Biology subjects

Maude, R. J.

Publications and source records attributed to Maude, R. J..

3 recordsLinked to original sources

bioRxiv2019

Evolution and expansion of multidrug resistant malaria in Southeast Asia: a genomic epidemiology study

BackgroundA multidrug resistant co-lineage of Plasmodium falciparum malaria, named KEL1/PLA1, spread across Cambodia c.2008-2013, causing high treatment failure rates to the frontline combination therapy dihydroartemisinin-piperaquine. Here, we report on the evolution and spread of KEL1/PLA1 in subsequent years.\n\nMethodsWe analysed whole genome sequencing data from 1,673 P. falciparum clinical samples collected in 2008-2018 from northeast Thailand, Laos, Cambodia and Vietnam. By investigating genome-wide relatedness between parasites, we inferred patterns of shared ancestry in the KEL1/PLA1 population.\n\nFindingsKEL1/PLA1 spread rapidly from 2015 into all of the surveyed countries and now exceeds 80% of the P. falciparum population in several regions. These parasites maintained a high level of genetic relatedness reflecting their common origin. However, several genetic subgroups have recently emerged within this co-lineage with diverse geographical distributions. Some of these emerging KEL1/PLA1 subgroups carry recent mutations in the chloroquine resistance transporter (crt) gene, which arise on a specific genetic background comprising multiple genomic regions.\n\nInterpretationAfter emerging and circulating for several years within Cambodia, the P. falciparum KEL1/PLA1 co-lineage diversified into multiple subgroups and acquired new genetic features including novel crt mutations. These subgroups have rapidly spread into neighbouring countries, suggesting enhanced fitness. These findings highlight the urgent need for elimination of this increasingly drug-resistant parasite co-lineage, and the importance of genetic surveillance in accelerating elimination efforts.\n\nFundingWellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, UK Department for International Development.\n\nResearch in context O_TEXTBOXEvidence before this studyThis study updates our previous work describing the emergence and spread of a multidrug resistant P. falciparum co-lineage (KEL1/PLA1) within Cambodia up to 2013. Since then, a regional genetic surveillance project, GenRe-Mekong, has reported that markers of dihydroartemisinin-piperaquine (DHA-PPQ) resistance have increased in frequency in neighbouring countries. A PubMed search (terms: \"artemisinin\", \"piperaquine\", \"resistance\", \"southeast asia\") for articles listed since our previous study (from 30/10/2017 to 05/01/2019) yielded 28 results, including reports of a recent sharp decline in DHA-PPQ clinical efficacy in Vietnam; the spread of genetic markers of DHA-PPQ resistance into neighbouring countries by Imwong and colleagues; and multiple reports associating mutations in the crt gene with piperaquine resistance, including newly emerging crt variants in Southeast Asia.\n\nAdded value of this studyWe analysed P. falciparum whole genomes collected up to early 2018 from Eastern Southeast Asia (Cambodia and surrounding regions), describing the fine-scale epidemiology of multiple KEL1/PLA1 genetic subgroups that have spread out from Cambodia since 2015 and taken over indigenous parasite populations in northeastern Thailand, southern and central Vietnam and parts of southern Laos. Several newly emerging crt mutations accompanied the spread and expansion of KEL1/PLA1 subgroups, suggesting an active proliferation of biologically fit, multidrug resistant parasites.\n\nImplications of all the available evidenceThe problem of P. falciparum multidrug resistance has dramatically worsened in Eastern Southeast Asia since previous reports. KEL1/PLA1 has diversified and spread widely across Eastern Southeast Asia since 2015, becoming the predominant parasite group in several regions. This may have been fuelled by continued parasite exposure to DHA-PPQ, resulting in sustained selection after KEL1/PLA1 became established. Continued drug pressure enabled the acquisition of further mutations, resulting in higher levels of resistance. These data demonstrate the value of pathogen genetic surveillance and the urgent need to eliminate these dangerous parasites.\n\nC_TEXTBOX

epidemiology↗

bioRxiv2018

The geography of malaria elimination in Bangladesh: combining data layers to estimate the spatial spread of parasites

Malaria control programs face difficult resource allocation decisions. Of particular concern for countries aiming for malaria elimination, the regular movement of individuals to and from endemic areas undermines local interventions by reintroducing infections and sustaining local transmission. Quantifying this movement of malaria parasites around a country has become a priority for national control programs, but remains methodologically challenging, particularly in areas with highly mobile populations. Here, we combined multiple data sources to measure the geographical spread of malaria parasites, including epidemiological surveillance data, travel surveys, parasite genetic data, and anonymized mobile phone data. We collected parasite genetic barcodes and travel surveys from 2,090 patients residing in 176 unions in southeast Bangladesh. We developed a genetic mixing index to quantify the likelihood of samples being local or imported. We then inferred the direction and intensity of parasite flow between locations using an epidemiological model, and estimated the proportion of imported cases assuming mobility patterns parameterized using the travel survey and mobile phone calling data. Our results show that each data source provided related but different information about the patterns of geographic spread of parasites. We identify a consistent north/south separation of the Chittagong Hill Tracts region in Bangladesh, and found that in addition to imported infections from forested regions, frequent mixing also occurs in low transmission but highly populated areas in the southwest. Thus, unlike risk maps generated from incidence alone, our maps provide evidence that elimination programs must address ongoing movement of parasites around the lower transmission areas in the southwest.

epidemiology↗

bioRxiv2018

Herd protection against Plasmodium falciparum infections conferred by mass antimalarial drug administrations and the implications for malaria elimination

IntroductionAll nations of the Greater Mekong Subregion have committed to elimination of malaria by the year 2030. Elimination efforts rely on increasing access to diagnosis and treatment. However, asymptomatic infections pose a major challenge for these efforts. One approach towards eliminating asymptomatic reservoirs is targeted mass antimalarial drug administration (MDA). Here we present a fine scale spatiotemporal analysis of malaria incidence and prevalence in villages undergoing MDA.\n\nMethodsFour villages along the Myanmar-Thailand border were selected for a MDA pilot study based on clinical records and prevalence surveys. Passive detection of clinical episodes was facilitated through community based malaria clinics in each village. All villagers were screened using venous blood and ultra-sensitive qPCR (uPCR) for detection of parasites at baseline and every subsequent 3 months until month 18 (M18). A final screening was done at M24. MDAs were conducted on M0, M1 and M2 in two villages and on M9, M10, M11 in the remaining two villages. Which villages received early or deferred MDA was decided using restricted randomization. MDA participation, clinical episodes and uPCR detected infections were mapped to participant houses. Scan statistics were used to test for clusters of malaria episodes, malaria infections and non-adherence to MDA. Mixed effects regressions were used to test for risk factors for clinical episodes after MDA.\n\nResultsNeighborhood level MDA adherence was a major predictor for clinical episodes of malaria post-MDA, suggesting a strong herd effect. Each village had a cluster of P. falciparum infections at M0. After M0, there were no clusters of uPCR detectable P. falciparum infections. Clinical episodes of P. falciparum occurred in one village only which had a cluster of non-adherence to MDA and a high mosquito vector human biting rate. Individuals with subclinical P.falciparum infections were more likely to have subsequent clinical episodes than individuals who had no subclinical infections. Individuals who lived in a house with someone who had a clinical episode were more likely to also have a clinical episode subsequently than individuals residing in a house free of P.falciparum infections.\n\nConclusionTo our knowledge this is the first study to show a herd effect from MDA for malaria. These data and results have significance for spatial targeting of interventions for malaria elimination. Clusters of non-adherence to MDA participation can lead to failed elimination if they occur among individuals with asymptomatic infections and given sufficient mosquito vector exposure. Community participation, which can be facilitated through community engagement, is key to MDA success.

epidemiology↗