article · The Lancet Microbe
Sulfadoxine-pyrimethamine is widely used to prevent malaria in pregnant women and young children, but its effectiveness faces risks from genetic mutations in Plasmodium falciparum parasites. Between 2014 and 2018, blood samples from symptomatic patients across seven central African nations were analysed to map drug-resistance mutations in the pfdhfr and pfdhps genes. The investigation revealed a marked spread of resistant parasite strains across the region, including a west-to-east rise in mutations known as K540E and A581G. Furthermore, a specific mutation known as I431V appeared frequently in Cameroon and Nigeria. Genomic evaluation demonstrated that the vagKgs allele, which incorporates this mutation, emerged recently in Africa and is expanding clonally. These findings indicate growing parasite resistance that may jeopardise regional malaria prevention programmes.
Sulfadoxine-pyrimethamine is a critical preventive medicine safeguarding vulnerable groups, specifically pregnant women and infants, against malaria in high-transmission regions. The rapid emergence and geographic expansion of genetically resistant parasite strains in central Africa threatens the efficacy of these preventative healthcare interventions. Tracking these mutations provides public health authorities with essential data needed to evaluate and update regional malaria treatment guidelines before current drug regimens fail.
The abstract does not describe a commercial product or direct commercialisation pathway, representing early-stage epidemiological and genomic research. However, the identified genetic markers can inform the design of molecular diagnostic tools and surveillance assays used by diagnostic developers and public health monitoring bodies. Any application remains at an early research stage, as the specific resistance phenotype linked to the vagKgs allele requires further confirmation before translation into standard diagnostic kits or revised drug development strategies.
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BACKGROUND: Efficacy of sulfadoxine-pyrimethamine, the malaria chemoprophylaxis used in pregnant women, and in children when combined with amodiaquine, is threatened by the accumulation of mutations in the Plasmodium falciparum dihydropteroate synthase (pfdhps) and dihydrofolate reductase (pfdhfr) genes. Data on the prevalence of resistant alleles in central Africa and the new pfdhps I431V mutation, particularly associated with other mutations to form the pfdhps vagKgs allele, are scarce. We explored the frequency and geographical distribution of pfdhps and pfdhfr mutations in central Africa in 2014-18, and assessed the evolutionary origin of the vagKgs allele. METHODS: Samples were collected at 18 health-care centres in seven countries (Angola, Cameroon, Central African Republic, Democratic Republic of the Congo, Gabon, Nigeria, and Republic of the Congo) from patients who showed possible symptoms of malaria between March 1, 2014, and Oct 31, 2018. Samples that were positive for P falciparum were transported to a laboratory in Toulouse, France, and genotyped. The frequency of pfdhfr and pfdhps mutations was studied in 1749 samples. Microsatellites in pfdhps flanking regions and whole-genome analysis compared with parasite genomes from the data-sharing network MalariaGEN were performed on samples carrying the vagKgs allele. FINDINGS: Mapping of the prevalence of single nucleotide polymorphisms and corresponding alleles of pfdhfr and pfdhps showed a substantial spread of alleles associated with sulfadoxine-pyrimethamine resistance in central Africa during the 2014-18 period, especially an increase going west to east in pfdhps alleles carrying the K540E and A581G mutations. A high prevalence of the pfdhps I431V mutation was observed in Cameroon (exceeding 50% in the northern region) and Nigeria. Genomic analysis showed a recent African emergence and a clonal expansion of the most frequent pfdhps vagKgs allele. INTERPRETATION: Reduced sulfadoxine-pyrimethamine efficacy due to increased resistance is a worrying situation, especially because the malaria transmission level is high in central Africa. Although the resistance phenotype remains to be confirmed, the emergence and spread of the vagKgs allele in west and central Africa could challenge the use of sulfadoxine-pyrimethamine. FUNDING: Toulouse Institute for Infectious and Inflammatory Diseases.
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DOI: 10.1016/s2666-5247(23)00211-2
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