Impact of dhps mutations on sulfadoxine-pyrimethamine protective efficacy and implications for malaria chemoprevention
Abstract Sulfadoxine-pyrimethamine (SP) is recommended for perennial malaria chemoprevention in young children in high burden areas across Africa. Mutations in the dihydropteroate synthase (dhps) gene (437 G/540E/581 G) associated with sulfadoxine resistance vary regionally, but their effect on SP p...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58326-z |
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| author | Andria Mousa Gina Cuomo-Dannenburg Hayley A. Thompson David J. Bell Umberto D’Alessandro Roly Gosling Alain Nahum Karen I. Barnes Jaishree Raman Lesley Workmann Yong See Foo Jennifer A. Flegg Emma Filtenborg Hocke Helle Hansson Ana Chopo-Pizarro Khalid B. Beshir Michael Alifrangis R. Matthew Chico Colin J. Sutherland Lucy C. Okell Cally Roper |
| author_facet | Andria Mousa Gina Cuomo-Dannenburg Hayley A. Thompson David J. Bell Umberto D’Alessandro Roly Gosling Alain Nahum Karen I. Barnes Jaishree Raman Lesley Workmann Yong See Foo Jennifer A. Flegg Emma Filtenborg Hocke Helle Hansson Ana Chopo-Pizarro Khalid B. Beshir Michael Alifrangis R. Matthew Chico Colin J. Sutherland Lucy C. Okell Cally Roper |
| author_sort | Andria Mousa |
| collection | DOAJ |
| description | Abstract Sulfadoxine-pyrimethamine (SP) is recommended for perennial malaria chemoprevention in young children in high burden areas across Africa. Mutations in the dihydropteroate synthase (dhps) gene (437 G/540E/581 G) associated with sulfadoxine resistance vary regionally, but their effect on SP protective efficacy is unclear. We retrospectively analyse time to microscopy and PCR-confirmed re-infection in seven efficacy trials including 1639 participants in 12 sites across Africa. We estimate the duration of SP protection against parasites with different genotypes using a Bayesian mathematical model that accounts for variation in transmission intensity and genotype frequencies. The longest duration of SP protection is >42 days against dhps sulfadoxine-susceptible parasites and 30.3 days (95%Credible Interval (CrI):17.1-45.1) against the West-African genotype dhps GKA (437G-K540-A581). A shorter duration of protection is estimated against parasites with additional mutations in the dhps gene, with 16.5 days (95%CrI:11.2-37.4) protection against parasites with the east-African genotype dhps GEA (437G-540E-A581) and 11.7 days (95%CrI:8.0-21.9) against highly resistant parasites carrying the dhps GEG (437G-540E−581G) genotype. Using these estimates and modelled genotype frequencies we map SP protection across Africa. This approach and our estimated parameters can be directly applied to any setting using local genomic surveillance data to inform decision-making on where to scale-up SP-based chemoprevention or consider alternatives. |
| format | Article |
| id | doaj-art-8cc8ea57ee8f4523a4e5535d94b2a3c5 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-8cc8ea57ee8f4523a4e5535d94b2a3c52025-08-20T02:15:12ZengNature PortfolioNature Communications2041-17232025-05-0116111310.1038/s41467-025-58326-zImpact of dhps mutations on sulfadoxine-pyrimethamine protective efficacy and implications for malaria chemopreventionAndria Mousa0Gina Cuomo-Dannenburg1Hayley A. Thompson2David J. Bell3Umberto D’Alessandro4Roly Gosling5Alain Nahum6Karen I. Barnes7Jaishree Raman8Lesley Workmann9Yong See Foo10Jennifer A. Flegg11Emma Filtenborg Hocke12Helle Hansson13Ana Chopo-Pizarro14Khalid B. Beshir15Michael Alifrangis16R. Matthew Chico17Colin J. Sutherland18Lucy C. Okell19Cally Roper20Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical MedicineMRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College LondonMalaria and Neglected Tropical Diseases, PATHDepartment of Infectious Disease, NHS Greater Glasgow and ClydeMRC Unit The Gambia at the London School of Hygiene and Tropical MedicineFaculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical MedicineCentre de recherche entomologique de CotonouDivision of Clinical Pharmacology, Department of Medicine, University of Cape TownSouth African National Institute for Communicable DiseasesDivision of Clinical Pharmacology, Department of Medicine, University of Cape TownSchool of Mathematics and Statistics, The University of MelbourneSchool of Mathematics and Statistics, The University of MelbourneDepartment of Immunology and Microbiology, Centre for translational Medicine and Parasitology, University of CopenhagenDepartment of Immunology and Microbiology, Centre for translational Medicine and Parasitology, University of CopenhagenFaculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical MedicineFaculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical MedicineDepartment of Immunology and Microbiology, Centre for translational Medicine and Parasitology, University of CopenhagenFaculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical MedicineFaculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical MedicineMRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College LondonFaculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical MedicineAbstract Sulfadoxine-pyrimethamine (SP) is recommended for perennial malaria chemoprevention in young children in high burden areas across Africa. Mutations in the dihydropteroate synthase (dhps) gene (437 G/540E/581 G) associated with sulfadoxine resistance vary regionally, but their effect on SP protective efficacy is unclear. We retrospectively analyse time to microscopy and PCR-confirmed re-infection in seven efficacy trials including 1639 participants in 12 sites across Africa. We estimate the duration of SP protection against parasites with different genotypes using a Bayesian mathematical model that accounts for variation in transmission intensity and genotype frequencies. The longest duration of SP protection is >42 days against dhps sulfadoxine-susceptible parasites and 30.3 days (95%Credible Interval (CrI):17.1-45.1) against the West-African genotype dhps GKA (437G-K540-A581). A shorter duration of protection is estimated against parasites with additional mutations in the dhps gene, with 16.5 days (95%CrI:11.2-37.4) protection against parasites with the east-African genotype dhps GEA (437G-540E-A581) and 11.7 days (95%CrI:8.0-21.9) against highly resistant parasites carrying the dhps GEG (437G-540E−581G) genotype. Using these estimates and modelled genotype frequencies we map SP protection across Africa. This approach and our estimated parameters can be directly applied to any setting using local genomic surveillance data to inform decision-making on where to scale-up SP-based chemoprevention or consider alternatives.https://doi.org/10.1038/s41467-025-58326-z |
| spellingShingle | Andria Mousa Gina Cuomo-Dannenburg Hayley A. Thompson David J. Bell Umberto D’Alessandro Roly Gosling Alain Nahum Karen I. Barnes Jaishree Raman Lesley Workmann Yong See Foo Jennifer A. Flegg Emma Filtenborg Hocke Helle Hansson Ana Chopo-Pizarro Khalid B. Beshir Michael Alifrangis R. Matthew Chico Colin J. Sutherland Lucy C. Okell Cally Roper Impact of dhps mutations on sulfadoxine-pyrimethamine protective efficacy and implications for malaria chemoprevention Nature Communications |
| title | Impact of dhps mutations on sulfadoxine-pyrimethamine protective efficacy and implications for malaria chemoprevention |
| title_full | Impact of dhps mutations on sulfadoxine-pyrimethamine protective efficacy and implications for malaria chemoprevention |
| title_fullStr | Impact of dhps mutations on sulfadoxine-pyrimethamine protective efficacy and implications for malaria chemoprevention |
| title_full_unstemmed | Impact of dhps mutations on sulfadoxine-pyrimethamine protective efficacy and implications for malaria chemoprevention |
| title_short | Impact of dhps mutations on sulfadoxine-pyrimethamine protective efficacy and implications for malaria chemoprevention |
| title_sort | impact of dhps mutations on sulfadoxine pyrimethamine protective efficacy and implications for malaria chemoprevention |
| url | https://doi.org/10.1038/s41467-025-58326-z |
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