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      Contrasting Transmission Dynamics of Co-endemic Plasmodium vivax and P. falciparum: Implications for Malaria Control and Elimination

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          Abstract

          Background

          Outside of Africa, P. falciparum and P. vivax usually coexist. In such co-endemic regions, successful malaria control programs have a greater impact on reducing falciparum malaria, resulting in P. vivax becoming the predominant species of infection. Adding to the challenges of elimination, the dormant liver stage complicates efforts to monitor the impact of ongoing interventions against P. vivax. We investigated molecular approaches to inform the respective transmission dynamics of P. falciparum and P. vivax and how these could help to prioritize public health interventions.

          Methodology/ Principal Findings

          Genotype data generated at 8 and 9 microsatellite loci were analysed in 168 P. falciparum and 166 P. vivax isolates, respectively, from four co-endemic sites in Indonesia (Bangka, Kalimantan, Sumba and West Timor). Measures of diversity, linkage disequilibrium (LD) and population structure were used to gauge the transmission dynamics of each species in each setting. Marked differences were observed in the diversity and population structure of P. vivax versus P. falciparum. In Bangka, Kalimantan and Timor, P. falciparum diversity was low, and LD patterns were consistent with unstable, epidemic transmission, amenable to targeted intervention. In contrast, P. vivax diversity was higher and transmission appeared more stable. Population differentiation was lower in P. vivax versus P. falciparum, suggesting that the hypnozoite reservoir might play an important role in sustaining local transmission and facilitating the spread of P. vivax infections in different endemic settings. P. vivax polyclonality varied with local endemicity, demonstrating potential utility in informing on transmission intensity in this species.

          Conclusions/ Significance

          Molecular approaches can provide important information on malaria transmission that is not readily available from traditional epidemiological measures. Elucidation of the transmission dynamics circulating in a given setting will have a major role in prioritising malaria control strategies, particularly against the relatively neglected non-falciparum species.

          Author Summary

          The malaria parasite Plasmodium vivax is a growing public health burden across the globe. Largely overshadowed by the more fatal P. falciparum parasite, increasing reports of anti-malarial drug resistance and life-threatening disease complications demand concerted efforts to eliminate P. vivax. Outside of Africa, P. vivax usually co-exists with P. falciparum. In these regions, malaria interventions have demonstrated greater success against falciparum. The authors genotyped P. vivax and P. falciparum parasites from 4 co-endemic sites in Indonesia, and used the data to gauge how frequently and how focally parasites were transmitted, and how much they spread between sites. Their results indicated that whilst the P. falciparum populations displayed evidence of low and unstable transmission, the P. vivax populations were more diverse and exhibited more stable transmission patterns, requiring different intervention approaches. Relative to P. falciparum, the P. vivax parasites demonstrated evidence of greater spread between populations, possibly facilitated by the dormant liver stage which enables P. vivax to be carried asymptomatically in patients for long periods of time. These findings highlight the need to reconcile the intervention requirements for non-falciparum malaria species in co-endemic regions, and the general utility of parasite genotyping to facilitate surveillance.

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          Most cited references50

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          A new world malaria map: Plasmodium falciparum endemicity in 2010

          Background Transmission intensity affects almost all aspects of malaria epidemiology and the impact of malaria on human populations. Maps of transmission intensity are necessary to identify populations at different levels of risk and to evaluate objectively options for disease control. To remain relevant operationally, such maps must be updated frequently. Following the first global effort to map Plasmodium falciparum malaria endemicity in 2007, this paper describes the generation of a new world map for the year 2010. This analysis is extended to provide the first global estimates of two other metrics of transmission intensity for P. falciparum that underpin contemporary questions in malaria control: the entomological inoculation rate (PfEIR) and the basic reproductive number (PfR). Methods Annual parasite incidence data for 13,449 administrative units in 43 endemic countries were sourced to define the spatial limits of P. falciparum transmission in 2010 and 22,212 P. falciparum parasite rate (PfPR) surveys were used in a model-based geostatistical (MBG) prediction to create a continuous contemporary surface of malaria endemicity within these limits. A suite of transmission models were developed that link PfPR to PfEIR and PfR and these were fitted to field data. These models were combined with the PfPR map to create new global predictions of PfEIR and PfR. All output maps included measured uncertainty. Results An estimated 1.13 and 1.44 billion people worldwide were at risk of unstable and stable P. falciparum malaria, respectively. The majority of the endemic world was predicted with a median PfEIR of less than one and a median PfR c of less than two. Values of either metric exceeding 10 were almost exclusive to Africa. The uncertainty described in both PfEIR and PfR was substantial in regions of intense transmission. Conclusions The year 2010 has a particular significance as an evaluation milestone for malaria global health policy. The maps presented here contribute to a rational basis for control and elimination decisions and can serve as a baseline assessment as the global health community looks ahead to the next series of milestones targeted at 2015.
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            Key gaps in the knowledge of Plasmodium vivax, a neglected human malaria parasite.

            Plasmodium vivax is geographically the most widely distributed cause of malaria in people, with up to 2.5 billion people at risk and an estimated 80 million to 300 million clinical cases every year--including severe disease and death. Despite this large burden of disease, P vivax is overlooked and left in the shadow of the enormous problem caused by Plasmodium falciparum in sub-Saharan Africa. The technological advances enabling the sequencing of the P vivax genome and a recent call for worldwide malaria eradication have together placed new emphasis on the importance of addressing P vivax as a major public health problem. However, because of this parasite's biology, it is especially difficult to interrupt the transmission of P vivax, and experts agree that the available methods for preventing and treating infections with P vivax are inadequate. It is thus imperative that the development of new methods and strategies become a priority. Advancing the development of such methods needs renewed emphasis on understanding the biology, pathogenesis, and epidemiology of P vivax. This Review critically examines what is known about P vivax, focusing on identifying the crucial gaps that create obstacles to the elimination of this parasite in human populations.
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              Microsatellite markers reveal a spectrum of population structures in the malaria parasite Plasmodium falciparum.

              Multilocus genotyping of microbial pathogens has revealed a range of population structures, with some bacteria showing extensive recombination and others showing almost complete clonality. The population structure of the protozoan parasite Plasmodium falciparum has been harder to evaluate, since most studies have used a limited number of antigen-encoding loci that are known to be under strong selection. We describe length variation at 12 microsatellite loci in 465 infections collected from 9 locations worldwide. These data reveal dramatic differences in parasite population structure in different locations. Strong linkage disequilibrium (LD) was observed in six of nine populations. Significant LD occurred in all locations with prevalence <1% and in only two of five of the populations from regions with higher transmission intensities. Where present, LD results largely from the presence of identical multilocus genotypes within populations, suggesting high levels of self-fertilization in populations with low levels of transmission. We also observed dramatic variation in diversity and geographical differentiation in different regions. Mean heterozygosities in South American countries (0.3-0.4) were less than half those observed in African locations (0. 76-0.8), with intermediate heterozygosities in the Southeast Asia/Pacific samples (0.51-0.65). Furthermore, variation was distributed among locations in South America (F:(ST) = 0.364) and within locations in Africa (F:(ST) = 0.007). The intraspecific patterns of diversity and genetic differentiation observed in P. falciparum are strikingly similar to those seen in interspecific comparisons of plants and animals with differing levels of outcrossing, suggesting that similar processes may be involved. The differences observed may also reflect the recent colonization of non-African populations from an African source, and the relative influences of epidemiology and population history are difficult to disentangle. These data reveal a range of population structures within a single pathogen species and suggest intimate links between patterns of epidemiology and genetic structure in this organism.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                7 May 2015
                May 2015
                : 9
                : 5
                : e0003739
                Affiliations
                [1 ]Eijkman Institute for Molecular Biology, Jakarta Pusat, Indonesia
                [2 ]The Ministry of Research and Technology (RISTEK), Jakarta Pusat, Indonesia
                [3 ]Agency for Assessment and Application of Technology, Jakarta, Indonesia
                [4 ]Faculty of Medicine, University of Indonesia, Jakarta Pusat, Indonesia
                [5 ]National Malaria Control Program, Ministry of Health, Jakarta, Indonesia
                [6 ]United Nations Children’s Fund (UNICEF), Jakarta, Jakarta, Indonesia
                [7 ]Eck Institute for Global Health, University of Notre Dame, Notre Dame, Indiana, United States of America
                [8 ]Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia
                [9 ]Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
                [10 ]Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom
                [11 ]Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom
                Barcelona Centre for International Health Research (CRESIB) and Institució Catalana de Recerca i Estudis Avançats (ICREA), SPAIN
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: RN FC RNP SA. Performed the experiments: RASU YKT LT AKu. Analyzed the data: HT TGC SA. Contributed reagents/materials/analysis tools: HT IS AKo RK WAH FL NL JM. Wrote the paper: RN RNP SA.

                Article
                PNTD-D-15-00186
                10.1371/journal.pntd.0003739
                4423885
                25951184
                e1fa5130-8314-4a0a-9b07-9cda1270535a

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication

                History
                : 5 February 2015
                : 5 April 2015
                Page count
                Figures: 4, Tables: 4, Pages: 19
                Funding
                The field and laboratory components of the study were funded by an Asia Pacific Malaria Elimination Network (APMEN) Project Grant awarded to RN (No. 107-04). Major funding for APMEN is provided by the Australian Government Department of Foreign Affairs and Trade, alongside funds received from the Bill and Melinda Gates Foundation. The Malaria Transmission Consortium (UNICEF contract # 43120943) and the Indonesia Ministry of Research and Technology also provided funding for this study. SA, RNP and HT were funded by the Wellcome Trust [Wellcome Trust Senior Fellow in Clinical Science (091625) awarded RNP]. SA is also part-funded by APMEN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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