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1. Strong isolation by distance and evidence of population microstructure reflect ongoing Plasmodium falciparum transmission in Zanzibar

Author

Sean V Connelly, Nicholas F Brazeau, Mwinyi Msellem, Billy E Ngasala, Ozkan Aydemir, Varun Goel, Karamoko Niaré, David J Giesbrecht, Zachary R Popkin-Hall, Chris Hennelly, Zackary Park, Ann M Moormann, John M Ong'echa, Robert Verity, Safia Mohammed, Shija J Shija, Lwidiko E Mhamilawa, Ulrika Morris, Andreas Mårtensson, Jessica T Lin, Anders Björkman, Jonathan J Juliano, and Jeffrey A Bailey

Subjects
Plasmodium falciparum, malaria, population microstructure, Tanzania, Zanzibar, molecular inversion probes, Medicine, Science, Biology (General), QH301-705.5
Abstract

Background: The Zanzibar archipelago of Tanzania has become a low-transmission area for Plasmodium falciparum. Despite being considered an area of pre-elimination for years, achieving elimination has been difficult, likely due to a combination of imported infections from mainland Tanzania and continued local transmission. Methods: To shed light on these sources of transmission, we applied highly multiplexed genotyping utilizing molecular inversion probes to characterize the genetic relatedness of 282 P. falciparum isolates collected across Zanzibar and in Bagamoyo district on the coastal mainland from 2016 to 2018. Results: Overall, parasite populations on the coastal mainland and Zanzibar archipelago remain highly related. However, parasite isolates from Zanzibar exhibit population microstructure due to the rapid decay of parasite relatedness over very short distances. This, along with highly related pairs within shehias, suggests ongoing low-level local transmission. We also identified highly related parasites across shehias that reflect human mobility on the main island of Unguja and identified a cluster of highly related parasites, suggestive of an outbreak, in the Micheweni district on Pemba island. Parasites in asymptomatic infections demonstrated higher complexity of infection than those in symptomatic infections, but have similar core genomes. Conclusions: Our data support importation as a main source of genetic diversity and contribution to the parasite population in Zanzibar, but they also show local outbreak clusters where targeted interventions are essential to block local transmission. These results highlight the need for preventive measures against imported malaria and enhanced control measures in areas that remain receptive to malaria reemergence due to susceptible hosts and competent vectors. Funding: This research was funded by the National Institutes of Health, grants R01AI121558, R01AI137395, R01AI155730, F30AI143172, and K24AI134990. Funding was also contributed from the Swedish Research Council, Erling-Persson Family Foundation, and the Yang Fund. RV acknowledges funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/R015600/1), jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 program supported by the European Union. RV also acknowledges funding by Community Jameel.

Published
2024
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2. An optimized GATK4 pipeline for Plasmodium falciparum whole genome sequencing variant calling and analysis

Author

Karamoko Niaré, Bryan Greenhouse, and Jeffrey A. Bailey

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

Abstract Background Accurate variant calls from whole genome sequencing (WGS) of Plasmodium falciparum infections are crucial in malaria population genomics. Here a falciparum variant calling pipeline based on GATK version 4 (GATK4) was optimized and applied to 6626 public Illumina WGS samples. Methods Control WGS and accurate PacBio assemblies of 10 laboratory strains were leveraged to optimize parameters that control the heterozygosity, local assembly region size, ploidy, mapping and base quality in both GATK HaplotypeCaller and GenotypeGVCFs. From these controls, a high-quality training dataset was generated to recalibrate the raw variant data. Results On current high-quality samples (read length = 250 bp, insert size = 405–524 bp), the optimized pipeline shows improved sensitivity (86.6 ± 1.7% for SNPs and 82.2 ± 5.9% for indels) compared to the default GATK4 pipeline (77.7 ± 1.3% for SNPs; and 73.1 ± 5.1% for indels, adjusted P

Published
2023
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3. Characterization of a novel Plasmodium falciparum merozoite surface antigen and potential vaccine target

Author

Karamoko Niaré, Timothy Chege, Micha Rosenkranz, Kennedy Mwai, Zoe Saßmannshausen, Dennis Odera, Lydia Nyamako, James Tuju, Tiono Alfred, John N. Waitumbi, Bernhards Ogutu, Sodiomon B. Sirima, Gordon Awandare, Bourema Kouriba, Julian C. Rayner, and Faith H. A. Osier

Subjects
Plasmodium falciparum malaria, PF3D7_1136200, ARMA, antigen diversity, IgG and IgM antibodies, vaccines, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionDetailed analyses of genetic diversity, antigenic variability, protein localization and immunological responses are vital for the prioritization of novel malaria vaccine candidates. Comprehensive approaches to determine the most appropriate antigen variants needed to provide broad protection are challenging and consequently rarely undertaken.MethodsHere, we characterized PF3D7_1136200, which we named Asparagine-Rich Merozoite Antigen (ARMA) based on the analysis of its sequence, localization and immunogenicity. We analyzed IgG and IgM responses against the common variants of ARMA in independent prospective cohort studies in Burkina Faso (N = 228), Kenya (N = 252) and Mali (N = 195) using a custom microarray, Div-KILCHIP.ResultsWe found a marked population structure between parasites from Africa and Asia. African isolates shared 34 common haplotypes, including a dominant pair although the overall selection pressure was directional (Tajima’s D = -2.57; Fu and Li’s F = -9.69; P < 0.02). ARMA was localized to the merozoite surface, IgG antibodies induced Fc-mediated degranulation of natural killer cells and strongly inhibited parasite growth in vitro. We found profound serological diversity, but IgG and IgM responses were highly correlated and a hierarchical clustering analysis identified only three major serogroups. Protective IgG and IgM antibodies appeared to target both cross-reactive and distinct epitopes across variants. However, combinations of IgG and IgM antibodies against selected variants were associated with complete protection against clinical episodes of malaria.DiscussionOur systematic strategy exploits genomic data to deduce the handful of antigen variants with the strongest potential to induce broad protection and may be broadly applicable to other complex pathogens for which effective vaccines remain elusive.

Published
2023
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4. The prevalence of molecular markers of resistance to sulfadoxine-pyrimethamine among pregnant women at first antenatal clinic attendance and delivery in the forest-savannah area of Ghana.

Author

David Kwame Dosoo, Jeffrey A Bailey, Kwaku Poku Asante, Felix Boakye Oppong, Karamoko Niaré, Jones Opoku-Mensah, Seth Owusu-Agyei, Brian Greenwood, and Daniel Chandramohan

Subjects
Medicine, Science
Abstract

Intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) is used to prevent malaria and associated unfavorable maternal and foetal outcomes in pregnancy in moderate to high malaria transmission areas. Effectiveness of IPTp-SP is, however, threatened by mutations in the Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes which confer resistance to pyrimethamine and sulfadoxine, respectively. This study determined the prevalence of molecular markers of SP resistance among pregnant women in a high malaria transmission area in the forest-savannah area of Ghana. Genomic DNA was extracted from 286 P. falciparum-positive dried blood spots obtained from pregnant women aged ≥18 years (255 at first Antenatal Care (ANC) clinic visit and 31 at delivery from 2017 to 2019) using Chelex 100. Mutations in Pfdhfr and Pfdhps genes were detected using molecular inversion probes and next generation sequencing. In the Pfdhfr gene, single nucleotide polymorphisms (SNPs) were detected in 83.1% (157/189), 92.0% (173/188) and 91.0% (171/188) at codons 51, 59, and 108 respectively in samples collected at first ANC visit, while SNPs were detected in 96.6 (28/29), 96.6% (28/29) and 96.8% (30/31) in isolates collected at delivery. The Pfdhfr triple mutant N51I, C59R and S108N (IRN) was carried by 80.5% (128/159) and 96.5% (28/29) of the typed isolates collected at ANC visit and at delivery respectively. In the Pfdhps gene, SNPs were detected in 0.6% (1/174), 76.2% (138/181), 33.2% (60/181), 1.2% (2/174), 0% (0/183), and 16.6% (27/173) at codons 431, 436, 437, 540, 581 and 613 respectively in samples collected at ANC, and 0% (0/25), 72% (18/25), 40% (10/25), 3.6% (1/25), 0% (0/29) and 7.4% (2/27) in samples collected at delivery. Quadruple mutant Pfdhfr N51I, C59R, and S108N + Pfdhps A437G (IRN-GK) was present in 25.8% (33/128) and 34.8% (8/23) of isolates at ANC and at delivery respectively. Quintuple mutant alleles Pfdhfr N51I, C59R, and S108N + Pfdhps A437G and K540E (IRN-GE) were detected in 0.8% (1/128) and 4.4% (1/23) of samples collected at ANC and at delivery respectively. No mutations were identified at Pfdhfr codons 16 or 164 or Pfdhps 581. There is a high prevalence of Pfdhfr triple mutant P. falciparum infections among pregnant women in the study area. However, prevalence of the combined Pfdhfr/Pfdhps quadruple and quintuple mutants IRN-GK and IRN-GE respectively prior to commencement of IPTp-SP were low, and no Pfdhps A581G mutant was detected, indicating that SP is still likely to be efficacious for IPTp-SP in the forest-savannah area in the middle belt of Ghana.

Published
2022
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5. Malaria Transmission Intensity Likely Modifies RTS, S/AS01 Efficacy Due to a Rebound Effect in Ghana, Malawi, and Gabon

Author

Griffin J Bell, Varun Goel, Paulin Essone, David Dosoo, Bright Adu, Benedicta Ayiedu Mensah, Stephaney Gyaase, Kenneth Wiru, Fabrice Mougeni, Musah Osei, Pamela Minsoko, Cyrus Sinai, Karamoko Niaré, Jonathan J Juliano, Michael Hudgens, Anita Ghansah, Portia Kamthunzi, Tisungane Mvalo, Selidji Todagbe Agnandji, Jeffrey A Bailey, Kwaku Poku Asante, and Michael Emch

Subjects
Malawi, Infectious Diseases, Malaria Vaccines, Plasmodium falciparum, Major Article, Humans, Infant, Immunology and Allergy, Gabon, Malaria, Falciparum, Child, Ghana, Malaria
Abstract

Background RTS,S/AS01 is the first malaria vaccine to be approved and recommended for widespread implementation by the World Health Organization (WHO). Trials reported lower vaccine efficacies in higher-incidence sites, potentially due to a “rebound” in malaria cases in vaccinated children. When naturally acquired protection in the control group rises and vaccine protection in the vaccinated wanes concurrently, malaria incidence can become greater in the vaccinated than in the control group, resulting in negative vaccine efficacies. Methods Using data from the 2009–2014 phase III trial (NCT00866619) in Lilongwe, Malawi; Kintampo, Ghana; and Lambaréné, Gabon, we evaluate this hypothesis by estimating malaria incidence in each vaccine group over time and in varying transmission settings. After estimating transmission intensities using ecological variables, we fit models with 3-way interactions between vaccination, time, and transmission intensity. Results Over time, incidence decreased in the control group and increased in the vaccine group. Three-dose efficacy in the lowest-transmission-intensity group (0.25 cases per person-year [CPPY]) decreased from 88.2% to 15.0% over 4.5 years, compared with 81.6% to −27.7% in the highest-transmission-intensity group (3 CPPY). Conclusions These findings suggest that interventions, including the fourth RTS,S dose, that protect vaccinated individuals during the potential rebound period should be implemented for high-transmission settings.

Published
2022

6. Plasmodium falciparum malaria exposure and carriage associate with reduced γδ T-cells and NK cell responses to infected red blood cells in vitro

Author

Bourèma Kouriba, Modibo Daou, Charles Arama, Nicolas Ouédraogo, Karamoko Niaré, Yamoussa Keita, Sibiri Sissoko, Boucary Ouologuem, Seydou Arama, Ogobara Doumbo, Robert Sauerwein, and Anja Scholzen

Abstract

Background Innate immune cells including γδ T-cells and NK cells are directly activated by Plasmodium falciparum parasites and contribute to the control of parasitaemia. The aim of this study was to determine whether a history of parasite exposure and/or carriage affect innate immune cell responses in vitro to P. falciparum infected red blood cells (PfRBC). Methods Peripheral blood mononuclear cells were collected from 61 Malian children aged 5 to 15 years at the start of the transmission season, and 10 malaria-naïve Dutch adults. Parasite carriage at the start of the transmission season was assessed by PCR and microscopy for Malian children. Peripheral blood mononuclear cells were stimulated with PfRBC to assess cytokine production and degranulation of innate lymphocytes (γδ T-cells, CD3+CD56+ cells and NK cells) by flow cytometry. Results Granzyme B production in response to PfRBC was observed by all three innate cell subsets in Malian children, as were IFNγ production by γδ T-cells and NK cells and γδ T-cell degranulation. However, both IFNγ production and degranulation by γδ T-cells, CD3+CD56+ cells and NK cells were significantly lower compared to malaria-naïve Dutch adults. Moreover, children with ongoing P. falciparuminfection showed significantly reduced PfRBC-specific IFNγ production and degranulation by γδ T-cells and NK cells as compared with those with undetectable parasitaemia by PCR and microscopy. Reduced degranulation responses by γδ T-cells and NK cells were already observed for children with submicroscopic parasitaemia as compared to those with negative PCR. Conclusions Malian children show reduced P. falciparum-specific innate IFNγ production and cytotoxic degranulation, which were further negatively impacted by ongoing infections of microscopic but also submicroscopic parasitaemia.

Published
2023

7. Strong isolation by distance and evidence of population microstructure reflect ongoing Plasmodium falciparum transmission in Zanzibar

Author

Sean V. Connelly, Nicholas F. Brazeau, Mwinyi Msellem, Billy E. Ngasala, Ozkan Aydemir, Varun Goel, Karamoko Niaré, David J. Giesbrecht, Zachary R. Popkin-Hall, Christopher M. Hennelly, Zackary Park, Ann M. Moormann, John Michael Ong’echa, Robert Verity, Safia Mohammed, Shija J. Shija, Lwidiko E. Mhamilawa, Ulrika Morris, Andreas Mårtensson, Jessica T. Lin, Anders Björkman, Jonathan J. Juliano, and Jeffrey A. Bailey

Subjects
Article
Abstract

The Zanzibar archipelago of Tanzania has become a low-transmission area forPlasmodium falciparum. Despite being considered an area of pre-elimination for years, achieving elimination has been difficult, likely due to a combination of imported infections from mainland Tanzania, and continued local transmission. To shed light on these sources of transmission, we applied highly multiplexed genotyping utilizing molecular inversion probes to characterize the genetic relatedness of 391P. falciparumisolates collected across Zanzibar and in Bagamoyo District on the coastal mainland from 2016-2018. Overall, parasite populations on the coastal mainland and Zanzibar archipelago remain highly related. However, in Zanzibar the parasite population exhibits microstructure due to rapid decay of parasite relatedness over very short distances. This, along with highly related pairs withinshehias, suggests ongoing low level local transmission. We also identified highly related parasites acrossshehiasthat reflect human mobility on the main island of Unguja and identified a cluster of highly related parasites, suggestive of an outbreak, in the Micheweni district on Pemba island. Parasites in asymptomatic infections demonstrated higher complexity of infection than those in symptomatic infections, but have similar core genomes. Our data support that importation remains a main source of genetic diversity and contribution to the parasite population on Zanzibar, but they also show local outbreak clusters where targeted interventions are essential to block local transmission. These results highlight the need for preventive measures against imported malaria and enhanced control measures in areas that remain receptive for malaria reemergence due to susceptible hosts and competent vectors.

Published
2023

8. Mutation in the Plasmodium falciparum BTB/POZ Domain of K13 Protein Confers Artemisinin Resistance

Author

Nina F. Gnädig, Françoise Benoit-Vical, Romain Coppée, Jérôme Clain, David A. Fidock, Karamoko Niaré, Jean-Michel Augereau, Barbara H. Stokes, Lucie Paloque, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), New Antimalarial Molecules and Pharmacological Approaches (ERL1289), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Université Toulouse III - Paul Sabatier (UT3), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut de pharmacologie et de biologie structurale (IPBS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 261), Institut de Recherche pour le Développement (IRD)-Université Paris Cité (UPCité), Columbia University Irving Medical Center (CUIMC), Malaria Research and Training Center [Bamako, Mali], Université de Bamako, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS), NIH (R01 AI109023), WorldWide Antimalarial Resistance Network (WWARN), ANR-17-CE15-0013,PlasmoPrim,Elucider les mécanismes d'action de deux agents redox antipaludiques aux propriétés gametocytocides et bloquant la transmission -- de la levure aux parasites du paludisme(2017), Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Gulli, Marie-Hélène, and Elucider les mécanismes d'action de deux agents redox antipaludiques aux propriétés gametocytocides et bloquant la transmission -- de la levure aux parasites du paludisme - - PlasmoPrim2017 - ANR-17-CE15-0013 - AAPG2017 - VALID

Subjects
medicine.medical_treatment, Plasmodium falciparum, Drug Resistance, Protozoan Proteins, Dihydroartemisinin, medicine.disease_cause, Epidemiology and Surveillance, Antimalarials, parasitic diseases, medicine, Coding region, CRISPR, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Pharmacology (medical), Artemisinin, BTB/POZ domain, Gene, Pharmacology, Mutation, biology, K13 mutation, [CHIM.COOR] Chemical Sciences/Coordination chemistry, Editor's Pick, biology.organism_classification, Virology, Artemisinins, Malaria, Infectious Diseases, Artemisinin resistance, BTB-POZ Domain, medicine.drug
Abstract

International audience; Partial artemisinin resistance, defined in patients as a delayed parasite clearance following artemisinin-based treatment, is conferred by non-synonymous mutations in the Kelch beta-propeller domain of the Plasmodium falciparum k13 (pfk13) gene. Here, we carried out in vitro selection over a 1-year period on a West African P. falciparum strain isolated from Kolle (Mali) under a dose-escalating artemisinin regimen. After 18 cycles of sequential drug pressure, the selected parasites exhibited enhanced survival to dihydroartemisinin in the ring-stage survival assay (RSA0-3h = 9.2%). Sanger and whole-genome sequence analyses identified the PfK13 P413A mutation, localized in the BTB/POZ domain, upstream of the propeller domain. This mutation was sufficient to confer in vitro artemisinin resistance when introduced into the PfK13 coding sequence of the parasite strain Dd2 by CRISPR/Cas9 gene editing. These results together with structural studies of the protein demonstrate that the propeller domain is not the sole in vitro mediator of PfK13-mediated artemisinin resistance, and highlight the importance of monitoring for mutations throughout PfK13.

Published
2022

9. Background malaria incidence and parasitemia during the three-dose RTS,S/AS01 vaccination series do not reduce magnitude of antibody response nor efficacy against the first case of malaria

Author

Griffin J Bell, Stephaney Gyaase, Varun Goel, Bright Adu, Benedicta Mensah, Paulin Essone, David Dosoo, Musah Osei, Karamoko Niare, Kenneth Wiru, Katerina Brandt, Michael Emch, Anita Ghansah, Kwaku Poku Asante, Tisungane Mvalo, Selidji Todagbe Agnandji, Jonathan J Juliano, and Jeffrey A Bailey

Subjects
Vaccine, Africa, Geographic information system, GIS, Immunology, Delayed Malaria, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background RTS,S/AS01 has been recommended by WHO for widespread implementation in medium to high malaria transmission settings. Previous analyses have noted lower vaccine efficacies in higher transmission settings, possibly due to the more rapid development of naturally acquired immunity in the control group. Methods To investigate a reduced immune response to vaccination as a potential mechanism behind lower efficacy in high transmission areas, we examine initial vaccine antibody (anti-CSP IgG) response and vaccine efficacy against the first case of malaria (to exclude the effect of naturally acquired immunity) using data from three study areas (Kintampo, Ghana; Lilongwe, Malawi; Lambaréné, Gabon) from the 2009–2014 phase III trial (NCT00866619). Our key exposures are parasitemia during the vaccination series and background malaria incidence. We calculate vaccine efficacy (one minus hazard ratio) using a cox-proportional hazards model and allowing for the time-varying effect of RTS,S/AS01. Results We find that antibody responses to the primary three-dose vaccination series were higher in Ghana than in Malawi and Gabon, but that neither antibody levels nor vaccine efficacy against the first case of malaria varied by background incidence or parasitemia during the primary vaccination series. Conclusions We find that vaccine efficacy is unrelated to infections during vaccination. Contributing to a conflicting literature, our results suggest that vaccine efficacy is also unrelated to infections before vaccination, meaning that control-group immunity is likely a major reason for lower efficacy in high transmission settings, not reduced immune responses to RTS,S/AS01. This may be reassuring for implementation in high transmission settings, though further studies are needed.

Published
2023
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10. Safety and immunogenicity of Pfs25H-EPA/Alhydrogel, a transmission-blocking vaccine against Plasmodium falciparum: a randomised, double-blind, comparator-controlled, dose-escalation study in healthy Malian adults

Author

Erin E. Gabriel, Ibrahima Baber, Mahamadoun H. Assadou, M'Bouye Doucoure, Rathy Mohan, Olga Muratova, Sekou F. Traore, David L Jones, Charles Anderson, Intimbeye Tembine, Karamoko Niaré, Nicholas J. MacDonald, David L. Narum, Mamady Kone, Mamadou B. Coulibaly, Kelly M. Rausch, Michael P. Fay, Issaka Sagara, Daming Zhu, Sara A. Healy, Ogobara K. Doumbo, Yimin Wu, Merepen A. Guindo, Amagana Dolo, Kourane Sissoko, Patrick E. Duffy, Malaria Research and Training Center [Bamako, Mali], Université de Bamako, National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], and Dupuis, Christine

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Plasmodium falciparum, Population, Protozoan Proteins, Mali, Antimalarials, 03 medical and health sciences, Double-Blind Method, Internal medicine, Malaria Vaccines, medicine, Humans, Malaria, Falciparum, education, Adverse effect, Aged, Aged, 80 and over, education.field_of_study, business.industry, Malaria vaccine, Hepatitis C, Middle Aged, Hepatitis B, medicine.disease, Vaccination, 030104 developmental biology, Infectious Diseases, Tolerability, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Cohort, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, business
Abstract

International audience; BACKGROUND:Pfs25H-EPA is a protein-protein conjugate transmission-blocking vaccine against Plasmodium falciparum that is safe and induces functional antibodies in malaria-naive individuals. In this field trial, we assessed Pfs25H-EPA/Alhydrogel for safety and functional immunogenicity in Malian adults.METHODS:This double-blind, randomised, comparator-controlled, dose-escalation trial in Bancoumana, Mali, was done in two staggered phases, an initial pilot safety assessment and a subsequent main phase. Healthy village residents aged 18-45 years were eligible if they had normal laboratory results (including HIV, hepatitis B, hepatitis C tests) and had not received a previous malaria vaccine or recent immunosuppressive drugs, vaccines, or blood products. Participants in the pilot safety cohort and the main cohort were assigned (1:1) by block randomisation to a study vaccine group. Participants in the pilot safety cohort received two doses of Pfs25H-EPA/Alhydrogel 16 μg or Euvax B (comparator vaccine), and participants in the main cohort received Pfs25H-EPA/Alhydrogel 47 μg or comparator vaccine (Euvax B for the first, second, and third vaccinations and Menactra for the fourth vaccination). Participants and investigators were masked to group assignment, and randomisation codes in sealed envelopes held by a site pharmacist. Vials with study drug for injection were covered by opaque tape and labelled with a study identification number. Group assignments were unmasked at final study visit. The primary outcomes were safety and tolerability for all vaccinees. The secondary outcome measure was immunogenicity 14 days after vaccination in the per-protocol population, as confirmed by the presence of antibodies against Pfs25H measured by ELISA IgG and antibody functionality assessed by standard membrane feeding assays and by direct skin feeding assays. This trial is registered with ClinicalTrials.gov, number NCT01867463.FINDINGS:Between May 15, and Jun 16, 2013, 230 individuals were screened for eligibility. 20 individuals were enrolled in the pilot safety cohort; ten participants were assigned to receive Pfs25H-EPA/Alhydrogel 16 μg, and ten participants were assigned to receive comparator vaccine. 100 individuals were enrolled in the main cohort; 50 participants were assigned to receive Pfs25H-EPA/Alhydrogel 47 μg, and 50 participants were assigned to receive comparator vaccine. Compared with comparator vaccinees, Pfs25H vaccinees had more solicited adverse events (137 events vs 86 events; p=0·022) and treatment-related adverse events (191 events vs 126 events, p=0·034), but the number of other adverse events did not differ between study vaccine groups (792 vs 683). Pfs25H antibody titres increased with each dose, with a peak geometric mean of 422·3 ELISA units (95% CI 290-615) after the fourth dose, but decreased relatively rapidly thereafter, with a half-life of 42 days for anti-Pfs25H and 59 days for anti-EPA (median ratio of titres at day 600 to peak, 0·19 for anti-Pfs25H vs 0·29 for anti-EPA; p=0·009). Serum transmission-reducing activity was greater for Pfs25H than for comparator vaccine after the fourth vaccine dose (p

Published
2018

11. Safety and efficacy of PfSPZ Vaccine against Plasmodium falciparum via direct venous inoculation in healthy malaria-exposed adults in Mali: a randomised, double-blind phase 1 trial

Author

Tooba Murshedkar, Amadou Niangaly, Adam Ruben, Kelly Ding, Yacouba Samake, Hama Diallo, Abdoulaye Katile, Amatigue Zeguime, Irfan Zaidi, Yonas Abebe, Thomas B. Nutman, Karamoko Niaré, Kourane Sissoko, Anusha Gunasekera, Elise M. O’Connell, Sharon Wong-Madden, Michael P. Fay, Minglin Li, Amagana Dolo, Stephen L. Hoffman, Bourama Kamate, Peter F. Billingsley, Patrick E. Duffy, Ismaila Thera, Ogobara K. Doumbo, Merepen A. Guindo, Sumana Chakravarty, Eric R. James, Freda Omaswa, Sara A. Healy, Mahamadou S. Sissoko, B. Kim Lee Sim, Anita Manoj, Michael Walther, Erin E. Gabriel, and Thomas L. Richie

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, Plasmodium falciparum, Mali, Placebo, Lumefantrine, Antimalarials, 03 medical and health sciences, chemistry.chemical_compound, Double-Blind Method, Internal medicine, medicine, Humans, Artemether, Malaria, Falciparum, Adverse effect, Immunization Schedule, Fluorenes, Reactogenicity, business.industry, Vaccination, Vaccine efficacy, Artemisinins, PfSPZ vaccine, Surgery, 030104 developmental biology, Infectious Diseases, chemistry, Ethanolamines, Female, business, medicine.drug
Abstract

Summary Background Plasmodium falciparum sporozite (PfSPZ) Vaccine is a metabolically active, non-replicating, whole malaria sporozoite vaccine that has been reported to be safe and protective against P falciparum controlled human malaria infection in malaria-naive individuals. We aimed to assess the safety and protective efficacy of PfSPZ Vaccine against naturally acquired P falciparum in malaria-experienced adults in Mali. Methods After an open-label dose-escalation study in a pilot safety cohort, we did a double-blind, randomised, placebo-controlled trial based in Doneguebougou and surrounding villages in Mali. We recruited 18–35-year-old healthy adults who were randomly assigned (1:1) in a double-blind manner, with stratification by village and block randomisation, to receive either five doses of 2·7 × 10 5 PfSPZ or normal saline at days 0, 28, 56, 84, and 140 during the dry season (January to July inclusive). Participants and investigators were masked to group assignments, which were unmasked at the final study visit, 6 months after receipt of the last vaccination. Participants received combined artemether and lumefantrine (four tablets, each containing 20 mg artemether and 120 mg lumefantrine, given twice per day over 3 days for a total of six doses) to eliminate P falciparum before the first and last vaccinations. We collected blood smears every 2 weeks and during any illness for 24 weeks after the fifth vaccination. The primary outcome was the safety and tolerability of the vaccine, assessed as local and systemic reactogenicity and adverse events. The sample size was calculated for the exploratory efficacy endpoint of time to first P falciparum infection beginning 28 days after the fifth vaccination. The safety analysis included all participants who received at least one dose of investigational product, whereas the efficacy analyses included only participants who received all five vaccinations. This trial is registered at ClinicalTrials.gov, number NCT01988636. Findings Between Jan 18 and Feb 24, 2014, we enrolled 93 participants into the main study cohort with 46 participants assigned PfSPZ Vaccine and 47 assigned placebo, all of whom were evaluable for safety. We detected no significant differences in local or systemic adverse events or laboratory abnormalities between the PfSPZ Vaccine and placebo groups, and only grade 1 (mild) local or systemic adverse events occurred in both groups. The most common solicited systemic adverse event in the vaccine and placebo groups was headache (three [7%] people in the vaccine group vs four [9%] in the placebo group) followed by fatigue (one [2%] person in the placebo group), fever (one [2%] person in the placebo group), and myalgia (one [2%] person in each group). The exploratory efficacy analysis included 41 participants from the vaccine group and 40 from the placebo group. Of these participants, 37 (93%) from the placebo group and 27 (66%) from the vaccine group developed P falciparum infection. The hazard ratio for vaccine efficacy was 0·517 (95% CI 0·313–0·856) by time-to-infection analysis (log-rank p=0·01), and 0·712 (0·528–0·918) by proportional analysis (p=0·006). Interpretation PfSPZ Vaccine was well tolerated and safe. PfSPZ Vaccine showed significant protection in African adults against P falciparum infection throughout an entire malaria season. Funding US National Institutes of Health Intramural Research Program, Sanaria.

Published
2017

12. Malaria Transmission-Blocking Vaccines: Present Status and Future Perspectives

Author

Ogobara K. Doumbo, Issaka Sagara, Sara A. Healy, Karamoko Niaré, and Patrick Emmet Duffy

Subjects
0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Malaria transmission, Blocking (radio), 030231 tropical medicine, Biology, Virology
Published
2018

13. Multiple phenotypic and genotypic artemisinin sensitivity evaluation of Malian Plasmodium falciparum isolates

Author

Sandie Menard, Antoine Berry, Françoise Benoit-Vical, Pety Tor, Arba Pramundita Ramadani, Antoine Dara, Jean-Michel Augereau, Karamoko Niaré, Ogobara K. Doumbo, Lucie Paloque, Malaria Research and Training Center [Bamako, Mali], Université de Bamako, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, University of Maryland School of Medicine, University of Maryland System-University of Maryland System, Service de Parasitologie et Mycologie, CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Service de Parasitologie-Mycologie [Toulouse], and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]

Subjects
0301 basic medicine, Genotype, medicine.medical_treatment, Plasmodium falciparum, 030106 microbiology, 030231 tropical medicine, Drug Resistance, Dihydroartemisinin, Drug resistance, Microbiology, Antimalarials, 03 medical and health sciences, 0302 clinical medicine, Gentamicin protection assay, Virology, parasitic diseases, medicine, Humans, Parasite hosting, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Artemisinin, ComputingMilieux_MISCELLANEOUS, biology, Articles, biology.organism_classification, Artemisinins, 3. Good health, Phenotype, Infectious Diseases, Parasitology, Ex vivo, medicine.drug
Abstract

International audience; We assessed the ex vivo/in vitro sensitivity of 54 Malian Plasmodium falciparum isolates to artemisinin for the monitoring of drug resistance in this area. The artemisinin sensitivity of parasites was evaluated using 1) the ex vivo and in vitro parasite recrudescence detection after treatment of the ring stage with 1–200 nM artemisinin for 48 hours and 2) the in vitro parasite recrudescence kinetics assay over 7 days after 6-hour treatment of the ring stage with 700 nM dihydroartemisinin (DHA). In addition, as recommended by the World Health Organization for artemisinin resistance characterization, the ring-stage survival assay (RSA0–3 h) was performed and the parasite isolates were sequenced at the kelch 13 propeller locus. No clinical and molecular evidence of artemisinin resistance was observed. However, these isolates present different phenotypic profiles in response to artemisinin treatments. Despite all RSA0–3 h values less than 1.5%, six out of 46 (13.0%) isolates tested ex vivo and four out of six (66.7%) isolates tested in vitro were able to multiply after 48-hour treatments with 100 nM artemisinin. Moreover, five out of eight isolates tested showed faster parasite recovery after DHA treatment in kinetic assays. The presence of such phenotypes needs to be taken into account in the assessment of the efficacy of artemisinins in Mali. The assays presented here appear as valuable tools for the monitoring of artemisinin sensitivity in the field and thus could help to evaluate the risk of emergence of artemisinin resistance in Africa.

Published
2018

15. A Worldwide Map of Plasmodium falciparum K13-Propeller Polymorphisms

Author

Benoit Witkowski, Hans-Peter Fuehrer, Garib Das Thakur, Céline Barnadas, Djibrine Djalle, Michael Ramharter, Mindy Leelawong, Wasif Ali-Khan, Harald Noedl, Bouasy Hongvanthong, Mohammad Shafiul-Alam, Hypolite Muhindo-Mavoko, Abdillahi Mohamed Hassan, Judith Straimer, Nimol Khim, Kigbafori D. Silué, Kaknika Loch, Barbara H. Stokes, Maria Dorina Bustos, Laura Berne, Dylan R. Pillai, Ayola A. Adegnika, Lin Hua Tang, Rotha Eam, Saorin Kim, Alioune Dieye, Mei Li, Carole E. Eboumbou-Moukoko, Lydie Canier, Marian Warsame, Didier Menard, David A. Fidock, Yap Boum, Lyndes Wini, Abdiqani Sheikh-Omar, Patrick Tshibangu-Wa-Tshibangu, Maman Laminou Ibrahim, Mohammad Jahirul-Karim, Malen Ken, Monique A. Dorkenoo, Sócrates Herrera, Odile Mercereau-Puijalon, Lise Musset, Valentine Duru, Eric Legrand, Maniphone Khanthavong, Pascal Ringwald, Bruno Pradines, Sandrine Houzé, Rachida Tahar, Olukemi K. Amodu, Johann Beghain, Sandie Menard, Liwang Cui, Colin J. Sutherland, Jun Hu Chen, Kesara Na-Bangchang, Khin Lin, Michael Nambozi, Rithea Leang, Jean Christophe Barale, Milijaona Randrianarivelojosia, Marcus V. G. Lacerda, Sophy Chy, Frédéric Ariey, Jean-Bosco Ouédraogo, Isabelle Morlais, Maria de Fátima Ferreira-da-Cruz, Lubin Jiang, Christophe Rogier, Jun Cao, Peter G. Kremsner, Bui Quang-Phuc, Inès Vigan-Womas, Din Syafruddin, Jetsumon Sattabongkot, Shigeyuki Kano, Abebe A. Fola, Louis Collet, Karamoko Niaré, Thierry Fandeur, Sedigheh Zakeri, Sodiomon B. Sirima, Antoine Berry, Jean Baptiste Mazarati, Fe Espino, Ghulam Rahim-Awab, Chanra Khean, Offianan Andre Toure, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Génétique et Génomique des Insectes vecteurs, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Centre de Recherche Médicale de Lambaréné, Albert Schweitzer, Leiden University Medical Center (LUMC), Universiteit Leiden, International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), University of Ibadan, Nangarhar University, Mahidol University [Bangkok], The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne, Papua New Guinea Institute for Medical Research (PNGIMR), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Mbarara University of Science and Technology [Mbarara] (MUST), Epicentre Ouganda [Mbarara] [Médecins Sans Frontières], Epicentre [Paris] [Médecins Sans Frontières], World Health Organization (WHO), country office for Thailand, Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), JiangSu University, National Institute of Parasitic Diseases, Center for Disease Control, China, Centre Hospitalier de Mayotte, Pennsylvania State University (Penn State), Penn State System, Epidemiology and Disease Control division (EDCD), Ministry of Public Health [Nepal], Institut Pasteur de Dakar, Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD), Institut Pasteur de Bangui, Université de Lomé [Togo], Université de Douala, Centre Pasteur du Cameroun, Research Institute for Tropical Medicine, Centre International de Recherches Médicales de Franceville (CIRMF), Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ), University of Gondar, Institute of Parasitology [Vienna], University of Veterinary Medicine, Vienna, World Health Organisation (WHO), country office for Somalia, Caucaseco scientific research center = Centro de Investigación Científica Caucaseco, National Center for Malariology, Parasitology and Entomology, Ministry of Health [Mozambique], Hôpital Bichat - Claude Bernard, Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5), Centre de Recherche Médicale et Sanitaire (Niamey, Niger) (CERMES), Directorate General of Health Services (DGHS), Institut Pasteur de Shanghai, Académie des Sciences de Chine - Chinese Academy of Sciences (IPS-CAS), National Center for Global Health and Medicine [Japan] (NCGM), Institut Pasteur du Laos, Instituto Leônidas e Maria Deane - Fiocruz Amazônia [Manaus, Brésil] (ILMD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), National Center for Malaria Control, Parasitology and Entomology, Ministry of Health of Cambodgia, Henry M. Jackson Foundation for the Advancement of Military Medicine (HJM), U.S. Naval Medical Research, The Department of Medical Research (Upper Myanmar), Rwanda Biomedical Center (RBC), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement [Yaoundé, Cameroun] (IRD [Cameroun]), Institut de Recherche pour le Développement (IRD), University of Kinshasa (UNIKIN), University of Antwerp (UA), Institut Pasteur de la Guyane, Thammasat University (TU), Tropical Diseases Research Center (TDRC), Université de Bamako, Medizinische Universität Wien = Medical University of Vienna, Institut de Recherche en Sciences de la Santé (IRSS) / Centre Muraz, Medicines for Malaria Venture (MMV), Université de Genève = University of Geneva (UNIGE), Global Malaria Programme, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence du Paludisme, Institut Pasteur de Madagascar, Ministry of Health and Human Services [Somalia], Centre Suisse de Recherches Scientifiques en Cote d'Ivoire [Abidjan] (CSRS-CI), Université Félix Houphouët-Boigny (UFHB), Groupe de recherche action en santé (GRAS), London School of Hygiene and Tropical Medicine (LSHTM), University of Hasanuddin, Eijkman Institute for Molecular Biology [Jakarta], Institut Pasteur de Côte d'Ivoire, Ministry of Health and Medical Services, Institut Pasteur d'Iran, Centre National de Référence du Paludisme [Cayenne, Guyane française] (CNR - laboratoire associé), Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Columbia University Irving Medical Center (CUIMC), Institut de Recherche Biomédicale des Armées [Antenne Marseille] (IRBA), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Supported by the Institut Pasteur Paris, Institut Pasteur International Division, Institut Pasteur Cambodia, and the World Health Organization, by a grant (ANR-10-LABX-62-IBEID) from the French Government Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases', a grant from Natixis Banques, a grant (R01I109023, to Dr. Fidock) from the National Institutes of Health, grants from the Fiocruz Fundação Oswaldo Cruz, Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro, Fundação de Amparo à Pesquisa do Estado do Amazonas, the Brazilian National Council for Scientific and Technological Development, the Agence Nationale de la Recherche (13-BSV3-0018-01 and11-BSV7-009-01), the Austrian Federal Ministry of Science, Research, and Econo-my, the Calgary Laboratory Services, the Centre International de Recherches Médicales de Franceville, the European and Developing Countries Clinical Trials Partnership (CT-2004-31070-001), the Drugs for Neglected Diseases Initiative, the Else Kroener Fresenius Stiftung, the Holger Poehlmann Stiftung, the European Community African–European Research Initiative 'IDEA' (HEALTH-F3-2009-241642), the Fonds Wetenschappelijk Onderzoek, the Vlaamse Interuniversitaire Raad–Universitaire Ontwikkelingssamenwerking, the Belgian Technical Cooperation in Democratic Republic of Congo, the European Community Seventh Framework Program (FP7/2007-2013, 242095, and 223601), the European Commission (REGPOT-CT-2011-285837-STRONGER), the Ministère de la Santé Publique du Niger (Laboratoire National de Référence Résistance aux Antipaludiques), the Foundation of National Science and Technology Major Program (2012ZX10004-220), the French Ministry of Health (Institut National de Veille Sanitaire), the Global Fund to Fight AIDS, Tuberculosis and Malaria, the 5% Initiative program (French Ministry of Foreign Affairs, France Expertise Internationale, 12INI109), the Institut Pasteur de Madagascar, the Government of the Philippines, the Institut de Recherche pour le Développement, the Foundation des Treilles, the Délégation Générale pour l’Armement (PDH-2-NRBC-4-B1-402), the Institut Pasteur de Bangui, the International Society for Health Research and Training, the Malaria Research Initiative Bandarban, Vienna, International Centre for Diarrhoeal Disease Research, Bangladesh, the Médecins sans Frontières (Centre Opérationnel Paris, France), Medicines for Malaria Venture, the National Research Council of Thailand, the Thammasat University, the National Natural Science Foundation of China (81271870, 81361120405, and 81271863), the Natural Science Foundation of Jiangsu Province (BK20130114 and BK20150001), the Jiangsu Science and Technology Department (BM2015024), the National Institutes of Health (R01 AI11646601, AI109023, and ICEMR U19AI089702, U19AI089672), the Pasteur Institute of Iran, the Malaria Division of the Iranian Center for Diseases Management and Control, Public Health England (Malaria Reference Service Contract), the Government of Rwanda, the U.S. Department of Defense Armed Forces Health Surveillance Center, Global Emerging Infections Surveillance and Response System (P0463-14-N6), the Fogarty International Center of the National Institutes of Health training (D43 TW007393), the Mahidol-Oxford Research Unit, the Government of Japan (Science and Technology Agency, Agency for Medical Research and Development, Japan International Cooperation Agency, and Science and Technology Research Partnership for Sustainable Development), and the President’s Malaria Initiative of the U.S. Agency for International Development., The KARMA Consortium, ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-13-BSV3-0018,MALARTRES,Résistance de Plasmodium aux antipaludiques de la famille des artémisinines(2013), ANR-13-BSV7-0009,NEBEDIV,Le rôle des ennemis naturels dans la diversité béta des arbres tropicaux(2013), European Project: CT-2004-31070-001,EDCCTP, European Project: HEALTH-F3-2009-24164,IDEA, European Project: FP7/2007-2013, 24209,FP7, European Project: FP7/2007-2013, 22360,FP7, European Project: 285837,EC:FP7:REGPOT,FP7-REGPOT-2011-1,STRONGER(2011), European Project: 242095,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,EVIMALAR(2009), European Project: 223601,EC:FP7:HEALTH,FP7-HEALTH-2007-B,MALVECBLOK(2009), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Fundação Oswaldo Cruz (FIOCRUZ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Genève (UNIGE), INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence du Paludisme [Cayenne, Guyane française] (CNR), Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Eberhard Karls Universität Tübingen, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia., Centre International de Recherches Médicales de Franceville, Caucaseco scientific research center, Mère et enfant face aux infections tropicales (MERIT - UMR_D 216), National Center for Global Health and Medicine (NCGM), Instituto Leônidas e Maria Deane (ILMD), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement [Yaoundé], Centre Suisse de Recherches Scientifiques en Côte d'Ivoire, Eijkman Institute for Molecular Biology, Laboratoire de Parasitologie, Centre National de Référence du Paludisme - Région Antilles-Guyane, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-WHO Collaborating Center for Surveillance of Antimalarial Drug Resistance, Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010), Van geertruyden, Jean-Pierre, and KARMA Consortium

Subjects
0301 basic medicine, Nonsynonymous substitution, MESH: Sequence Analysis, DNA, Endemic Diseases, MESH: Asia, Southeastern, Drug Resistance, Protozoan Proteins, Drug resistance, MESH: Genotype, Lactones, 0302 clinical medicine, Genotype, Artemisinin, Malaria, Falciparum, MESH: Protozoan Proteins, Asia, Southeastern, MESH: Plasmodium falciparum, Genetics, biology, MESH: Malaria, Falciparum, General Medicine, Artemisinins, MESH: China, 3. Good health, MESH: Endemic Diseases, MESH: Drug Resistance, Algorithms, MESH: Lactones, medicine.drug, China, MESH: Mutation, 030231 tropical medicine, 030106 microbiology, Plasmodium falciparum, MESH: Algorithms, 03 medical and health sciences, parasitic diseases, MESH: Artemisinins, MESH: Polymorphism, Genetic, medicine, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Allele, Polymorphism, Genetic, MESH: Humans, Haplotype, Sequence Analysis, DNA, medicine.disease, biology.organism_classification, Virology, Mutation, Human medicine, Malaria
Abstract

Comment inK13-Propeller Mutations and Malaria Resistance, http://www.nejm.org/doi/full/10.1056/NEJMe1604520; International audience; BACKGROUND:Recent gains in reducing the global burden of malaria are threatened by the emergence of Plasmodium falciparum resistance to artemisinins. The discovery that mutations in portions of a P. falciparum gene encoding kelch (K13)-propeller domains are the major determinant of resistance has provided opportunities for monitoring such resistance on a global scale.METHODS:We analyzed the K13-propeller sequence polymorphism in 14,037 samples collected in 59 countries in which malaria is endemic. Most of the samples (84.5%) were obtained from patients who were treated at sentinel sites used for nationwide surveillance of antimalarial resistance. We evaluated the emergence and dissemination of mutations by haplotyping neighboring loci.RESULTS:We identified 108 nonsynonymous K13 mutations, which showed marked geographic disparity in their frequency and distribution. In Asia, 36.5% of the K13 mutations were distributed within two areas--one in Cambodia, Vietnam, and Laos and the other in western Thailand, Myanmar, and China--with no overlap. In Africa, we observed a broad array of rare nonsynonymous mutations that were not associated with delayed parasite clearance. The gene-edited Dd2 transgenic line with the A578S mutation, which expresses the most frequently observed African allele, was found to be susceptible to artemisinin in vitro on a ring-stage survival assay.CONCLUSIONS:No evidence of artemisinin resistance was found outside Southeast Asia and China, where resistance-associated K13 mutations were confined. The common African A578S allele was not associated with clinical or in vitro resistance to artemisinin, and many African mutations appear to be neutral. (Funded by Institut Pasteur Paris and others.).

Published
2016

16. In vivo efficacy and parasite clearance of artesunate plus sulfadoxine-pyrimethamine versus artemether-lumefantrine in Mali

Author

Issaka Sagara, Ogobara K. Doumbo, Nana H. Cissé, Pascal Ringwald, Antoine Berry, Antoine Dara, Mahamadou S. Sissoko, Françoise Benoit-Vical, Cheick Oumar Coulibaly, Cheick Oumar Guindo, Abdoulaye A Djimdé, Karamoko Niaré, Gulli, Marie-Hélène, Département d'Epidémiologie des Affections parasitaires, Malaria Research and training center Université de Bamako, Mali, Université de Bamako, Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, University of Maryland School of Medicine, University of Maryland System-University of Maryland System, Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Service de Parasitologie et Mycologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Service de Parasitologie et Mycologie, CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], and CHU Toulouse [Toulouse]

Subjects
Male, Artemether/lumefantrine, Artesunate, Pharmacology, Mali, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Interquartile range, 030212 general & internal medicine, Artemether, Artemisinin, Malaria, Falciparum, Child, biology, Articles, Artemisinins, 3. Good health, Drug Combinations, Infectious Diseases, Pyrimethamine, Ethanolamines, Child, Preschool, Female, medicine.drug, medicine.medical_specialty, 030231 tropical medicine, Plasmodium falciparum, 03 medical and health sciences, Antimalarials, Virology, Internal medicine, Sulfadoxine, parasitic diseases, medicine, Humans, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Fluorenes, business.industry, Artemether, Lumefantrine Drug Combination, [CHIM.COOR] Chemical Sciences/Coordination chemistry, medicine.disease, biology.organism_classification, Sulfadoxine/pyrimethamine, chemistry, Parasitology, business, Malaria
Abstract

International audience; Although artemisinin resistance has yet to be reported in Africa, surveillance of the efficacy of artemisinin-based combination therapies (ACTs) is warranted. Here, the efficacy of artesunate + sulfadoxine-pyrimethamine (AS+SP) and artemether-lumefantrine (AL) was evaluated in Mali. Randomized open-label comparative in vivo assay of AS+SP versus AL were carried out using the 28-day follow-up World Health Organization protocol. Patients with uncomplicated falciparum malaria and at least 6 months of age were recruited between October 2010 and January 2014. A subset of these patients was selected to measure Plasmodium falciparum clearance time. Polymerase chain reaction corrected adequate clinical and parasitological responses were 100% for AS+SP and 98.2% for AL with no significant difference (P = 0.06). The reinfection rates were comparable (P = 0.63) with 8.0% for AS+SP and 12.6% for AL. Individuals under 8 years were more susceptible to treatment failure (relative risk = 1.9; 95% confidence interval = 1.2, 3.3). Median parasite clearance half-life was 1.7 hours (interquartile range [IQR] = 1.3-2.2) for AS+SP and 1.9 hours (IQR = 1.5-2.5) for AL with no statistically significant difference (P = 0.24). Efficacy of AS+SP and AL was high. This study provides baseline information on parasite clearance half-lives after ACT treatment, particularly AS+SP, in Mali.

Published
2016

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