81) years). The majority of patients (N = 279, 92%) considered for inclusion into the clinical trial were not eligible mainly due to safety concerns caused by health conditions or co-medications. Most common were QT prolonging drugs (N = 188, 62%) and hematologic/hemato-oncologic diseases (N = 39, 13%) which prohibited the administration of hydroxychloroquine in our clinical trial. Additionally, 165 (54%) patients had health conditions and 167 (55%) were on co-medications that did not prohibit hydroxychloroquine treatment but had a risk of adverse interactions with hydroxychloroquine. Most common were diabetes (N = 86, 28%), renal insufficiency (N = 69, 23%) and heart failure (N = 58, 19%). CONCLUSION: The majority of hospitalized COVID-19 patients had health conditions or took co-medications precluding safe treatment with hydroxychloroquine. Therefore, especially in elderly, hydroxychloroquine should be administered with extreme caution and only in clinical trials.

Published
2021

7. Comparative genomics revealed adaptive admixture in Cryptosporidium hominis in Africa

Author

Tichkule, S, Jex, AR, van Oosterhout, C, Sannella, AR, Krumkamp, R, Aldrich, C, Maiga-Ascofare, O, Dekker, D, Lamshoeft, M, Mbwana, J, Rakotozandrindrainy, N, Borrmann, S, Thye, T, Schuldt, K, Winter, D, Kremsner, PG, Oppong, K, Manouana, P, Mbong, M, Gesase, S, Minja, DTR, Mueller, I, Bahlo, M, Nader, J, May, J, Rakotozandrindrain, R, Adegnika, AA, Lusingu, JPA, Amuasi, J, Eibach, D, Caccio, SM, Tichkule, S, Jex, AR, van Oosterhout, C, Sannella, AR, Krumkamp, R, Aldrich, C, Maiga-Ascofare, O, Dekker, D, Lamshoeft, M, Mbwana, J, Rakotozandrindrainy, N, Borrmann, S, Thye, T, Schuldt, K, Winter, D, Kremsner, PG, Oppong, K, Manouana, P, Mbong, M, Gesase, S, Minja, DTR, Mueller, I, Bahlo, M, Nader, J, May, J, Rakotozandrindrain, R, Adegnika, AA, Lusingu, JPA, Amuasi, J, Eibach, D, and Caccio, SM

Abstract

Cryptosporidiosis is a major cause of diarrhoeal illness among African children, and is associated with childhood mortality, malnutrition, cognitive development and growth retardation. Cryptosporidium hominis is the dominant pathogen in Africa, and genotyping at the glycoprotein 60 (gp60) gene has revealed a complex distribution of different subtypes across this continent. However, a comprehensive exploration of the metapopulation structure and evolution based on whole-genome data has yet to be performed. Here, we sequenced and analysed the genomes of 26 C. hominis isolates, representing different gp60 subtypes, collected at rural sites in Gabon, Ghana, Madagascar and Tanzania. Phylogenetic and cluster analyses based on single-nucleotide polymorphisms showed that isolates predominantly clustered by their country of origin, irrespective of their gp60 subtype. We found a significant isolation-by-distance signature that shows the importance of local transmission, but we also detected evidence of hybridization between isolates of different geographical regions. We identified 37 outlier genes with exceptionally high nucleotide diversity, and this group is significantly enriched for genes encoding extracellular proteins and signal peptides. Furthermore, these genes are found more often than expected in recombinant regions, and they show a distinct signature of positive or balancing selection. We conclude that: (1) the metapopulation structure of C. hominis can only be accurately captured by whole-genome analyses; (2) local anthroponotic transmission underpins the spread of this pathogen in Africa; (3) hybridization occurs between distinct geographical lineages; and (4) genetic introgression provides novel substrate for positive or balancing selection in genes involved in host-parasite coevolution.

Published
2021

8. Viewpoint of a WHO Advisory Group Tasked to Consider Establishing a Closely-monitored Challenge Model of Coronavirus Disease 2019 (COVID-19) in Healthy Volunteers

Author

Levine, MM, Abdullah, S, Arabi, YM, Darko, DM, Durbin, AP, Estrada, V, Jamrozik, E, Kremsner, PG, Lagos, R, Pitisuttithum, P, Plotkin, SA, Sauerwein, R, Shi, S-L, Sommerfelt, H, Subbarao, K, Treanor, JJ, Vrati, S, King, D, Balasingam, S, Weller, C, Aguilar, AO, Cassetti, MC, Krause, PR, Restrepo, AMH, Levine, MM, Abdullah, S, Arabi, YM, Darko, DM, Durbin, AP, Estrada, V, Jamrozik, E, Kremsner, PG, Lagos, R, Pitisuttithum, P, Plotkin, SA, Sauerwein, R, Shi, S-L, Sommerfelt, H, Subbarao, K, Treanor, JJ, Vrati, S, King, D, Balasingam, S, Weller, C, Aguilar, AO, Cassetti, MC, Krause, PR, and Restrepo, AMH

Abstract

WHO convened an Advisory Group (AG) to consider the feasibility, potential value, and limitations of establishing a closely-monitored challenge model of experimental severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) in healthy adult volunteers. The AG included experts in design, establishment, and performance of challenges. This report summarizes issues that render a COVID-19 model daunting to establish (the potential of SARS-CoV-2 to cause severe/fatal illness, its high transmissibility, and lack of a "rescue treatment" to prevent progression from mild/moderate to severe clinical illness) and it proffers prudent strategies for stepwise model development, challenge virus selection, guidelines for manufacturing challenge doses, and ways to contain SARS-CoV-2 and prevent transmission to household/community contacts. A COVID-19 model could demonstrate protection against virus shedding and/or illness induced by prior SARS-CoV-2 challenge or vaccination. A limitation of the model is that vaccine efficacy in experimentally challenged healthy young adults cannot per se be extrapolated to predict efficacy in elderly/high-risk adults.

Published
2021

10. Controlled human malaria infection with Plasmodium falciparum demonstrates impact of naturally acquired immunity on virulence gene expression

Author

Rowe, A, Bachmann, A, Bruske, E, Krumkamp, R, Turners, L, Wichers, JS, Petter, M, Held, J, Duffy, MF, Sim, BKL, Hoffman, SL, Kremsner, PG, Lell, B, Laystsen, T, Frank, M, Mordmueller, B, Tannich, E, Rowe, A, Bachmann, A, Bruske, E, Krumkamp, R, Turners, L, Wichers, JS, Petter, M, Held, J, Duffy, MF, Sim, BKL, Hoffman, SL, Kremsner, PG, Lell, B, Laystsen, T, Frank, M, Mordmueller, B, and Tannich, E

Abstract

The pathogenesis of Plasmodium falciparum malaria is linked to the variant surface antigen PfEMP1, which mediates tethering of infected erythrocytes to the host endothelium and is encoded by approximately 60 var genes per parasite genome. Repeated episodes of malaria infection result in the gradual acquisition of protective antibodies against PfEMP1 variants. The antibody repertoire is believed to provide a selective pressure driving the clonal expansion of parasites expressing unrecognized PfEMP1 variants, however, due to the lack of experimental in vivo models there is only limited experimental evidence in support of this concept. To get insight into the impact of naturally acquired immunity on the expressed var gene repertoire early during infection we performed controlled human malaria infections of 20 adult African volunteers with life-long malaria exposure using aseptic, purified, cryopreserved P. falciparum sporozoites (Sanaria PfSPZ Challenge) and correlated serological data with var gene expression patterns from ex vivo parasites. Among the 10 African volunteers who developed patent infections, individuals with low antibody levels showed a steep rise in parasitemia accompanied by broad activation of multiple, predominantly subtelomeric var genes, similar to what we previously observed in naïve volunteers. In contrast, individuals with intermediate antibody levels developed asymptomatic infections and the ex vivo parasite populations expressed only few var gene variants, indicative of clonal selection. Importantly, in contrast to parasites from naïve volunteers, expression of var genes coding for endothelial protein C receptor (EPCR)-binding PfEMP1 that are associated with severe childhood malaria was rarely detected in semi-immune adult African volunteers. Moreover, we followed var gene expression for up to six parasite replication cycles and demonstrated for the first time in vivo a shift in the dominant var gene variant. In conclusion, our data suggest th

Published
2019

12. Abstracts of the Eighth EDCTP Forum, 6-9 November 2016.

Author

Makanga, M, Beattie, P, Breugelmans, G, Nyirenda, T, Bockarie, M, Tanner, M, Volmink, J, Hankins, C, Walzl, G, Chegou, N, Malherbe, S, Hatherill, M, Scriba, TJ, Zak, DE, Barry, CE, Kaufmann, SHE, Noor, A, Strub-Wourgaft, N, Phillips, P, Munguambe, K, Ravinetto, R, Tinto, H, Diro, E, Mahendrahata, Y, Okebe, J, Rijal, S, Garcia, C, Sundar, S, Ndayisaba, G, Sopheak, T, Ngoduc, T, Van Loen, H, Jacobs, J, D'Alessandro, U, Boelaert, M, Buvé, A, Kamalo, P, Manda-Taylor, L, Rennie, S, Mokgatla, B, Bahati, Ijsselmuiden, C, Afolabi, M, Mcgrath, N, Kampmann, B, Imoukhuede, E, Alexander, N, Larson, H, Chandramohan, D, Bojang, K, Kasaro, MP, Muluka, B, Kaunda, K, Morse, J, Westfall, A, Kapata, N, Kruuner, A, Henostroza, G, Reid, S, Alabi, A, Foguim, F, Sankarganesh, J, Bruske, E, Mfoumbi, A, Mevyann, C, Adegnika, A, Lell, B, Kranzer, K, Kremsner, P, Grobusch, M, Sabiiti, W, Ntinginya, N, Kuchaka, D, Azam, K, Kampira, E, Mtafya, B, Bowness, R, Bhatt, N, Davies, G, Kibiki, G, Gillespie, S, Lejon, V, Ilboudo, H, Mumba, D, Camara, M, Kaba, D, Lumbala, C, Fèvre, E, Jamonneau, V, Bucheton, B, Büscher, P, Chisenga, C, Sinkala, E, Chilengi, R, Chitundu, H, Zyambo, Z, Wandeler, G, Vinikoor, M, Emilie, D, Camara, O, Mathurin, K, Guiguigbaza-Kossigan, D, Philippe, B, Regassa, F, Hassane, S, Bienvenu, SM, Fabrice, C, Ouédraogo, E, Kouakou, L, Owusu, M, Mensah, E, Enimil, A, Mutocheluh, M, Ndongo, FA, Tejiokem, MC, Texier, G, Penda, C, Ndiang, S, Ndongo, J-A, Guemkam, G, Sofeu, CL, Afumbom, K, Faye, A, Msellati, P, Warszawski, J, Vos, A, Devillé, W, Barth, R, Klipstein-Grobusch, K, Tempelman, H, Venter, F, Coutinho, R, Grobbee, D, Ssemwanga, D, Lyagoba, F, Magambo, B, Kapaata, A, Kirangwa, J, Nannyonjo, M, Nassolo, F, Nsubuga, R, Yebra, G, Brown, A, Kaleebu, P, Nylén, H, Habtewold, A, Makonnen, E, Yimer, G, Burhenne, J, Diczfalusy, U, Aklillu, E, Steele, D, Walker, R, Simuyandi, M, Beres, L, Bosomprah, S, Ansumana, R, Taitt, C, Lamin, JM, Jacobsen, KH, Mulvaney, SP, Leski, T, Bangura, U, 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Vos, A, Devillé, W, Barth, R, Klipstein-Grobusch, K, Tempelman, H, Venter, F, Coutinho, R, Grobbee, D, Ssemwanga, D, Lyagoba, F, Magambo, B, Kapaata, A, Kirangwa, J, Nannyonjo, M, Nassolo, F, Nsubuga, R, Yebra, G, Brown, A, Kaleebu, P, Nylén, H, Habtewold, A, Makonnen, E, Yimer, G, Burhenne, J, Diczfalusy, U, Aklillu, E, Steele, D, Walker, R, Simuyandi, M, Beres, L, Bosomprah, S, Ansumana, R, Taitt, C, Lamin, JM, Jacobsen, KH, Mulvaney, SP, Leski, T, Bangura, U, Stenger, D, De Vries, S, Zinsou, FJ, Honkpehedji, J, Dejon, JC, Loembe, MM, Bache, B, Pakker, N, Van Leeuwen, R, Hounkpatin, AB, Yazdanbakhsh, M, Bethony, J, Hotez, P, Diemert, D, Bache, BE, Fernandes, JF, Obiang, RM, Kabwende, AL, Grobusch, MP, Krishna, S, Kremsner, PG, Todagbe, AS, Nambozi, M, Kabuya, J-B, Hachizovu, S, Mwakazanga, D, Kasongo, W, Buyze, J, Mulenga, M, Geertruyden, J-P, Gitaka, J, Chan, C, Kongere, J, Kagaya, W, Kaneko, A, Kabore, N, Barry, N, Kabre, Z, Werme, K, Fofana, A, Compaore, D, Nikiema, F, Some, F, Djimde, A, Zongo, I, Ouedraogo, B, Kone, A, Sagara, I, Björkman, A, Gil, JP, Nchinda, G, Bopda, A, Nji, N, Ambada, G, Ngu, L, Tchadji, J, Sake, C, Magagoum, S, Njambe, GD, Lisom, A, Park, CG, Tait, D, Sibusiso, H, Manda, O, Croucher, K, Van Der Westhuizen, A, Mshanga, I, Levin, J, Nanvubya, A, Kibengo, F, Jaoko, W, Pala, P, Perreau, M, Namuniina, A, Kitandwe, P, Tapia, G, Serwanga, J, Yates, N, Fast, P, Mayer, B, Montefiori, D, Tomaras, G, Robb, M, Lee, C, Wagner, R, Sanders, E, Kilembe, W, Kiwanuka, N, Gilmour, J, Kuipers, H, Vooij, D, Chinyenze, K, Priddy, F, Ding, S, Hanke, T, Pantaleo, G, Ngasala, B, Jovel, I, Malmberg, M, Mmbando, B, Premji, Z, Mårtensson, A, Mwaiswelo, R, Agbor, L, Apinjoh, T, Mwanza, S, Chileshe, J, Joshi, S, Malunga, P, Manyando, C, Laufer, M, Dara, A, Niangaly, A, Sinha, I, Brodin, D, Fofana, B, Dama, S, Dembele, D, Sidibe, B, Diallo, N, Thera, M, Wright, K, Gil, J, Doumbo, O, Baraka, V, Nabasumba, C, Francis, F, Lutumba, P, Mavoko, H, Alifrangis, M, Van Geertruyden, J-P, Sissoko, S, Sangaré, C, Toure, S, Sanogo, K, Diakite, H, Doumbia, D, Haidara, K, Julé, A, Ashurst, H, Merson, L, Olliaro, P, Marsh, V, Lang, T, Guérin, P, Awuondo, K, Njenga, D, Nyakarungu, E, Titus, P, Sutamihardja, A, Lowe, B, Ogutu, B, Billingsley, P, Soulama, I, Kaboré, M, Coulibaly, A, Ouattara, M, Sanon, S, Diarra, A, Bougouma, E, Ouedraogo, A, Sombie, B, Kargougou, D, Ouattara, D, Issa, N, Tiono, A, Sirima, S, Chaponda, M, Dabira, E, Dao, F, Dara, N, Coulibaly, M, Tolo, A, Maiga, H, Ouologuem, N, Niangaly, H, Botchway, F, Wilson, N, Dickinson-Copeland, CM, Adjei, AA, Wilson, M, Stiles, JK, Hamid, MA, Awad-Elgeid, M, Nasr, A, Netongo, P, Kamdem, S, Velavan, T, Lasry, E, Diarra, M, Bamadio, A, Traore, A, Coumare, S, Soma, B, Dicko, Y, Sangare, B, Tembely, A, Traore, D, Haidara, A, Dicko, A, Diawara, E, Beavogui, A, Camara, D, Sylla, M, Yattara, M, Sow, A, Camara, GC, Diallo, S, Mombo-Ngoma, G, Remppis, J, Sievers, M, Manego, RZ, Endamne, L, Hutchinson, D, Held, J, Supan, C, Salazar, CLO, Bonkian, LN, Nahum, A, Sié, A, Abdulla, S, Cantalloube, C, Djeriou, E, Bouyou-Akotet, M, Mordmüller, B, Siribie, M, Sirima, SB, San Maurice Ouattara, Coulibaly, S, Kabore, JM, Amidou, D, Tekete, M, Traore, O, Haefeli, W, Borrmann, S, Kaboré, N, Kabré, Z, Nikèma, F, Compaoré, D, Somé, F, Djimdé, A, Ouédraogo, J, Chalwe, V, Miller, J, Diakité, H, Greco, B, Spangenberg, T, Kourany-Lefoll, E, Oeuvray, C, Mulry, J, Tyagarajan, K, Magsaam, B, Barnes, K, Hodel, EM, Humphreys, G, Pace, C, Banda, CG, Denti, P, Allen, E, Lalloo, D, Mwapasa, V, Terlouw, A, Mwesigwa, J, Achan, J, Jawara, M, Ditanna, G, Worwui, A, Affara, M, Koukouikila-Koussounda, F, Kombo, M, Vouvoungui, C, Ntoumi, F, Etoka-Beka, MK, Deibert, J, Poulain, P, Kobawila, S, Gueye, NG, Seda, B, Kwambai, T, Jangu, P, Samuels, A, Kuile, FT, Kariuki, S, Barry, A, Bousema, T, Okech, B, Egwang, T, Corran, P, Riley, E, Ezennia, I, Ekwunife, O, Muleba, M, Stevenson, J, Mbata, K, Coetzee, M, Norris, D, Moneke-Anyanwoke, N, Momodou, J, Clarke, E, Scott, S, Tijani, A, Djimde, M, Vaillant, M, Samouda, H, Mensah, V, Roetynck, S, Kanteh, E, Bowyer, G, Ndaw, A, Oko, F, Bliss, C, Jagne, YJ, Cortese, R, Nicosia, A, Roberts, R, D'Alessio, F, Leroy, O, Faye, B, Cisse, B, Gerry, S, Viebig, N, Lawrie, A, Ewer, K, Hill, A, Nebie, I, Tiono, AB, Sanou, G, Konate, AT, Yaro, BJ, Sodiomon, S, Honkpehedji, Y, Agobe, JCD, Zinsou, F, Mengue, J, Richie, T, Hoffman, S, Nouatin, O, Ngoa, UA, Edoa, JR, Homoet, A, Engelhon, JE, Massinga-Louembe, M, Esen, M, Theisen, M, Sim, KL, Luty, AJ, Moutairou, K, Dinko, B, King, E, Targett, G, Sutherland, C, Likhovole, C, Ouma, C, Vulule, J, Musau, S, Khayumbi, J, Okumu, A, Murithi, W, Otu, J, Gehre, F, Zingue, D, Kudzawu, S, Forson, A, Mane, M, Rabna, P, Diarra, B, Kayede, S, Adebiyi, E, Kehinde, A, Onyejepu, N, Onubogu, C, Idigbe, E, Ba, A, Diallo, A, Mboup, S, Disse, K, Kadanga, G, Dagnra, Y, Baldeh, I, Corrah, T, De Jong, B, Antonio, M, Musanabaganwa, C, Musabyimana, JP, Karita, E, Diop, B, Nambajimana, A, Dushimiyimana, V, Karame, P, Russell, J, Ndoli, J, Hategekimana, T, Sendegeya, A, Condo, J, Binagwaho, A, Okonko, I, Okerentugba, P, Opaleye, O, Awujo, E, Frank-Peterside, N, Moyo, S, Kotokwe, K, Mohammed, T, Boleo, C, Mupfumi, L, Chishala, S, Gaseitsiwe, S, Tsalaile, L, Bussmann, H, Makhema, J, Baum, M, Marlink, R, Engelbretch, S, Essex, M, Novitsky, V, Saka, E, Kalipalire, Z, Bhairavabhotla, R, Midiani, D, Sherman, J, Mgode, G, Cox, C, Bwana, D, Mtui, L, Magesa, D, Kahwa, A, Mfinanga, G, Mulder, C, Borain, N, Petersen, L, Du Plessis, J, Theron, G, Holm-Hansen, C, Tekwu, EM, Sidze, LK, Assam, JPA, Eyangoh, S, Niemann, S, Beng, VP, Frank, M, Atiadeve, S, Hilmann, D, Awoniyi, D, Baumann, R, Kriel, B, Jacobs, R, Kidd, M, Loxton, A, Kaempfer, S, Singh, M, Mwanza, W, Milimo, D, Moyo, M, Kasese, N, Cheeba-Lengwe, M, Munkondya, S, Ayles, H, De Haas, P, Muyoyeta, M, Namuganga, AR, Kizza, HM, Mendy, A, Tientcheu, L, Ayorinde, A, Coker, E, Egere, U, Coussens, A, Naude, C, Chaplin, G, Noursadeghi, M, Martineau, A, Jablonski, N, Wilkinson, R, Ouedraogo, HG, Matteelli, A, Regazzi, M, Tarnagda, G, Villani, P, Sulis, G, Diagbouga, S, Roggi, A, Giorgetti, F, Kouanda, S, Bidias, A, Ndjonka, D, Olemba, C, Souleymanou, A, Mukonzo, J, Kuteesa, R, Ogwal-Okeng, J, Gustafsson, LL, Owen, J, Bassi, P, Gashau, W, Olaf, K, Dodoo, A, Okonkwo, P, Kanki, P, Maruapula, D, Seraise, B, Einkauf, K, Reilly, A, Rowley, C, Musonda, R, Framhein, A, Mpagama, S, Semvua, H, Maboko, L, Hoelscher, M, Heinrich, N, Mulenga, L, Kaayunga, C, Davies, M-A, Egger, M, Musukuma, K, Dambe, R, Usadi, B, Ngari, M, Thitiri, J, Mwalekwa, L, Fegan, G, Berkley, J, Nsagha, D, Munamunungu, V, Bolton, C, Siyunda, A, Shilimi, J, Bucciardini, R, Fragola, V, Abegaz, T, Lucattini, S, Halifom, A, Tadesse, E, Berhe, M, Pugliese, K, De Castro, P, Terlizzi, R, Fucili, L, Di Gregorio, M, Mirra, M, Zegeye, T, Binelli, A, Vella, S, Abraham, L, Godefay, H, Rakotoarivelo, R, Raberahona, M, Randriamampionona, N, Andriamihaja, R, Rasamoelina, T, Cornet, M, De Dieu Randria, MJ, Benet, T, Vanhems, P, Andrianarivelo, MR, Chirwa, U, Michelo, C, Hamoonga, R, Wandiga, S, Oduor, P, Agaya, J, Sharma, A, Cavanaugh, S, Cain, K, Mukisa, J, Mupere, E, Worodria, W, Ngom, JT, Koro, F, Godwe, C, Adande, C, Ateugieu, R, Onana, T, Ngono, A, Kamdem, Y, Ngo-Niobe, S, Etoa, F-X, Kanengoni, M, Ruzario, S, Ndebele, P, Shana, M, Tarumbiswa, F, Musesengwa, R, Gutsire, R, Fisher, K, Thyagarajan, B, Akanbi, O, Binuyo, M, Ssengooba, W, Respeito, D, Mambuque, E, Blanco, S, Mandomando, I, Cobelens, F, Garcia-Basteiro, A, Tamene, A, Topp, S, Mwamba, C, Padian, N, Sikazwe, I, Geng, E, Holmes, C, Sikombe, K, Hantuba, Czaicki, N, Simbeza, S, Somwe, P, Umulisa, M, Ilo, J, Kestelyn, E, Uwineza, M, Agaba, S, Delvaux, T, Wijgert, J, Gethi, D, Odeny, L, Tamandjou, C, Kaindjee-Tjituka, F, Brandt, L, Cotton, M, Nel, E, Preiser, W, Andersson, M, Adepoju, A, Magana, M, Etsetowaghan, A, Chilikwazi, M, Sutcliffe, C, Thuma, P, Sinywimaanzi, K, Matakala, H, Munachoonga, P, Moss, W, Masenza, IS, Geisenberger, O, Agrea, P, Rwegoshora, F, Mahiga, H, Olomi, W, Kroidl, A, Kayode, G, Amoakoh-Coleman, M, Ansah, E, Uthman, O, Fokam, J, Santoro, M-M, Musolo, C, Chimbiri, I, Chikwenga, G, Deula, R, Massari, R, Lungu, A, Perno, C-F, Ndzengue, G, Loveline, N, Lissom, A, Flaurent, T, Sosso, S, Essomba, C, Kpeli, G, Otchere, I, Lamelas, A, Buultjens, A, Bulach, D, Baines, S, Seemann, T, Giulieri, S, Nakobu, Z, Aboagye, S, Owusu-Mireku, E, Danso, E, Hauser, J, Hinic, V, Pluschke, G, Stinear, T, Yeboah-Manu, D, Elshayeb, A, Siddig, ME, Ahmed, AA, Hussien, AE, Kabwe, M, Tembo, J, Chilukutu, L, Chilufya, M, Ngulube, F, Lukwesa, C, Enne, V, Wexner, H, Mwananyanda, L, Hamer, D, Sinyangwe, S, Ahmed, Y, Klein, N, Maeurer, M, Zumla, A, Bates, M, Beyala, L, Etienne, G, Anthony, N, Benjamin, A, Ateudjieu, J, Chibwe, B, Ojok, D, Tarr, CA, Perez, GM, Omeonga, S, Kibungu, F, Meyer, A, Lansana, P, Mayor, A, Onyango, P, Van Loggerenberg, F, Furtado, T, Boggs, L, Segrt, A, Dochez, C, Burnett, R, Mphahlele, MJ, Miiro, G, Mbidde, E, Peshu, N, Kivaya, E, Ngowi, B, Kavishe, R, Maowia, M, Sandstrom, E, Ayuo, E, Mmbaga, B, Leisegang, C, Thorpe, M, Batchilly, E, N'Guessan, J-P, Kanteh, D, Søfteland, S, Sebitloane, M, Vwalika, B, Taylor, M, Galappaththi-Arachchige, H, Holmen, S, Gundersen, SG, Ndhlovu, P, Kjetland, EF, Kombe, F, Toohey, J, Pienaar, E, Kredo, T, Cham, PM, Abubakar, I, Dondeh, BL, Vischer, N, Pfeiffer, C, Burri, C, Musukwa, K, Zürcher, S, Mwandu, T, Bauer, S, Adriko, M, Mwaura, P, Omolloh, K, Jones, C, Malecela, M, Hamidu, BA, Jenner, TE, Asiedu, LJ, Osei-Atweneboana, M, Afeke, I, Addo, P, Newman, M, Durnez, L, Eddyani, M, Ammisah, N, Abas, M, Quartey, M, Ablordey, A, Akinwale, O, Adeneye, A, Ezeugwu, S, Olukosi, Y, Adewale, B, Sulyman, M, Mafe, M, Okwuzu, J, Gyang, P, Nwafor, T, Henry, U, Musa, B, Ujah, I, Agobé, JCD, Grau-Pujol, B, Sacoor, C, Nhabomba, A, Casellas, A, Quintó, L, Subirà, C, Giné, R, Valentín, A, Muñoz, J, Nikiema, M, Ky-Ba, A, Comapore, KAM, Sangare, L, Oluremi, A, Michel, M, Camara, Y, Sanneh, B, Cuamba, I, Gutiérrez, J, Lázaro, C, Mejia, R, Adedeji, A, Folorunsho, S, Demehin, P, Akinsanya, B, Cowley, G, Da Silva, ET, Nabicassa, M, De Barros, PDP, Blif, MM, Bailey, R, Last, A, Mahendradhata, Y, Gotuzzo, E, De Nys, K, Casteels, M, Nona, SK, Lumeka, K, Todagbe, A, Djima, MM, Ukpong, M, Sagay, A, Khamofu, H, Torpey, K, Afiadigwe, E, Anenih, J, Ezechi, O, Nweneka, C, Idoko, J, Muhumuza, S, Katahoire, A, Nuwaha, F, Olsen, A, Okeyo, S, Omollo, R, Kimutai, R, Ochieng, M, Egondi, T, Moonga, C, Chileshe, C, Magwende, G, Anumudu, C, Onile, O, Oladele, V, Adebayo, A, Awobode, H, Oyeyemi, O, Odaibo, A, Kabuye, E, Lutalo, T, Njua-Yafi, C, Nkuo-Akenji, T, Anchang-Kimbi, J, Mugri, R, Chi, H, Tata, R, Njumkeng, C, Dodoo, D, Achidi, E, Fernandes, J, Bache, EB, Matakala, K, Searle, K, Greenman, M, and Rainwater-Lovett, K

Published
2017

13. Mortality patterns and site heterogeneity of severe malaria in African children

Author

Kendjo, E, Agbenyega, T, Bojang, K, Newton, CR, Bouyou-Akotet, M, Pedross, F, Kombila, M, Helbok, R, and Kremsner, PG

Subjects
Male, Pediatric Critical Care, Critical Care and Emergency Medicine, Time Factors, Epidemiology, lcsh:Medicine, Pediatrics, Population Metrics, Cause of Death, parasitic diseases, Death Rate, Parasitic Diseases, Humans, Hospital Mortality, Malaria, Falciparum, lcsh:Science, Pediatric Epidemiology, Biology, Africa South of the Sahara, Population Biology, lcsh:R, Infant, Malaria, Plasmodium Falciparum, Infectious Diseases, Child, Preschool, Medicine, lcsh:Q, Female, Research Article
Abstract

BACKGROUND: In this study we aimed to assess site heterogeneity of early, intermediate, and late mortality prediction in children with severe Plasmodium falciparum malaria in sub-Saharan Africa. METHODS: Medical records of 26,036 children admitted with severe Plasmodium falciparum malaria in six hospital research centers between December 2000 to May 2005 were analyzed. Demographic, clinical and laboratory data of children who died within 24 hours (early), between 24 and 47 hours (intermediate) and thereafter (48 hours or later, late mortality) were compared between groups and survivors. RESULTS: Overall mortality was 4·3% (N = 1,129). Median time to death varied across sites (P

Published
2016

14. A phase 2b randomized, controlled trial of the efficacy of the GMZ2 malaria vaccine in African children

Author

Sirima, SB, Mordmüller, B, Milligan, P, Ngoa, UA, Kironde, F, Atuguba, F, Tiono, AB, Issifou, S, Kaddumukasa, M, Bangre, O, Flach, C, Christiansen, M, Bang, P, Chilengi, R, Jepsen, S, Kremsner, PG, Theisen, M, GMZ2 Trial Study Group, COLLABORATORS, Ouédraogo, A, Kargougou, D, Nébié, I, Débé, S, Diarra, A, Bougouma, E, Hounkpatin, AB, Adegnika, AA, Lell, B, Joanny, F, Honkpehedji, YJ, Agobe, JC, Esen, M, Ajua, A, Asoala, V, Anyorigiya, T, Ansah, NA, Buwembo, W, Mworozi, E, Sekikubo, M, Abubakar, I, Bojang, K, Noor, R, Okech, B, and Ejigu, DA

Subjects
parasitic diseases
Abstract

GMZ2 is a recombinant protein malaria vaccine, comprising two blood-stage antigens of Plasmodium falciparum, glutamate-rich protein and merozoite surface protein 3. We assessed efficacy of GMZ2 in children in Burkina Faso, Gabon, Ghana and Uganda. : Children 12-60months old were randomized to receive three injections of either 100μg GMZ2 adjuvanted with aluminum hydroxide or a control vaccine (rabies) four weeks apart and were followed up for six months to measure the incidence of malaria defined as fever or history of fever and a parasite density ⩾5000/μL. : A cohort of 1849 children were randomized, 1735 received three doses of vaccine (868 GMZ2, 867 control-vaccine). There were 641 malaria episodes in the GMZ2/Alum group and 720 in the control group. In the ATP analysis, vaccine efficacy (VE), adjusted for age and site was 14% (95% confidence interval [CI]: 3.6%, 23%, p-value=0.009). In the ITT analysis, age-adjusted VE was 11.3% (95% CI 2.5%, 19%, p-value=0.013). VE was higher in older children. In GMZ2-vaccinated children, the incidence of malaria decreased with increasing vaccine-induced anti-GMZ2 IgG concentration. There were 32 cases of severe malaria (18 in the rabies vaccine group and 14 in the GMZ2 group), VE 27% (95% CI -44%, 63%). : GMZ2 is the first blood-stage malaria vaccine to be evaluated in a large multicenter trial. GMZ2 was well tolerated and immunogenic, and reduced the incidence of malaria, but efficacy would need to be substantially improved, using a more immunogenic formulation, for the vaccine to have a public health role.

Published
2016

17. Mosquito Passage Dramatically Changes var Gene Expression in Controlled Human Plasmodium falciparum Infections

Author

Dzikowski, R, Bachmann, A, Petter, M, Krumkamp, R, Esen, M, Held, J, Scholz, JAM, Li, T, Sim, BKL, Hoffman, SL, Kremsner, PG, Mordmueller, B, Duffy, MF, Tannich, E, Dzikowski, R, Bachmann, A, Petter, M, Krumkamp, R, Esen, M, Held, J, Scholz, JAM, Li, T, Sim, BKL, Hoffman, SL, Kremsner, PG, Mordmueller, B, Duffy, MF, and Tannich, E

Abstract

Virulence of the most deadly malaria parasite Plasmodium falciparum is linked to the variant surface antigen PfEMP1, which is encoded by about 60 var genes per parasite genome. Although the expression of particular variants has been associated with different clinical outcomes, little is known about var gene expression at the onset of infection. By analyzing controlled human malaria infections via quantitative real-time PCR, we show that parasite populations from 18 volunteers expressed virtually identical transcript patterns that were dominated by the subtelomeric var gene group B and, to a lesser extent, group A. Furthermore, major changes in composition and frequency of var gene transcripts were detected between the parental parasite culture that was used to infect mosquitoes and Plasmodia recovered from infected volunteers, suggesting that P. falciparum resets its var gene expression during mosquito passage and starts with the broad expression of a specific subset of var genes when entering the human blood phase.

Published
2016

18. Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at 11 African Sites

Author

Agnandji, ST, Lell, B, Fernandes, JF, Abossolo, BP, Kabwende, AL, Adegnika, AA, Mordmueller, B, Issifou, S, Kremsner, PG, Loembe, MM, Sacarlal, J, Aide, P, Madrid, L, Lanaspa, M, Mandjate, S, Aponte, JJ, Bulo, H, Nhama, A, Macete, E, Alonso, P, Abdulla, S, Salim, N, Mtoro, AT, Mutani, P, Tanner, M, Mavere, C, Mwangoka, G, Lweno, O, Juma, OA, Shekalaghe, S, Tinto, H, D'Alessandro, U, Sorgho, H, Valea, I, Ouedraogo, JB, Lompo, P, Diallo, S, Traore, O, Bassole, A, Dao, E, Hamel, MJ, Kariuki, S, Oneko, M, Odero, C, Otieno, K, Awino, N, Muturi-Kioi, V, Omoto, J, Laserson, KF, Slutsker, L, Otieno, W, Otieno, L, Otsyula, N, Gondi, S, Otieno, A, Ogutu, B, Ochola, J, Onyango, I, Oyieko, J, Njuguna, P, Chilengi, R, Akoo, P, Kerubo, C, Maingi, C, Olotu, A, Bejon, P, Marsh, K, Mwabingu, G, Gitaka, J, Owusu-Agyei, S, Asante, KP, Boahen, O, Dosoo, D, Adjei, G, Adeniji, E, Yawson, AK, Kayan, K, Chandramohan, D, Greenwood, B, Lusingu, J, Gesase, S, Malabeja, A, Abdul, O, Mahende, C, Liheluka, E, Lemnge, M, Theander, TG, Drakeley, C, Mbwana, J, Ansong, D, Agbenyega, T, Adjei, S, Boateng, HO, Rettig, T, Bawa, J, Sylverken, J, Sambian, D, Sarfo, A, Agyekum, A, Martinson, F, Hoffman, I, Mvalo, T, Kamthunzi, P, Nkomo, R, Tembo, T, Tsidya, GTM, Kilembe, J, Chawinga, C, Ballou, WR, Cohen, J, Guerra, Y, Jongert, E, Lapierre, D, Leach, A, Lievens, M, Ofori-Anyinam, O, Olivier, A, Vekemans, J, Kaslow, D, Leboulleux, D, Savarese, B, Schellenberg, D, and Partnership, RTSSCT

Subjects
Pediatrics, medicine.medical_specialty, 030231 tropical medicine, Plasmodium falciparum, Immunology, 03 medical and health sciences, 0302 clinical medicine, parasitic diseases, Vaccine Development, Malaria Vaccines, medicine, Prevalence, Medicine and Health Sciences, Parasitic Diseases, Humans, Malaria, Falciparum, Adverse effect, Africa South of the Sahara, 030304 developmental biology, 0303 health sciences, Vaccines, Intention-to-treat analysis, Malaria vaccine, business.industry, Incidence, Vaccination, 1. No poverty, RTS,S, Immunity, Infant, Biology and Life Sciences, General Medicine, medicine.disease, Vaccine efficacy, Tropical Diseases, Vaccination and Immunization, 3. Good health, Malaria, Infectious Diseases, Medicine, Clinical Immunology, business, Meningitis, Research Article
Abstract

Mary Hamel and colleagues in the RTS,S Clinical Trials Partnership report updated safety and efficacy results from an ongoing Phase 3 trial, including calculations of vaccine impact (malaria cases prevented). Please see later in the article for the Editors' Summary, Background A malaria vaccine could be an important addition to current control strategies. We report the safety and vaccine efficacy (VE) of the RTS,S/AS01 vaccine during 18 mo following vaccination at 11 African sites with varying malaria transmission. Methods and Findings 6,537 infants aged 6–12 wk and 8,923 children aged 5–17 mo were randomized to receive three doses of RTS,S/AS01 or comparator vaccine. VE against clinical malaria in children during the 18 mo after vaccine dose 3 (per protocol) was 46% (95% CI 42% to 50%) (range 40% to 77%; VE, p, Editors' Summary Background Every year, more than 200 million cases of malaria occur worldwide, and more than 600,000 people, mainly children living in sub-Saharan Africa, die from this parasitic disease. Malaria parasites are transmitted to people through the bites of infected night-flying mosquitoes and cause fever that needs to be treated promptly with anti-malarial drugs to prevent anemia (a reduction in red blood cell numbers) and life-threatening organ damage. Malaria transmission can be prevented by using long-lasting insecticides sprayed on the indoor walls of homes to kill the mosquitoes that spread the malaria parasite or by sleeping under insecticide-treated nets to avoid mosquito bites and further reduce mosquito numbers. Widespread use of these preventative measures, together with the introduction of artemisinin combination therapy (an effective anti-malarial treatment), has reduced the global burden of malaria by 45% in all age groups, and by 51% among young children, since 2000. Why Was This Study Done? Unfortunately, the emergence of insecticide and drug resistance is threatening this advance in malaria control. Moreover, additional interventions—specifically, effective malaria vaccines—will be needed to eliminate malaria in the large areas of Africa where malaria transmission remains high. Currently, there is no licensed malaria vaccine, but RTS,S/AS01, the most advanced malaria vaccine candidate, is undergoing phase 3 clinical trials (the last stage of testing before licensing) in infants and children in seven African countries. The RTS,S Clinical Trials Partnership reported encouraging results on the efficacy and safety of RTS,S/AS01 during 12 months of follow-up in 2011 and 2012. Here, researchers report on the 18-month efficacy and safety of RTS,S/AS01. Vaccine efficacy (VE) is the reduction in the incidence of a disease (the number of new cases that occur in a population in a given period) among trial participants who receive the vaccine compared to the incidence among participants who do not receive the vaccine. What Did the Researchers Do and Find? The researchers randomly assigned 6,537 infants aged 6–12 weeks and 8,923 children aged 5–17 months to receive three doses of RTS,S/AS01 or a control vaccine. During 18 months of follow-up, there were 0.69 episodes of clinical malaria (a high temperature and parasites in the blood) per person-year among the children who received all the planned doses of RTS,S/AS01 (the “per protocol” population) and 1.17 episodes per person-year among the control children—a VE against clinical malaria in the per-protocol population of 46%. A similar VE was seen in an intention-to-treat analysis that included all the enrolled children, regardless of whether they received all of the planned vaccine doses; intention-to-treat analyses reflect the real-life situation—in which children sometimes miss vaccine doses—better than per-protocol analyses. In intention-to-treat analyses, the VE among children against severe malaria (fever, parasites in the blood, and symptoms such as anemia) and hospitalization for malaria was 34% and 41%, respectively. Among infants, the VE against clinical malaria was 27% in both per-protocol and intention-to-treat analyses; the vaccine showed no protection against severe malaria or hospitalization. In both infants and children, VE waned with time since vaccination. Across all the study sites, RTS,S/AS01 averted an average of 829 and 449 cases of clinical malaria per 1,000 children and infants vaccinated, respectively. Finally, the serious adverse event meningitis (inflammation of the tissues lining the brain and spinal cord) occurred more frequently in trial participants given RTS,S/AS01 than in those given the control vaccine, but the incidence of other serious adverse events was similar in both groups of participants. What Do These Findings Mean? These and other findings show that, during 18 months of follow-up, vaccination of children and young infants with RTS,S/AS01 prevented many cases of clinical and severe malaria and that the impact of vaccination was highest in regions with the highest incidence of malaria. They indicate, as in the earlier analysis, that the VE against clinical and severe malaria is higher in children than in young infants and suggest that protection wanes over time. Whether or not the vaccine played a causal role in the observed cases of meningitis cannot be determined from these results, and the occurrence of meningitis will be followed closely during the remainder of the trial. Other study limitations (for example, variations in the clinical characteristics of participants from one center to another) may also affect the accuracy of these findings and their interpretation. However, by showing that even a modest VE can avert a substantial number of malaria cases, these findings suggest that vaccination with RTS,S/AS01 could have a major public health impact in sub-Saharan Africa. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001685. Information is available from the World Health Organization on all aspects of malaria (in several languages), including malaria immunization; the World Malaria Report 2013 provides details of the current global malaria situation; the World Health Organization also provides information on its Global Immunization Vision and Strategy (in English and French) The US Centers for Disease Control and Prevention provides information on malaria, including a selection of personal stories about malaria Information is available from the Roll Back Malaria Partnership on the global control of malaria and on the Global Malaria Action Plan (in English and French); its website includes a fact sheet about malaria in Africa The latest results from the phase 3 trial of RTS,S are available on the website of the PATH Malaria Vaccine Initiative, a global program of the international nonprofit organization PATH that aims to accelerate the development of malaria vaccines and ensure their availability and accessibility in the developing world MedlinePlus provides links to additional information on malaria and on immunization (in English and Spanish)

Published
2014

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

Author

Abdulla, S, Adam, I, Adjei, GO, Adjuik, MA, Alemayehu, B, Allan, R, Arinaitwe, E, Ashley, EA, Ba, MS, Barennes, H, Barnes, KI, Bassat, Q, Baudin, E, Berens-Riha, N, Bjoerkman, A, Bompart, F, Bonnet, M, Borrmann, S, Bousema, T, Brasseur, P, Bukirwa, H, Checchi, F, Dahal, P, D'Alessandro, U, Desai, M, Dicko, A, Djimde, AA, Dorsey, G, Doumbo, OK, Drakeley, CJ, Duparc, S, Eshetu, T, Espie, E, Etard, J-F, Faiz, AM, Falade, CO, Fanello, CI, Faucher, J-F, Faye, B, Faye, O, Filler, S, Flegg, JA, Fofana, B, Fogg, C, Gadalla, NB, Gaye, O, Genton, B, Gething, PW, Gil, JP, Gonzalez, R, Grandesso, F, Greenhouse, B, Greenwood, B, Grivoyannis, A, Guerin, PJ, Guthmann, J-P, Hamed, K, Hamour, S, Hay, SI, Hodel, EM, Humphreys, GS, Hwang, J, Ibrahim, ML, Jima, D, Jones, JJ, Jullien, V, Juma, E, Kachur, PS, Kager, PA, Kamugisha, E, Kamya, MR, Karema, C, Kayentao, K, Kiechel, J-R, Kironde, F, Kofoed, P-E, Kremsner, PG, Krishna, S, Lameyre, V, Lell, B, Lima, A, Makanga, M, Malik, EM, Marsh, K, Martensson, A, Massougbodji, A, Menan, H, Menard, D, Menendez, C, Mens, PF, Meremikwu, M, Moreira, C, Nabasumba, C, Nambozi, M, Ndiaye, J-L, Ngasala, BE, Nikiema, F, Nsanzabana, C, Ntoumi, F, Oguike, M, Ogutu, BR, Olliaro, P, Omar, SA, Ouedraogo, J-B, Owusu-Agyei, S, Penali, LK, Pene, M, Peshu, J, Piola, P, Plowe, CV, Premji, Z, Price, RN, Randrianarivelojosia, M, Rombo, L, Roper, C, Rosenthal, PJ, Sagara, I, Same-Ekobo, A, Sawa, P, Schallig, HDFH, Schramm, B, Seck, A, Shekalaghe, SA, Sibley, CH, Sinou, V, Sirima, SB, Som, FA, Sow, D, Staedke, SG, Stepniewska, K, Sutherland, CJ, Swarthout, TD, Sylla, K, Talisuna, AO, Taylor, WRJ, Temu, EA, Thwing, JI, Tine, RCK, Tinto, H, Tommasini, S, Toure, OA, Ursing, J, Vaillant, MT, Valentini, G, Van den Broek, I, Van Vugt, M, Ward, SA, Winstanley, PA, Yavo, W, Yeka, A, Zolia, YM, Zongo, I, Abdulla, S, Adam, I, Adjei, GO, Adjuik, MA, Alemayehu, B, Allan, R, Arinaitwe, E, Ashley, EA, Ba, MS, Barennes, H, Barnes, KI, Bassat, Q, Baudin, E, Berens-Riha, N, Bjoerkman, A, Bompart, F, Bonnet, M, Borrmann, S, Bousema, T, Brasseur, P, Bukirwa, H, Checchi, F, Dahal, P, D'Alessandro, U, Desai, M, Dicko, A, Djimde, AA, Dorsey, G, Doumbo, OK, Drakeley, CJ, Duparc, S, Eshetu, T, Espie, E, Etard, J-F, Faiz, AM, Falade, CO, Fanello, CI, Faucher, J-F, Faye, B, Faye, O, Filler, S, Flegg, JA, Fofana, B, Fogg, C, Gadalla, NB, Gaye, O, Genton, B, Gething, PW, Gil, JP, Gonzalez, R, Grandesso, F, Greenhouse, B, Greenwood, B, Grivoyannis, A, Guerin, PJ, Guthmann, J-P, Hamed, K, Hamour, S, Hay, SI, Hodel, EM, Humphreys, GS, Hwang, J, Ibrahim, ML, Jima, D, Jones, JJ, Jullien, V, Juma, E, Kachur, PS, Kager, PA, Kamugisha, E, Kamya, MR, Karema, C, Kayentao, K, Kiechel, J-R, Kironde, F, Kofoed, P-E, Kremsner, PG, Krishna, S, Lameyre, V, Lell, B, Lima, A, Makanga, M, Malik, EM, Marsh, K, Martensson, A, Massougbodji, A, Menan, H, Menard, D, Menendez, C, Mens, PF, Meremikwu, M, Moreira, C, Nabasumba, C, Nambozi, M, Ndiaye, J-L, Ngasala, BE, Nikiema, F, Nsanzabana, C, Ntoumi, F, Oguike, M, Ogutu, BR, Olliaro, P, Omar, SA, Ouedraogo, J-B, Owusu-Agyei, S, Penali, LK, Pene, M, Peshu, J, Piola, P, Plowe, CV, Premji, Z, Price, RN, Randrianarivelojosia, M, Rombo, L, Roper, C, Rosenthal, PJ, Sagara, I, Same-Ekobo, A, Sawa, P, Schallig, HDFH, Schramm, B, Seck, A, Shekalaghe, SA, Sibley, CH, Sinou, V, Sirima, SB, Som, FA, Sow, D, Staedke, SG, Stepniewska, K, Sutherland, CJ, Swarthout, TD, Sylla, K, Talisuna, AO, Taylor, WRJ, Temu, EA, Thwing, JI, Tine, RCK, Tinto, H, Tommasini, S, Toure, OA, Ursing, J, Vaillant, MT, Valentini, G, Van den Broek, I, Van Vugt, M, Ward, SA, Winstanley, PA, Yavo, W, Yeka, A, Zolia, YM, and Zongo, I

Abstract

BACKGROUND: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs). METHODS: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data. RESULTS: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5-64.9) on day 1 to 6.7 % (95 % CI: 4.8-8.7) on day 2 and 0.9 % (95 % CI: 0.5-1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08-1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 °C) (AOR = 1.50 (95 % CI: 1.06-2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21-3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38

Published
2015

20. The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data

Author

Adjuik, MA, Allan, R, Anvikar, AR, Ashley, EA, Ba, MS, Barennes, H, Barnes, KI, Bassat, Q, Baudin, E, Bjorkman, A, Bompart, F, Bonnet, M, Borrmann, S, Brasseur, P, Bukirwa, H, Checchi, F, Cot, M, Dahal, P, D'Alessandro, U, Deloron, P, Desai, M, Diap, G, Djimde, AA, Dorsey, G, Doumbo, OK, Espie, E, Etard, J-F, Fanello, CI, Faucher, J-F, Faye, B, Flegg, JA, Gaye, O, Gething, PW, Gonzalez, R, Grandesso, F, Guerin, PJ, Guthmann, J-P, Hamour, S, Hasugian, AR, Hay, SI, Humphreys, GS, Jullien, V, Juma, E, Kamya, MR, Karema, C, Kiechel, JR, Kremsner, PG, Krishna, S, Lameyre, V, Ibrahim, LM, Lee, SJ, Lell, B, Martensson, A, Massougbodji, A, Menan, H, Menard, D, Menendez, C, Meremikwu, M, Moreira, C, Nabasumba, C, Nambozi, M, Ndiaye, J-L, Nikiema, F, Nsanzabana, C, Ntoumi, F, Ogutu, BR, Olliaro, P, Osorio, L, Ouedraogo, J-B, Penali, LK, Pene, M, Pinoges, L, Piola, P, Price, RN, Roper, C, Rosenthal, PJ, Rwagacondo, CE, Same-Ekobo, A, Schramm, B, Seck, A, Sharma, B, Sibley, CH, Sinou, V, Sirima, SB, Smith, JJ, Smithuis, F, Some, FA, Sow, D, Staedke, SG, Stepniewska, K, Swarthout, TD, Sylla, K, Talisuna, AO, Tarning, J, Taylor, WRJ, Temu, EA, Thwing, JI, Tjitra, E, Tine, RCK, Tinto, H, Vaillant, MT, Valecha, N, Van den Broek, I, White, NJ, Yeka, A, Zongo, I, Adjuik, MA, Allan, R, Anvikar, AR, Ashley, EA, Ba, MS, Barennes, H, Barnes, KI, Bassat, Q, Baudin, E, Bjorkman, A, Bompart, F, Bonnet, M, Borrmann, S, Brasseur, P, Bukirwa, H, Checchi, F, Cot, M, Dahal, P, D'Alessandro, U, Deloron, P, Desai, M, Diap, G, Djimde, AA, Dorsey, G, Doumbo, OK, Espie, E, Etard, J-F, Fanello, CI, Faucher, J-F, Faye, B, Flegg, JA, Gaye, O, Gething, PW, Gonzalez, R, Grandesso, F, Guerin, PJ, Guthmann, J-P, Hamour, S, Hasugian, AR, Hay, SI, Humphreys, GS, Jullien, V, Juma, E, Kamya, MR, Karema, C, Kiechel, JR, Kremsner, PG, Krishna, S, Lameyre, V, Ibrahim, LM, Lee, SJ, Lell, B, Martensson, A, Massougbodji, A, Menan, H, Menard, D, Menendez, C, Meremikwu, M, Moreira, C, Nabasumba, C, Nambozi, M, Ndiaye, J-L, Nikiema, F, Nsanzabana, C, Ntoumi, F, Ogutu, BR, Olliaro, P, Osorio, L, Ouedraogo, J-B, Penali, LK, Pene, M, Pinoges, L, Piola, P, Price, RN, Roper, C, Rosenthal, PJ, Rwagacondo, CE, Same-Ekobo, A, Schramm, B, Seck, A, Sharma, B, Sibley, CH, Sinou, V, Sirima, SB, Smith, JJ, Smithuis, F, Some, FA, Sow, D, Staedke, SG, Stepniewska, K, Swarthout, TD, Sylla, K, Talisuna, AO, Tarning, J, Taylor, WRJ, Temu, EA, Thwing, JI, Tjitra, E, Tine, RCK, Tinto, H, Vaillant, MT, Valecha, N, Van den Broek, I, White, NJ, Yeka, A, and Zongo, I

Abstract

Background

Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria.

Methods

Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites.

Results

Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-2

Published
2015

21. Classification of Rhinoentomophthoromycosis into Atypical, Early, Intermediate, and Late Disease: A Proposal

Author

Blumentrath, Cg, Grobusch, Mp, Matsiégui, P, Pahlke, F, Zoleko Manego, R, Nzenze Aféne, S, Mabicka, B, Sanguinetti, Maurizio, Kremsner, Pg, Schaumburg, F., Sanguinetti, Maurizio (ORCID:0000-0002-9780-7059), Blumentrath, Cg, Grobusch, Mp, Matsiégui, P, Pahlke, F, Zoleko Manego, R, Nzenze Aféne, S, Mabicka, B, Sanguinetti, Maurizio, Kremsner, Pg, Schaumburg, F., and Sanguinetti, Maurizio (ORCID:0000-0002-9780-7059)

Abstract

Rhinoentomophthoromycosis, or rhino-facial conidiobolomycosis, is a rare, grossly disfiguring disease due to an infection with entomophthoralean fungi. We report a case of rhinoentomophthoromycosis from Gabon and suggest a staging system, which provides information on the prognosis and duration of antifungal therapy.

Published
2015

22. A demonstration of mobile phone deployment to support the treatment of acutely ill children under five in Bushenyi district, Uganda

Author

Matsiegui Pb, Yazdanbakhsh M, Mackanga, Ramharter M, Umeh Ib, Duan, Chen A, Ruperez M, Vala A, Bi Y, Yang Z, Nduka So, Wang J, Gonzalez R, Macete E, Tibebu S, Tumusiime D, Barigye C, Geressu T, Azasi E, Wakasiaka S, Coeytaux F, Nettle-Aquirre A, Massougbodji A, Danmusa S, McNally T, Kakolwa Ma, Lavender T, Agnandji St, Singhal N, Abdulla S, Potts J, Menendez C, Mombo-Ngoma G, Finch J, Ouedraogo S, Ekwunife Oi, Cot M, Khisa W, Maling S, Sevene E, McGowan L, Manego Rz, Wells E, Kabakyenga J, Kremsner Pg, Otive-Igbuzor E, Aponte Jj, Buchner D, Adegnika Aa, MacLeod S, Campbell M, Basra A, Kabanywany Am, Kyomuhangi T, Yin S, Pang X, Brenner J, and Jia Weijun

Subjects
Adult, Diarrhea, Rural Population, Economic growth, Child Health Services, Population, Developing country, mobile phone deployment, ill children under five, Bushenyi district, Uganda, Scientific evidence, 03 medical and health sciences, 0302 clinical medicine, Humans, Uganda, Community Health Services, 030212 general & internal medicine, Program Development, Child, education, Community Health Workers, Government, education.field_of_study, 030219 obstetrics & reproductive medicine, Pneumonia, Articles, General Medicine, Focus Groups, Millennium Development Goals, Child development, Malaria, Call to action, Child mortality, Evaluation Studies as Topic, Child, Preschool, Female, Case Management, Cell Phone, Program Evaluation
Abstract

Background: Benefits of mobile phone deployment for children

Published
2016

23. Evidence of decline of malaria in the general hospital of Libreville, Gabon from 2000 to 2008

Author

Bouyou-Akotet, MK, Mawili-Mboumba, DP, Kendjo, E, Mabika-Mamfoumbi, M, Ngoungou, EB, Dzeing-Ella, A, Pemba-Mihindou, M, Ibinga, E, Efame-Eya, E, MCRU team, Planche, T, Kremsner, PG, and Kombila, M

Subjects
parasitic diseases
Abstract

BACKGROUND: Substantial decline in malaria transmission, morbidity and mortality has been reported in several countries where new malaria control strategies have been implemented. In Gabon, the national malaria policy changed in 2003, according to the WHO recommendations. The trend in malaria morbidity was evaluated among febrile children before and after their implementation in Libreville, the capital city of Gabon.\ud \ud METHODS: From August 2000 to December 2008, febrile paediatric outpatients and inpatients, under 11 years of age, were screened for malaria by microscopic examination at the Malaria Clinical Research Unit (MCRU) located in the largest public hospital in Gabon. Climatic data were also collected.\ud \ud RESULTS: In total, 28,092 febrile children were examined; those under five years always represented more than 70%. The proportion of malaria-positive slides was 45% in 2000, and declined to 15% in 2008. The median age of children with a positive blood smear increased from 24(15-48) to 41(21-72) months over the study period (p < 0.01). Rainfall patterns had no impact on the decline observed throughout the study period.\ud \ud CONCLUSION: The decrease of malaria prevalence among febrile children during the last nine years is observed following the introduction of new strategies of malaria cases management, and may announce epidemiological changes. Moreover, preventive measures must be extended to children older than five years.

Published
2009

29. Plasmodium falciparum: in vitro chloroquine susceptibility and allele-specific PCR detection of Pfmdr1 Asn86Tyr polymorphism in Lambarene, Gabon

Author

Grobusch Mp, Adagu Is, Kremsner Pg, Warhurst Dc, and Other departments

Subjects
Plasmodium falciparum, Mutant, Drug Resistance, Protozoan Proteins, Polymerase Chain Reaction, Sensitivity and Specificity, law.invention, Apicomplexa, Antimalarials, law, Chloroquine, parasitic diseases, Prevalence, medicine, Animals, Humans, Point Mutation, ATP Binding Cassette Transporter, Subfamily B, Member 1, Gabon, Codon, Polymerase chain reaction, DNA Primers, Electrophoresis, Agar Gel, Polymorphism, Genetic, Dose-Response Relationship, Drug, biology, Point mutation, medicine.disease, biology.organism_classification, Virology, Phenotype, Infectious Diseases, Animal Science and Zoology, Parasitology, Variants of PCR, Biomarkers, Polymorphism, Restriction Fragment Length, Malaria, medicine.drug
Abstract

Plasmodium falciparum resistance to chloroquine has been described in many parts of the world particularly in Africa where malaria is endemic. High levels of chloroquine resistance in our study area, Lambarene-Gabon, has led to the use of an alternative regimen for treatment and prevention of P. falciparum infection. In this study, we examined the in vitro chloroquine sensitivity of 15 isolates from this area and assessed the prevalence of a putative chloroquine resistance associated Pfmdrl polymorphism ( Asn 86 TYr ) using a novel allele-specific polymerase chain reaction (PCR). Only 4 of the isolates examined were chloroquine sensitive. The allele-specific PCR shows that all 15 isolates carried the variant (86 TYr ) codon. Eleven of these were resistant to chloroquine suggesting a 73% agreement between chloroquine resistance phenotype and the point mutation. This molecular marker was examined in a further 73 Gabonese isolates, where 58 (79.5 (%) showed 86 TYr and 15 (20.5 %) showed 86 Asn . In all, 4 (4.5 %) of the 88 isolates assessed carry both mutant and wild-type codons, suggesting mixed parasite populations. The incomplete agreement found between chloroquine resistance phenotype and Pfmdrl (86 TYr ) polymorphism would support the view that other genetic factors as well as Pfmdrl may be involved in chloroquine resistance. While our results suggest a high prevalence of 86 TYr polymorphism in Lambarene, the ASP 1246 TYr polymorphism (a point mutation which to date has only been associated with South American P. falciparum) seems to be absent in our study area.

Published
1998

30. Impact of the hepatitis B virus genotype and genotype mixtures on the course of liver disease in Vietnam

Author

Toan, NL, Song, LH, Kremsner, PG, Duy, DN, Binh, VQ, Koeberlein, B, Kaiser, S, Kandolf, R, Torresi, J, Bock, C-T, Toan, NL, Song, LH, Kremsner, PG, Duy, DN, Binh, VQ, Koeberlein, B, Kaiser, S, Kandolf, R, Torresi, J, and Bock, C-T

Abstract

Eight genotypes (A-H) of hepatitis B virus (HBV) have been identified. However, the impact of different genotypes on the clinical course of hepatitis B infection remains controversial. We investigated the frequency and clinical outcome of HBV genotypes and genotype mixtures in HBV-infected patients from Vietnam, Europe, and Africa. In addition, we analyzed the effects of genotype mixtures on alterations in in vitro viral replication. In Asian patients, seven genotypes (A-G) were detected, with A, C, and D predominating. In European and African patients, only genotypes A, C, D, and G were identified. Genotype mixtures were more frequently encountered in African than in Asian (P = .01) and European patients (P = .06). In Asian patients, the predominant genotype mixtures included A/C and C/D, compared to C/D in European and A/D in African patients. Genotype A was more frequent in asymptomatic compared with symptomatic patients (P < .0001). Genotype C was more frequent in patients with hepatocellular carcinoma (HCC; P = .02). Genotype mixtures were more frequently encountered in patients with chronic hepatitis in comparison to patients with acute hepatitis B (P = .015), liver cirrhosis (P = .013), and HCC (P = .002). Viral loads in patients infected with genotype mixtures were significantly higher in comparison to patients with a single genotype (P = .019). Genotype mixtures were also associated with increased in vitro HBV replication. In conclusion, infection with mixtures of HBV genotypes is frequent in Asia, Africa, and Europe. Differences in the replication-phenotype of single genotypes compared to genotype-mixtures suggest that co-infection with different HBV-genotypes is associated with altered pathogenesis and clinical outcome.

Published
2006

31. Plasmodium falciparum: molecular background to strain-specific rosettedisruption by glycosaminoglycans and sulfated glycoconjugates

Author

Barragan, A, Spillmann, Dorothe, Kremsner, PG, Wahlgren, M, Carlson, J, Barragan, A, Spillmann, Dorothe, Kremsner, PG, Wahlgren, M, and Carlson, J

Abstract

Rosetting, the adhesion of Plasmodium falciparum-infected erythrocytes to uninfected erythrocytes, is a virulent parasite phenotype associated with the occurrence of severe malaria, e.g., cerebral malaria. Compounds with specific anti-rosetting activity are potential therapeutic agents. Glycosaminoglycans and sulfated glycoconjugates were found to disrupt rosettes in a strain- and isolate-specific manner. Rosette disruption was strongly connected to the presence of N-sulfate groups in heparin/heparan sulfate as demonstrated by modified heparin preparations. This finding was corroborated by the disruption of rosettes with mono- and disaccharides derived from heparin/heparan sulfate that contained N-sulfated glucosamine. Furthermore, heparinase III treatment of erythrocyte cultures infected by FCR3S1 (and to some extent TM 284) P. falciparum strains abolished rosetting. Heparinase III treatment of the uninfected erythrocytes prior to mixing with the infected culture impeded formation of rosettes, indicating that the rosetting receptors at least partially are of glycosaminoglycan nature.

Published
1999
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32. Comparison of chlorproguanil-dapsone with sulfadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in young African children: double-blind randomised controlled trial

Author

Alloueche, A, primary, Bailey, W, additional, Barton, S, additional, Bwika, J, additional, Chimpeni, P, additional, Falade, CO, additional, Fehintola, FA, additional, Horton, J, additional, Jaffar, S, additional, Kanyok, T, additional, Kremsner, PG, additional, Kublin, JG, additional, Lang, T, additional, Missinou, MA, additional, Mkandala, C, additional, Premji, Z, additional, Robertson, L, additional, Sowunmi, A, additional, Ward, SA, additional, Winstanley, PA, additional, and Oduola, A, additional

Published
2004
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34. A simplified intravenous artesunate regimen for severe malaria.

Author

Kremsner PG, Taylor T, Issifou S, Kombila M, Chimalizeni Y, Kawaza K, Bouyou Akotet MK, Duscha M, Mordmüller B, Kösters K, Humberg A, Miller RS, Weina P, Duparc S, Möhrle J, Kun JF, Planche T, Teja-Isavadharm P, Simpson JA, and Köhler C

Abstract

Background: We compared a conventional empirically derived regimen with a simplified regimen for parenteral artesunate in severe malaria.Methods: This was a randomized, double-blind, placebo-controlled comparison to assess the noninferiority of a simplified 3-dose regimen (given at 0, 24, and 48 hours) compared with the conventional 5-dose regimen of intravenous artesunate (given at 0, 12, 24, 48, and 72 hours) in African children with Plasmodium falciparum malaria with a prespecified delta of 0.2. The total dose of artesunate in each group was 12 mg/kg. The primary end point was the proportion of children clearing ≥ 99% of their admission parasitemia at 24 hours. Safety data, secondary efficacy end points, and pharmacokinetics were also analyzed.Results: In 171 children (per protocol), 78% of the recipients (95% confidence interval [CI], 69%-87%) in the 3-dose group achieved ≥ 99% parasite clearance 24 hours after the start of treatment, compared with 85% (95% CI, 77%-93%) of those receiving the conventional regimen (treatment difference, -7.2%; 95% CI, -18.9% to 4.4%). Dihydroartemisinin was cleared slightly more slowly in those children receiving the higher 3-dose regimen (7.4 vs 8.8 L/h for a 13-kg child; P 5 .008).Conclusions: Pharmacodynamic analysis suggests that 3 doses of artesunate were not inferior to 5 doses for the treatment of severe malaria in children.Clinical Trials Registration: NCT00522132. [ABSTRACT FROM AUTHOR]

Published
2012
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36. The Lambaréné Organ Dysfunction Score (LODS) is a simple clinical predictor of fatal malaria in African children.

Author

Helbok R, Kendjo E, Issifou S, Lackner P, Newton CR, Kombila M, Agbenyega T, Bojang K, Dietz K, Schmutzhard E, and Kremsner PG

Abstract

BACKGROUND: Plasmodium falciparum malaria accounts for >1 million deaths annually, mostly among young children in sub-Saharan Africa. Identifying those individuals who are likely to die is crucial. Several factors have been independently associated with death. Because malaria is a systemic disease, a quantitative score combining such risk factors may be superior. METHODS: We used both forward and backward stepwise logistic regression to select the best predictors of death, as evaluated for 23,890 African children with severe P. falciparum malaria. The study was conducted from December 2000 through May 2005 in 6 hospital-based research units (in Banjul in the Gambia, Blantyre in Malawi, Kilifi in Kenya, Kumasi in Ghana, and Lambaréné and Libreville in Gabon) in a network established to study severe malaria in African children (ie, the SMAC Network). RESULTS: The Lambaréné Organ Dysfunction Score (LODS) combines 3 variables: coma, prostration, and deep breathing. A LODS >0 (odd ratio, 9.6; 95% confidence interval, 8.0-11.4) has 85% sensitivity to predict death, and a LODS <3 is highly (98%) specific for survival. CONCLUSIONS: The LODS is a simple clinical predictor of fatal malaria in African children. This score provides accurate and rapid identification of children needing either referral or increased attention. [ABSTRACT FROM AUTHOR]

Published
2009
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37. No rebound of morbidity following intermittent preventive sulfadoxine-pyrimethamine treatment of malaria in infants in Gabon.

Author

Grobusch MP, Gabor JJ, Aponte JJ, Schwarz NG, Poetschke M, Doernemann J, Schuster K, Koester KB, Profanter K, Borchert LB, Kurth F, Pongratz P, Issifou S, Lell B, and Kremsner PG

Abstract

In the context of a trial studying intermittent preventive sulfadoxine-pyrimethamine treatment of malaria in infants in Lambaréné, Gabon, children aged 18-30 months were followed up after having received their last dose at an age of 15 months. In the intention-to-treat population, the protective efficacy against all malaria episodes was -18.0 (95% confidence interval, -97.4 to 29.5; P = .529). The protective efficacy against first or only anemia episode was -45.3 (95% confidence interval, -234.5 to 36.3; P=.375). The protective efficacies were negative and were not statistically significant. These results do not appear to support the concept of a rebound effect after intermittent preventive sulfadoxine-pyrimethamine treatment of malaria in infants. Clinical trials registration. NCT00167843. [ABSTRACT FROM AUTHOR]

Published
2009
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38. Detection and quantification of Plasmodium DNA in dried blood spots using a commercial real-time PCR assay and filter card system.

Author

Hanscheid T, Codices V, Luty AJF, Adegnika AA, Kremsner PG, and Grobusch MP

Abstract

Blood collected on FTA® filter cards was analysed qualitatively and quantitatively with real-time PCR and the results compared with expert microscopy performed on-site in Gabon. There was 100% concordance for fresh blood samples. However, correlation of quantitative PCR-results was rather weak (0.52) and reproducibility showed coefficients of variation ranging from 10%-90%. [ABSTRACT FROM AUTHOR]

Published
2009
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39. The association between Mannan-binding lectin Gene polymorphism and clinical leprosy: new insight into an old paradigm.

Author

de Messias-Reason IJ, Boldt AB, Moraes Braga AC, Stahlke ERS, Dornelles L, Pereira-Ferrari L, Kremsner PG, and Kun JF

Abstract

Background. Mannan-binding lectin (MBL), a soluble protein of innate immunity, is known to play a role in pathogen recognition and clearance. For more than a decade, it has been proposed that MBL deficiency may be protective against intracellular pathogens, such as Mycobacterium leprae.Methods. The polymorphisms at the promoter and exon 1 regions of the MBL2 gene were assessed by polymerase chain reaction and sequencing performed on 264 patients with leprosy and 214 matched healthy control subjects from southern Brazil.Results. The distribution of MBL2-gene polymorphisms in patients was significantly different from that in controls, with a decreased frequency of haplotypes/genotypes associated with low expression of circulating MBL in lepromatous patients when compared with tuberculoid patients (odds ratio [OR] for haplotypes, 0.56 [95% confidence interval {CI}, 0.33-0.93] [P=.020]; OR for genotypes, 0.31 [95% CI, 0.13-0.71] [P=.004]). The LYPA haplotype was associated with susceptibility to leprosy per se (OR, 2.25 [95% CI, 1.31-3.88] [P=.003]) and to progression to the lepromatous (OR, 2.2 [95% CI, 1.21-4.05] [P=.008]) and borderline (OR, 2.98 [95% CI, 1.29-6.87] [P=.008]) forms of the disease.Conclusions. These results suggest that MBL2-gene polymorphisms play a role in susceptibility to leprosy per se and in the clinical progression of the disease. Copyright © 2007 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Published
2007

40. Suppression of prostaglandin E2 by malaria parasite products and antipyretics promotes overproduction of tumor necrosis factor-alpha: association with the pathogenesis of childhood malarial anemia.

Author

Keller CC, Davenport GC, Dickman KR, Hittner JB, Kaplan SS, Weinberg JB, Kremsner PG, Perkins DJ, Keller, Christopher C, Davenport, Gregory C, Dickman, Katherine R, Hittner, James B, Kaplan, Sandra S, Weinberg, J Brice, Kremsner, Peter G, and Perkins, Douglas J

Abstract

Cytokines and effector molecules are important immunoregulatory molecules in human malaria. Tumor necrosis factor (TNF)-alpha limits malaria parasitemia but also promotes pathogenesis at high concentrations, whereas prostaglandin E2 (PGE2) inhibits TNF-alpha production and is reduced in childhood malaria, at least in part, through suppression of cyclooxygenase (COX)-2 following the ingestion of Plasmodium falciparum hemozoin (pfHz; malarial pigment) by peripheral blood mononuclear cells (PBMCs). Although molecular interactions between TNF-alpha and PGE2 are largely unexplored in human malaria, results presented here show that pfHz-induced suppression of PBMC COX-2 gene products induces overproduction of TNF-alpha. Moreover, addition of exogenous PGE2 to pfHz-treated PBMCs dose-dependently decreased TNF-alpha production, whereas experimental COX inhibitors and antipyretics used during human malaria generated increased TNF-alpha production. Healthy, malaria-exposed children had elevated levels of circulating bicyclo-PGE2/TNF-alpha, compared with children with malarial anemia (P<.01), with systemic bicyclo-PGE2 and TNF-alpha significantly associated with hemoglobin concentrations (r=0.745; P<.01). The results of the present study illustrate that pfHz-induced suppression of PGE2 promotes overproduction of TNF-alpha, which is associated with enhanced malarial anemia. [ABSTRACT FROM AUTHOR]

Published
2006
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41. Reduced cord blood immune effector-cell responsiveness mediated by CD4+ cells induced in utero as a consequence of placental Plasmodium falciparum infection.

Author

Brustoski K, Moller U, Kramer M, Hartgers FC, Kremsner PG, Krzych U, and Luty AJF

Abstract

To determine mechanisms of neonatal parasite antigen (Ag)-specific immune suppression associated with placental Plasmodium falciparum infection, we isolated cord blood mononuclear cells (CBMCs) from Gabonese neonates born to mothers with differing histories of P. falciparum infection and performed ex vivo and in vitro studies to evaluate immune regulatory activity. We found increased ex vivo percentages of CD4(+)CD25(hi) and CD4(+)CD25(+)CTLA-4(+) cells and increased interleukin (IL)-10 responses to parasite Ag in vitro in CBMCs from neonates born to mothers with placental P. falciparum infection at delivery. Depleting CBMCs of CD4(+)CD25(+) cells before cell culture led to the abrogation of parasite Ag-specific IL-10 responses, to enhanced interferon- gamma responses, and to enhanced expression of CD25 on CD8(+) T cells and of major histocompatibility complex class I and II on monocytes. These data demonstrate that parasite Ag-specific CD4(+) regulatory cells are generated in utero as a consequence of placental P. falciparum infection. Copyright © 2006 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Published
2006
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42. Influence of carriage of hemoglobin AS and the Fc gamma receptor IIa-R131 allele on levels of immunoglobulin G2 antibodies to Plasmodium falciparum merozoite antigens in Gabonese children.

Author

Ntoumi F, Flori L, Mayengue PI, Matondo Maya DW, Issifou S, Deloron P, Lell B, Kremsner PG, and Rihet P

Abstract

BACKGROUND: To extend our previous findings showing an imbalanced distribution of immunoglobulin G2 (IgG2) antibodies to Plasmodium falciparum merozoite surface protein 2 (MSP2) and a higher frequency of infection with multiple P. falciparum strains in Gabonese children with sickle cell trait (hemoglobin AS), human Fc gamma receptor (Fc gamma R) IIa (CD32) polymorphism and the rate of in vitro invasion of red blood cells (RBCs) from subjects with either hemoglobin AA or AS by multiple P. falciparum strains were investigated. METHODS: Fc gamma RIIa mutation at amino acid position 131 (arginine or histidine) was detected by polymerase chain reaction, and in vitro cultures for parasites were used to assess the invasion rate. RESULTS: Fc gamma RIIa polymorphism is normally distributed in this population, with no preferential carriage by children with hemoglobin AS. Lower levels of IgG2 subclass antibodies to MSP2 peptides were independently associated with the Fc gamma RIIa-R131 allele and with carriage of hemoglobin AS. Our data suggest that IgG3 antibody responses to MSP2 epitopes could be exacerbated by lower IgG2 levels in children with hemoglobin AS. CONCLUSIONS: The higher rate of invasion of RBCs in the presence of multiple strains may indicate that several invasion pathways are solicited simultaneously, and the longer persistence of ring forms in RBCs from the subjects with hemoglobin AS might reflect a slower multiplication phase, leading to a longer circulation and enhanced phagocytosis of these nonpathogenic parasite forms. This may contribute to the protection against P. falciparum malaria observed in children with hemoglobin AS. Copyright © 2005 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Published
2005
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45. Atopy and malaria

Author

Lell, B., Borrmann, S., Maria Yazdanbakhsh, and Kremsner, Pg

47. Parasitic infections during pregnancy : birth outcomes and immunological changes

Author

Mombo-Ngoma, G., Yazdanbakhsh, M., Kremsner, PG., Ramharter, M., Luty, A., Vlas, S.J. de, Geluk, A., Kuijper, E.J., Hokke, C.H., and Leiden University

Subjects
Loiasis, Low birthweight, Pregnancy, parasitic diseases, Schistosomiasis, Parasites, Gabon, Malaria, Filariasis
Abstract

Low birth weight including preterm birth and intrauterine growth retardation, remains important in sub-Saharan Africa and particularly highly prevalent in Gabon. Among the risk factors of low birth weight in sub-Saharan Africa are very young maternal age, first pregnancy, poor gestational nutrition and small stature of the mother. In Gabon, besides malaria, the other two major parasitic infections namely urogenital schistosomiasis and the filarial infection Loa loa, are common in pregnant women. Maternal schistosomiasis like malaria showed to be associated with higher proportions of low birth weight babies. Mefloquine as an alternative preventive treatment, despite showing no difference with sulphadoxine – pyrimethamine in preventing low birth weight, was however more effective in preventing malaria infection and anaemia. Mefloquine administered for the prevention of malaria was effective against concomitant urogenital schistosomiasis, suggesting that mefloquine could seriously be considered as a combined intervention for both malaria and schistosomiasis during pregnancy, and an alternative to praziquantel. Maternal infection with L. loa was associated with expansion in the neonatal cord blood of functionally activate Tregs that kept Th1 and Th17 immune responses in check, providing some insights on the impact of in utero exposure on the offspring’s development and health.

Published
2016

48. Fosmidomycin for malaria.

Author

Missinou MA, Borrmann S, Schindler A, Issifou S, Adegnika AA, Matsiegui P, Binder R, Lell B, Wiesner J, Baranek T, Jomaa H, and Kremsner PG

Published
2002
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49. Resistance of Anopheles gambiae s.s. against commonly used insecticides and implication of cytochrome P450 monooxygenase in resistance to pyrethroids in Lambaréné (Gabon).

Author

Boussougou-Sambe ST, Djida Y, Doumba-Ndalembouly AG, Ngossanga B, Boussougou LN, Ambinintsoa MF, Bikangui R, Nguiffo-Nguete D, Nkemngo FN, Agonhossou R, Akoton R, Mbama Ntabi JD, Lissom A, Ntoumi F, Wondji CS, Kremsner PG, Mordmüller B, Borrmann S, and Adegnika AA

Subjects
Animals, Gabon, Mosquito Vectors drug effects, Mosquito Vectors genetics, Mosquito Vectors enzymology, Permethrin pharmacology, Nitriles pharmacology, Larva drug effects, Larva genetics, Piperonyl Butoxide pharmacology, Voltage-Gated Sodium Channels genetics, Voltage-Gated Sodium Channels metabolism, Acetylcholinesterase metabolism, Acetylcholinesterase genetics, Female, Anopheles drug effects, Anopheles genetics, Anopheles enzymology, Insecticide Resistance genetics, Insecticides pharmacology, Pyrethrins pharmacology, Cytochrome P-450 Enzyme System genetics, Cytochrome P-450 Enzyme System metabolism
Abstract

Background: Insecticides are a crucial component of vector control. However, resistance constitute a threat on their efficacy and the gains obtained over the years through malaria vector control. In Gabon, little data on phenotypic insecticide resistance in Anopheles vectors are published, compromising the rational implementation of resistance management strategies. We assessed the susceptibility to pyrethroids, carbamates and organophosphates of Anopheles gambiae sensu lato (s.l.) and discuss the mechanisms involved in the pyrethroid resistance-phenotype., Methods: A. gambiae s.l. larvae were collected from breeding sites in Lambaréné. Emerging adults were used in WHO tube assays at an insecticide concentration that defines resistance (diagnostic concentration). Subsequently, deltamethrin and permethrin were used at 5x and 10x diagnostic concentrations and after preexposure with the cytochrome p450 (and glutathione S-transferase) inhibitor piperonyl butoxide (PBO). A subset of mosquitoes was typed by molecular methods and screened using Taqman assays for mutations conferring target site resistance at the Voltage-gated sodium channel 1014 (Vgsc-1014) locus and the acetylcholinesterase (Ace-1) gene., Results: All mosquitoes were A. gambiae sensu stricto (s.s.) and resistant to permethrin, deltamethrin and alphacypermethrin (mortality less than 98%). However, mosquitoes were susceptible to malathion but resistant to bendiocarb. The level of resistance was high for permethrin and at least moderate for deltamethrin. Pre-exposure to PBO significantly increased the mortality of resistant mosquitoes (P < 0.0001). They became fully susceptible to deltamethrin and permethrin-induced mortality increased 4-fold. The G119S Ace-1 resistance allele, which confers resistance to both organophosphates and carbamates, was not present. All sampled mosquitoes were either homozygous for the Vgsc-L1014F or heterozygous for Vgsc-L1014F/L1014S, a marker for resistance to pyrethroids and organochlorides., Conclusion: These findings demonstrate a role of cytochrome P450 monooxygenases in the pyrethroid-resistance of A. gambiae s.s. from Lambaréné. Combining PBO with pyrethroids, as done in second generation bednets, may be used to revert resistance. In addition, malathion could also be used in combination with pyrethroids-based methods for resistance management., (© 2024. The Author(s).)

Published
2024
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