Genetic and Genomic epidemiology of Plasmodium vivax: dissecting patterns of transmission and adaptation

Project Overview

Study sites in Africa and Asia. Sites in red have genomic as well as genotypic quality samples.

Signatures of positive selection in comparisons of Thai and Papua Indonesian P. vivax populations

Once considered a benign infection, Plasmodium vivax is now acknowledged to be an important public health threat capable of causing severe and even fatal disease. Chloroquine remains the mainstay for treating P. vivax infection in most endemic regions, but evidence of declining efficacy underpins the urgency to contain this species. P. vivax has proven challenging to control owing to the species’ ability to form dormant liver stages (hypnozoites) that can relapse weeks or months after initial infection, and pre-symptomatic development of transmissible blood stages (gametocytes). P. vivax also exhibits extensive genetic diversity. These properties enhance the parasite’s ability to survive and adapt to antimalarial drugs, local vectors, host immunity and other selective pressures. The successful interruption of P. vivax transmission will therefore require a better understanding of local patterns of transmission, infection spread, key reservoirs of infection, and drug resistance and other forms of adaptation.  This DPhil project aims to address these knowledge gaps using genetic and genomic approaches to dissect the epidemiology of P. vivax in endemic sites across Asia and the horn of Africa.

You will use a unique biobank of P. vivax samples collected within the framework of ongoing longitudinal cohorts and cross-sectional studies in Asia and the horn of Africa to conduct explore the following research areas:

Training Opportunities

The project will suit a student interested in bioinformatic analysis, with opportunities to also perform some complementary wet-lab research. You will be supported by a multi-disciplinary team of clinicians and scientists with expertise in clinical studies, pathophysiology, and genetic and genomic epidemiology of malaria. The team has well established programs in antimalarial drug resistance and has built a strong collaborative network for clinical and molecular epidemiology studies of P. vivax. There will be an opportunity to learn and develop skills in laboratory-based molecular biology techniques, clinical epidemiology, population genetics and genomics.

Theme

Genetics & Genomics and Tropical Medicine & Global Health

Admissions

Project reference number: 971

Funding and admissions information

Supervisors

Name Department Institution Country Email
Professor Richard Price Tropical Medicine Oxford University, Asia Pacific AUS ric.price@ndm.ox.ac.uk
Dr Sarah Auburn Menzies AUS Sarah.Auburn@menzies.edu.au

Auburn S, Barry AE. 2017. Dissecting malaria biology and epidemiology using population genetics and genomics. Int. J. Parasitol., 47 (2-3), pp. 77-85. Read abstract | Read more

Molecular approaches have an increasingly recognized utility in surveillance of malaria parasite populations, not only in defining prevalence and incidence with higher sensitivity than traditional methods, but also in monitoring local and regional parasite transmission patterns. In this review, we provide an overview of population genetic and genomic studies of human-infecting Plasmodium species, highlighting recent advances in the field. In accordance with the renewed impetus for malaria eradication, many studies are now using genetic and genomic epidemiology to support local evidence-based intervention strategies. Microsatellite genotyping remains a popular approach for both Plasmodium falciparum and Plasmodium vivax. However, with the increasing availability of whole genome sequencing data enabling effective single nucleotide polymorphism-based panels tailored to a given study question and setting, this approach is gaining popularity. The availability of new reference genomes for Plasmodium malariae and Plasmodium ovale should see a surge in similar molecular studies on these currently neglected species. Genomic studies are revealing new insights into important adaptive mechanisms of the parasite including antimalarial drug resistance. The advent of new methodologies such as selective whole genome amplification for dealing with extensive human DNA in low density field isolates should see genome-wide approaches becoming routine for parasite surveillance once the economic costs outweigh the current cost benefits of targeted approaches. Hide abstract

Pearson RD, Amato R, Auburn S, Miotto O, Almagro-Garcia J, Amaratunga C, Suon S, Mao S, Noviyanti R, Trimarsanto H, Marfurt J, Anstey NM, William T, Boni MF, Dolecek C, Hien TT, White NJ, Michon P, Siba P, Tavul L, Harrison G, Barry A, Mueller I, Ferreira MU, Karunaweera N, Randrianarivelojosia M, Gao Q, Hubbart C, Hart L, Jeffery B, Drury E, Mead D, Kekre M, Campino S, Manske M, Cornelius VJ, MacInnis B, Rockett KA, Miles A, Rayner JC, Fairhurst RM, Nosten F, Price RN, Kwiatkowski DP. 2016. Genomic analysis of local variation and recent evolution in Plasmodium vivax. Nat. Genet., 48 (8), pp. 959-964. Read abstract | Read more

The widespread distribution and relapsing nature of Plasmodium vivax infection present major challenges for the elimination of malaria. To characterize the genetic diversity of this parasite in individual infections and across the population, we performed deep genome sequencing of >200 clinical samples collected across the Asia-Pacific region and analyzed data on >300,000 SNPs and nine regions of the genome with large copy number variations. Individual infections showed complex patterns of genetic structure, with variation not only in the number of dominant clones but also in their level of relatedness and inbreeding. At the population level, we observed strong signals of recent evolutionary selection both in known drug resistance genes and at new loci, and these varied markedly between geographical locations. These findings demonstrate a dynamic landscape of local evolutionary adaptation in the parasite population and provide a foundation for genomic surveillance to guide effective strategies for control and elimination of P. vivax. Hide abstract

Price RN, von Seidlein L, Valecha N, Nosten F, Baird JK, White NJ. 2014. Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis. Lancet Infect Dis, 14 (10), pp. 982-91. Read abstract | Read more

BACKGROUND: Chloroquine is the first-line treatment for Plasmodium vivax malaria in most endemic countries, but resistance is increasing. Monitoring of antimalarial efficacy is essential, but in P. vivax infections the assessment of treatment efficacy is confounded by relapse from the dormant liver stages. We systematically reviewed P. vivax malaria treatment efficacy studies to establish the global extent of chloroquine resistance. METHODS: We searched Medline, Web of Science, Embase, and the Cochrane Database of Systematic Reviews to identify studies published in English between Jan 1, 1960, and April 30, 2014, which investigated antimalarial treatment efficacy in P. vivax malaria. We excluded studies that did not include supervised schizonticidal treatment without primaquine. We determined rates of chloroquine resistance according to P. vivax malaria recurrence rates by day 28 whole-blood chloroquine concentrations at the time of recurrence and study enrolment criteria. FINDINGS: We identified 129 eligible clinical trials involving 21,694 patients at 179 study sites and 26 case reports describing 54 patients. Chloroquine resistance was present in 58 (53%) of 113 assessable study sites, spread across most countries that are endemic for P. vivax. Clearance of parasitaemia assessed by microscopy in 95% of patients by day 2, or all patients by day 3, was 100% predictive of chloroquine sensitivity. INTERPRETATION: Heterogeneity of study design and analysis has confounded global surveillance of chloroquine-resistant P. vivax, which is now present across most countries endemic for P. vivax. Improved methods for monitoring of drug resistance are needed to inform antimalarial policy in these regions. FUNDING: Wellcome Trust (UK). Hide abstract