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Molecular tools for monitoring the impact of intensified malaria control on malaria epidemiology

English title Molecular tools for monitoring the impact of intensified malaria control on malaria epidemiology
Applicant Felger Ingrid
Number 134889
Funding scheme Project funding (Div. I-III)
Research institution Department of Epidemiology and Public Health Swiss Tropical and Public Health Institute Universität Basel
Institution of higher education University of Basel - BS
Main discipline Infectious Diseases
Start/End 01.04.2011 - 30.04.2015
Approved amount 375'000.00
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All Disciplines (2)

Discipline
Infectious Diseases
Methods of Epidemiology and Preventive Medicine

Keywords (8)

malaria; molecular epidemiology; interventions ; genotyping ; molecular monitoring; gametocytes; transmission; infection dynamics

Lay Summary (English)

Lead
Lay summary

Molecular tools for monitoring the impact of

intensified malaria control on malaria epidemiology

 

Since an unsuccessful attempt by the World Health Organization in the late 1950s to eradicate malaria globally, malaria research and public health efforts focused primarily on reducing morbidity and mortality. Due to the substantial impact of the burden of malaria on the economic and social development of many countries, malaria control efforts have been intensified over the past decade. After demonstrating the efficacy of several anti-malarial intervention programs, a recent expert view suggested to initiate a massive roll out of the currently available malaria control measures. Malaria elimination is considered again to be accomplishable.

 

has led to renewed interest in field-based malaria research. As a result of scaling up usage of insecticide-treated bed nets, through improved diagnosis with rapid simple tests facilitating early treatment with new effective, This recent paradigm shift from malaria control to elimination malaria transmission is expected to decrease.  Such effects on transmission are difficult to quantify. One possibility is monitoring the prevalence of the parasite’s transmission stages, the gametocytes, in human blood samples. In the past gametocytemia has been largely underestimated by microscopy detection. More precise estimates, also applied in this project, are obtained by molecular detection of gene expression specific for gametocytes.

 

In Papua New Guinea (PNG species prevail. Malaria control aiming at elimination is likely to cause changes Plasmodium) all four human species. Interactions among multi-clonal co-infections of all four species can be monitored over time by investigating their infection dynamics and persistence in a longitudinal study conducted among naturally infected individuals from a malaria endemic area.  The survival of individual infections is tracked by genotyping all multiple co-infecting parasite clones using Plasmodium in the relationship between these sympatric highly polymorphic genotyping markers. This permits a precise estimation of the force of infection despite concurrent ongoing infections. We have recently shown that molecular determined force of infection is a highly suitable novel parameter explaining malaria incidence and variability in exposure.

 

This project undertakes research and development paralleling the upcoming control programs and public health activities in PNG by providing tools for monitoring the impact of intensified interventions on malaria epidemiology. Effects of control measures will be quantified by molecular parameters in a comparative analysis of cohort data gathered pre- and post-intervention. Additional investigations will clarify whether renders them differentially susceptible to control measures. B speciesPlasmodiumthe biological differences between the 4 sympatric co-infectionsPlasmodiumasic knowledge will be gained on the epidemiology of transmission stages and transmission biology of multiple species and multiple-clone This project will make use of archived blood samples from field surveys in exposed populations conducted in 2009-2010 (i.e. before start of up-scaled massive anti-malarial interventions in late 2010) and from comparable studies which we will conducted in 2012/13 (i.e. 2 years after start of anti-malarial interventions).

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Critical Evaluation of Molecular Monitoring in Malaria Drug Efficacy Trials and Pitfalls of Length-Polymorphic Markers
Messerli Camilla, Hofmann Natalie E., Beck Hans-Peter, Felger Ingrid (2016), Critical Evaluation of Molecular Monitoring in Malaria Drug Efficacy Trials and Pitfalls of Length-Polymorphic Markers, in Antimicrobial Agents and Chemotherapy, 61(1), e01500-16-e01500-16.
Sensitive and accurate quantification of human malaria parasites using droplet digital PCR (ddPCR).
Koepfli Cristian, Nguitragool Wang, Hofmann Natalie E, Robinson Leanne J, Ome-Kaius Maria, Sattabongkot Jetsumon, Felger Ingrid, Mueller Ivo (2016), Sensitive and accurate quantification of human malaria parasites using droplet digital PCR (ddPCR)., in Scientific reports, 6, 39183-39183.
Blood-Stage Parasitaemia and Age Determine Plasmodium falciparum and P. vivax Gametocytaemia in Papua New Guinea.
Koepfli Cristian, Robinson Leanne J, Rarau Patricia, Salib Mary, Sambale Naomi, Wampfler Rahel, Betuela Inoni, Nuitragool Wang, Barry Alyssa E, Siba Peter, Felger Ingrid, Mueller Ivo (2015), Blood-Stage Parasitaemia and Age Determine Plasmodium falciparum and P. vivax Gametocytaemia in Papua New Guinea., in PloS one, 10(5), 0126747-0126747.
Blood-Stage Parasitaemia and Age Determine Plasmodium falciparum and P. vivax Gametocytaemia in Papua New Guinea.
Koepfli Cristian, Robinson Leanne J, Rarau Patricia, Salib Mary, Sambale Naomi, Wampfler Rahel, Betuela Inoni, Nuitragool Wang, Barry Alyssa E, Siba Peter, Felger Ingrid, Mueller Ivo (2015), Blood-Stage Parasitaemia and Age Determine Plasmodium falciparum and P. vivax Gametocytaemia in Papua New Guinea., in PloS one, 10(5), 0126747-0126747.
Plasmodium vivax Diversity and Population Structure across Four Continents.
Koepfli Cristian, Rodrigues Priscila T, Antao Tiago, Orjuela-Sánchez Pamela, Van den Eede Peter, Gamboa Dionicia, van Hong Nguyen, Bendezu Jorge, Erhart Annette, Barnadas Céline, Ratsimbasoa Arsène, Menard Didier, Severini Carlo, Menegon Michela, Nour Bakri Y M, Karunaweera Nadira, Mueller Ivo, Ferreira Marcelo U, Felger Ingrid (2015), Plasmodium vivax Diversity and Population Structure across Four Continents., in PLoS neglected tropical diseases, 9(6), 0003872-0003872.
Plasmodium vivax populations are more genetically diverse and less structured than sympatric Plasmodium falciparum populations.
Jennison Charlie, Arnott Alicia, Tessier Natacha, Tavul Livingstone, Koepfli Cristian, Felger Ingrid, Siba Peter M, Reeder John C, Bahlo Melanie, Mueller Ivo, Barry Alyssa E (2015), Plasmodium vivax populations are more genetically diverse and less structured than sympatric Plasmodium falciparum populations., in PLoS neglected tropical diseases, 9(4), 0003634-0003634.
Strategies for understanding and reducing the Plasmodium vivax and Plasmodium ovale hypnozoite reservoir in Papua New Guinean children: a randomised placebo-controlled trial and mathematical model.
Robinson Leanne J, Wampfler Rahel, Betuela Inoni, Karl Stephan, White Michael T, Li Wai Suen Connie S N, Hofmann Natalie E, Kinboro Benson, Waltmann Andreea, Brewster Jessica, Lorry Lina, Tarongka Nandao, Samol Lornah, Silkey Mariabeth, Bassat Quique, Siba Peter M, Schofield Louis, Felger Ingrid, Mueller Ivo (2015), Strategies for understanding and reducing the Plasmodium vivax and Plasmodium ovale hypnozoite reservoir in Papua New Guinean children: a randomised placebo-controlled trial and mathematical model., in PLoS medicine, 12(10), 1001891-1001891.
Ultra-sensitive detection of Plasmodium falciparum by amplification of multi-copy subtelomeric targets.
Hofmann Natalie, Mwingira Felista, Shekalaghe Seif, Robinson Leanne J, Mueller Ivo, Felger Ingrid (2015), Ultra-sensitive detection of Plasmodium falciparum by amplification of multi-copy subtelomeric targets., in PLoS medicine, 12(3), 1001788-1001788.
Asymptomatic malaria infections: detectability, transmissibility and public health relevance.
Bousema Teun, Okell Lucy, Felger Ingrid, Drakeley Chris (2014), Asymptomatic malaria infections: detectability, transmissibility and public health relevance., in Nature reviews. Microbiology, 12(12), 833-40.
Novel genotyping tools for investigating transmission dynamics of Plasmodium falciparum.
Wampfler Rahel, Timinao Lincoln, Beck Hans-Peter, Soulama Issiaka, Tiono Alfred B, Siba Peter, Mueller Ivo, Felger Ingrid (2014), Novel genotyping tools for investigating transmission dynamics of Plasmodium falciparum., in The Journal of infectious diseases, 210(8), 1188-97.
A high force of plasmodium vivax blood-stage infection drives the rapid acquisition of immunity in papua new guinean children.
Koepfli Cristian, Colborn Kathryn L, Kiniboro Benson, Lin Enmoore, Speed Terence P, Siba Peter M, Felger Ingrid, Mueller Ivo (2013), A high force of plasmodium vivax blood-stage infection drives the rapid acquisition of immunity in papua new guinean children., in PLoS neglected tropical diseases, 7(9), 2403-2403.
Strategies for detection of Plasmodium species gametocytes.
Wampfler Rahel, Mwingira Felistas, Javati Sarah, Robinson Leanne, Betuela Inoni, Siba Peter, Beck Hans-Peter, Mueller Ivo, Felger Ingrid (2013), Strategies for detection of Plasmodium species gametocytes., in PloS one, 8(9), 76316-76316.
The Force of Infection is key to understanding the epidemiology of Plasmodium falciparum malaria in Papua New Guinean children
Mueller Ivo, Schoepflin Sonja, Thomas Smith, Benton Kathryn, Bretscher Michael, Lin Enmoore, Kiniboro Benson, Zimmerman Peter, Speed Terence, Felger Ingrid (2012), The Force of Infection is key to understanding the epidemiology of Plasmodium falciparum malaria in Papua New Guinean children, in Proceedings of the National Academy of Sciences of the United States of America, 109(25), 10030-10035.
A large Plasmodium vivax reservoir and little population structure in the South Pacific
Koepfli Cristian, Timinao Lincoln, Antao Tiago, Barry Alyssa E., Siba Peter, Mueller Ivo, Felger Ingrid, A large Plasmodium vivax reservoir and little population structure in the South Pacific, in PLoS ONE.

Collaboration

Group / person Country
Types of collaboration
Papua New Guinea Institute of Medical Research PapuaNew Guinea (Oceania)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Walter and Eliza Hall Institute Australia (Oceania)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
American Society of Tropical Medicine and Hygiene Talk given at a conference Symposium Assessing the human infectious reservoir of malaria 25.10.2014 New Orleans, United States of America Felger Ingrid; Hofmann Natalie; Silkey Mariabeth; Amstutz-Wampfler Rahel; Müller Ivo;
American Society of Tropical Medicine and Hygiene Talk given at a conference Symposium Population Genetic Strategies to Address Field-Relevant Malaria Questions 25.10.2014 New Orleans, United States of America Felger Ingrid; Müller Ivo;
Conference "Challenges in Malaria Research Conference: Core science and innovation" Talk given at a conference DYNAMICS OF P. VIVAX CLONES IN A COHORT OF CHILDREN WITH OR WITHOUT PRIMAQUINE TREATMENT AT BASELINE 22.09.2014 Oxford, Great Britain and Northern Ireland Müller Ivo; Silkey Mariabeth; Hofmann Natalie; Felger Ingrid; Amstutz-Wampfler Rahel;
10th Annual BioMalPar I EVIMalaR Conference and EVIMalaR Symposium Poster Ultrasensitive detection of Plasmodium falciparum by amplification of multi-copy telomeric targets using quantitative PCR 12.05.2014 Heidelberg, Germany Amstutz-Wampfler Rahel; Felger Ingrid; Hofmann Natalie; Müller Ivo;
Meeting of the American Society of Tropical Medicine and Hygiene Poster Highly sensitive RNA-based parallel detection of Plasmodium falciparum and P. vivax asexual stages and gametocytes 13.11.2013 Washington, United States of America Amstutz-Wampfler Rahel; Felger Ingrid; Müller Ivo;
Advances in Plasmodium vivax Malaria Research Poster IMPROVING THE MOLECULAR DETECTION OF PLASMODIUM VIVAX: DNA- VERSUS RNA-BASED DETECTION OF BLOOD STAGES IN COMBINATION WITH GAMETOCYTES 29.05.2013 Barcelona, Spain Felger Ingrid; Amstutz-Wampfler Rahel; Müller Ivo;
Advances in Plasmodium vivax Malaria Research Poster MOLECULAR EPIDEMIOLOGY OF PLASMODIUM VIVAX IN THE WORLD’S HIGHEST TRANSMISSION SETTING 29.05.2013 Barcelona, Spain Amstutz-Wampfler Rahel; Felger Ingrid; Müller Ivo;
9th Annual BioMalPar I EVIMalaR Conference Talk given at a conference Molecular tools for monitoring transmission dynamics of Plasmodium falciparum 13.05.2013 EMBL Heidelberg, Germany, Germany Müller Ivo; Amstutz-Wampfler Rahel; Hofmann Natalie; Felger Ingrid;
10th Malaria Meeting of Paul Ehrlich Society Talk given at a conference Detection of P. falciparum and P. vivax gametocytes in field surveys 09.11.2012 Marburg, Germany, Germany Amstutz-Wampfler Rahel;
Challenges in Malaria Research: Progress Towards Elimination Talk given at a conference Measuring Force of Infection and vaccine effects on transmission stages in clinical trials of experimental malaria vaccines 10.10.2012 Basel, Switzerland, Switzerland Felger Ingrid;
Challenges in Malaria Research: Progress Towards Elimination Poster Multiplicity and Diversity of Plasmodium falciparum Gametocytes 10.10.2012 Basel, Switzerland Amstutz-Wampfler Rahel; Müller Ivo; Felger Ingrid;
60th Annual Meeting of the American Society of Tropical Medicine & Hygiene (ASTMH), December 4 - 8, 2011 in Talk given at a conference The Force of Infection: The key to understanding the epidemiology of Plasmodium falciparum malaria in Papua New Guinean children 04.12.2011 Philadelphia, USA, United States of America Felger Ingrid; Müller Ivo;
7th European Congress on Tropical Medicine and International Health Poster Plasmodium vivax in Papua New Guinea: molecular epidemiology in a population were four malaria species are endemic 03.10.2011 Barcelona, Spain, Spain Amstutz-Wampfler Rahel; Felger Ingrid; Müller Ivo;


Knowledge transfer events



Self-organised

Title Date Place
Plasmodium transmission dynamics 02.05.2014 Madang, PapuaNew Guinea
Establishment of External Quality Control for molecular Plasmodium sp. diagnostics; genotyping strategies 01.07.2013 Madang , PapuaNew Guinea

Associated projects

Number Title Start Funding scheme
59380 Dynamics of malaria parasites in areas of high transmission 01.09.2000 Project funding (Div. I-III)
164182 Addressing the challenges of declining malaria transmission in the Amazon on the way to elimination: non-malarial fevers and low parasitaemias 01.05.2016 Bilateral programmes
159580 Epidemiology of ultra-low density malaria infections and their relevance for control and elimination 01.05.2015 Project funding (Div. I-III)
112196 Fitness costs of antimalarial drug resistance 01.05.2006 Project funding (Div. I-III)

Abstract

1. Summary of the research plan Background: The recent paradigm shift from malaria control to malaria elimination has led to renewed interest in field-based malaria research. As a result of roll out of intensified control by combined and sustained interventions, malaria transmission is expected to change. However, effects on transmission are difficult to quantify. The only Plasmodium stages transmittable to mosquitoes are gametocytes, but gametocytemia has been largely underestimated previously by light microscopy. Molecular typing of genes expressed only in gametocytes can provide more precise estimates. In Papua New Guinea (PNG) all four human Plasmodium species prevail. Malaria control aiming at elimination is likely to cause changes in the relationship between the sympatric Plasmodium species. Interactions among multi-clonal co-infections of any species can be monitored over time in a longitudinal cohort. Survival of individual infections is tracked by genotyping each parasite clone using highly polymorphic markers. This permits a precise estimation of the force of infection despite concurrent ongoing infections, thus providing a novel molecular parameter. Here we propose a research agenda paralleling these upcoming control programs and public health activities in PNG. Our research will address key gaps in our knowledge and will provide tools for monitoring the effects of control measures on malaria epidemiology. Aims: This proposal aims at quantifying the impact of intensified interventions by using novel molecular parameters. In addition, we will investigate whether the biological differences between the 4 sympatric Plasmodium species renders them differentially susceptible to control measures. Hypotheses tested: (i) Infection dynamics (rate at which individual infections are gained or lost) is modified as a result of successful interventions.(ii) Progress in successful control is reflected in a greater reduction in force of infection in P. falciparum compared to P. vivax, leading to a relative increase in P. vivax prevalence.(iii) Reduction in prevalence and incidence in turn leads to a more pronounced reduction in prevalence of P. falciparum gametocytes compared to P. vivax gametocytes.(iv) Changes observed in P. vivax differ from those in P. falciparum due to the ability of P. vivax to form long-lasting dormant liver stages.Approach: We will use archived samples from field surveys conducted in 2009-2010 (i.e. before start of up-scaled massive anti-malarial interventions in late 2010) and from comparable studies which we will conducted in 2012/13 (i.e. 2 years after start of anti-malarial interventions). The novelty compared to previous field studies consists in dedicated sampling procedures permitting RNA extractions. We will design and evaluate precise and robust tools for investigating density and diversity of gametocytes of three Plasmodium species in the study area by quantitative reverse transcription PCR or by capillary electrophoresis based genotyping of size polymorphic genes expressed in sexual stages. In addition we will genotype all blood stage infections in cohort samples. The longitudinal design of our field work permits to identify each incoming parasite clone and investigate the duration and interaction with concurrent parasite infections of the same or different Plasmodium species as well as an in-depth evaluation of the (temporal) relationship between presence, density and genetic complexity of sexual stages of P. falciparum and P. vivax. Expected outcomes(i) Basic knowledge on the differential effects of intensified malaria control on the incidence, complexity and dynamics of infection of P. falciparum and P. vivax (ii) Basic knowledge on the epidemiology of transmission stages and transmission biology of multiple species and multiple-clone Plasmodium co-infections. (iii) Novel tools and molecular parameters will be made available for monitoring differential effects of control interventions on sympatric Plasmodium species.
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