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Epidemiology of ultra-low density malaria infections and their relevance for control and elimination

English title Epidemiology of ultra-low density malaria infections and their relevance for control and elimination
Applicant Felger Ingrid
Number 159580
Funding scheme Project funding (Div. I-III)
Research institution Abt. öff. Gesundheitswesen und Epidemiologie Schweizerisches Tropen- und Public Health-Institut
Institution of higher education University of Basel - BS
Main discipline Infectious Diseases
Start/End 01.05.2015 - 30.04.2019
Approved amount 491'486.00
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All Disciplines (2)

Discipline
Infectious Diseases
Methods of Epidemiology and Preventive Medicine

Keywords (9)

interventions ; malaria; reservoir of infection; genotyping ; gametocytes; molecular epidemiology; molecular monitoring; malaria elimination; infection dynamics

Lay Summary (German)

Lead
Neue molekularbiologische Techniken ermöglichen den Nachweis von Malaria-Parasiten auch noch in Blutproben von Menschen, die nur mit sehr wenigen Parasiten infiziert sind. Als Folge von weltweiter und seit einigen Jahren intensivierter Malaria-Kontrolle wird erwartet, dass der Anteil an symptomfreien Infektionen mit sehr niedriger Parasitendichte in Zukunft im Verhältnis zu symptomatischen Malariafällen weiter zunehmen wird. Daher stellt sich nun die Frage, ob diese extrem niedrigen Parasiteninfektionen für die Übertragung auf Anopheles Moskitos überhaupt eine Rolle spielen? Das Forschungsprojekt hat zum Ziel, speziell die epidemiologische Bedeutung von Infektionen mit sehr niedrigen Parasitendichten durch molekular-diagnostische Untersuchungen an Patienten und Moskitos aufzuklären.
Lay summary

In der bisherigen Diagnostik von Plasmodium Parasiten konnten bei Malaria-Feldstudien vor allem Infektionen mit geringer Parasitendichte nur unzureichend nachgewiesen werden. Nun zeigte der Einsatz von molekularbiologischen Methoden, dass der bisherige mikroskopische Nachweis nur die Spitze eines Eisbergs diagnostizierte. Niedrige Parasitenzahlen kommen sehr häufig bei symptomfreien Plasmodium-infizierten Erwachsenen aus Malariagebieten vor. Sie bleiben meist unbemerkt und werden daher auch nicht behandelt. Nun  stellt sich die Frage, inwiefern diese Infektionen überhaupt für die weitere Übertragung von Bedeutung sind? Wenn ja, dann müssten auch gering infizierte Parasitenträger behandelt werden, um die Ausrottung dieser Infektionskrankheit zu erreichen. 

Aktuelle Forschungsergebnisse  haben gezeigt, dass mit fortschreitendem  Zurückdrängen der Malaria in vielen Ländern die  Malariaparasiten immer weniger in symptomatischen Infektionen  vorliegen, sondern über Monate in asymptomatischen Trägern existieren können.  Methoden, die auch kleinste Parasitenmengen noch zuverlässig detektieren können, werden daher dringend benötigt und könnten entscheidende Einsichten zur Planung und Überwachung von Malaria-Kontrollprogrammen beitragen.

Im Rahmen dieses Forschungsprojekts werden hochsensitive, molekulare Nachweismethoden für Malariaparasiten entwickelt. Zudem wird untersucht, ob derart geringe Infektionen für Anopheles Moskitos überhaupt infektiös sind und ob sie für die Transmission relevant sind. Die Forschungsergebnisse sollen die Frage klären, welche Diagnose- und Behandlungsstrategien für Malaria-Eliminierungs-Progamme gewählt werden sollten.

Direct link to Lay Summary Last update: 21.04.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Longitudinal tracking and quantification of individual Plasmodium falciparum clones in complex infections
Lerch Anita, Koepfli Cristian, Hofmann Natalie E., Kattenberg Johanna H., Rosanas-Urgell Anna, Betuela Inoni, Mueller Ivo, Felger Ingrid (2019), Longitudinal tracking and quantification of individual Plasmodium falciparum clones in complex infections, in Scientific Reports, 9(1), 3333-3333.
Plasmodium vivax molecular diagnostics in community surveys: pitfalls and solutions
Gruenberg Maria, Moniz Clara Antunes, Hofmann Natalie Ellen, Wampfler Rahel, Koepfli Cristian, Mueller Ivo, Monteiro Wuelton Marcelo, Lacerda Marcus, de Melo Gisely Cardoso, Kuehn Andrea, Siqueira Andre M., Felger Ingrid (2018), Plasmodium vivax molecular diagnostics in community surveys: pitfalls and solutions, in Malaria Journal, 17(1), 55-55.
Assessment of ultra-sensitive malaria diagnosis versus standard molecular diagnostics for malaria elimination: an in-depth molecular community cross-sectional study
Hofmann Natalie E, Gruenberg Maria, Nate Elma, Ura Alice, Rodriguez-Rodriguez Daniela, Salib Mary, Mueller Ivo, Smith Thomas A, Laman Moses, Robinson Leanne J, Felger Ingrid (2018), Assessment of ultra-sensitive malaria diagnosis versus standard molecular diagnostics for malaria elimination: an in-depth molecular community cross-sectional study, in The Lancet Infectious Diseases, 18(10), 1108-1116.
Development of amplicon deep sequencing markers and data analysis pipeline for genotyping multi-clonal malaria infections
Lerch Anita, Koepfli Cristian, Hofmann Natalie E., Messerli Camilla, Wilcox Stephen, Kattenberg Johanna H., Betuela Inoni, O’Connor Liam, Mueller Ivo, Felger Ingrid (2017), Development of amplicon deep sequencing markers and data analysis pipeline for genotyping multi-clonal malaria infections, in BMC Genomics, 18(1), 864-864.
The complex relationship of exposure to new Plasmodium infections and incidence of clinical malaria in Papua New Guinea
Hofmann Natalie E, Karl Stephan, Wampfler Rahel, Kiniboro Benson, Teliki Albina, Iga Jonah, Waltmann Andreea, Betuela Inoni, Felger Ingrid, Robinson Leanne J, Mueller Ivo (2017), The complex relationship of exposure to new Plasmodium infections and incidence of clinical malaria in Papua New Guinea, in eLife, 6, e23708.

Collaboration

Group / person Country
Types of collaboration
Ifakara Health Institute (IHI), Dar es Salaam Tanzania (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Faculty of Tropical Medicine, Mahidol University, Bangkok Thailand (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
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
- Industry/business/other use-inspired collaboration
Walter and Eliza Hall Institute (WEHI) Melbourne Australia (Oceania)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Fundaçao do Medicine Tropical, Manaus Brazil (South America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
BioMalPar XV: Biology and Pathology of the Malaria Parasite Poster Amplicon deep sequencing improves genotyping in clinical trials of antimalarial drugs 27.05.2019 Heidelberg, Germany Gruenberg Maria;
American Socienty of Tropical Medicine and Hygiene 67th Annual Meeting Talk given at a conference How relevant is ultra-sensitive malaria diagnostics for malaria elimination? 28.10.2018 New Orleans, United States of America Felger Ingrid;
American Socienty of Tropical Medicine and Hygiene 67th Annual Meeting Poster Evaluation of the performance of ultra-sensitive RDT compared to conventional RDT and ultra-sensitive qPCR for the diagnosis of malaria 28.10.2018 New Orleans, United States of America Felger Ingrid;
14th International Congress of Parasitology (ICOPA) Talk given at a conference Innovative diagnostics for deeper understanding of malaria epidemiology and public health applications 19.08.2018 Daegu, Korean Republic (South Korea) Felger Ingrid;
Genomic Epidemiology of Malaria 2018 Individual talk Development of a novel amplicon deep sequencing marker and data analysis pipeline for genotyping of multi-clonal Plasmodium falciparum infections 01.06.2018 Hinxton, Great Britain and Northern Ireland Lerch Anita; Felger Ingrid;
American Socienty of Tropical Medicine and Hygiene 66th Annual Meeting Poster Maximized diagnostic sensitivity reveals unexpected reservoir for malaria transmission 05.11.2017 Baltimore, United States of America Hofmann Natalie; Felger Ingrid;
10th European Congress on Tropical Medicine and International Health Talk given at a conference Raising standards and quality of parasite diagnostics in non-endemic clinical settings using molecular and lateral flow technologies 16.10.2017 Antwerp, Belgium Felger Ingrid;
6th International Conference on Plasmodium vivax Research Talk given at a conference Limitations of nucleic acid amplification tests for diagnosis of P. vivax in community surveys and possible solutions 11.06.2017 Manaos, Brazil Felger Ingrid;
Building on Success – Malaria Control and Elimination Talk given at a conference Diagnostics for Malaria Surveillance 08.12.2016 Basel, Switzerland Felger Ingrid;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved


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)
134889 Molecular tools for monitoring the impact of intensified malaria control on malaria epidemiology 01.04.2011 Project funding (Div. I-III)
112196 Fitness costs of antimalarial drug resistance 01.05.2006 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

Abstract

Plasmodium parasites from symptomatic individuals are relatively easy to diagnose owing to high densities and they usually get cleared by treatment. But most malaria infections even in low endemic areas are asymptomatic and often undetectable by microscopy due to low parasite densities. They remain uncured but may contribute substantially to transmission. Since the recent paradigm shift from malaria control to elimination, major efforts are undertaken worldwide to intensify control and interrupt local transmission of malaria. As in most areas it is not feasible to eliminate the mosquito vector, the road to elimination thus entails identifying and treating all infected individuals irrespective of symptoms. Yet, a major hurdle for successful control is detection of very low density infections. The currently used molecular methods are more sensitive, but still imperfect in detecting ultra-low parasitaemias. The extent of ultra-low density infections represents a major research gap, which we will address in this proposal. Aims: We propose to develop ultra-sensitive methods for detection of Plasmodium falciparum and P. vivax to investigate the magnitude of infections that are not detected by both, microscopy and standard PCR. These new assays will be validated for ultra-sensitive parasite detection in malaria surveillance and monitoring of interventions. A secondary objective is to investigate the contribution of the ultra-low density infections to transmission. The specific objectives are: ¦ To measure the proportion of parasites missed by microscopy and standard PCR in field surveys. ¦ To examine how host age and levels of malaria endemicity influence this proportion. ¦ To determine whether ultra-low density infections carry gametocytes and estimate their contribution to the human reservoir of infection to mosquitoes. ¦ To find ways to increase the sensitivity of parasite detection in large scale field surveys. Approach: Ultra-sensitive nucleic acid based detection methods for P. falciparum and P. vivax will be developed by targeting highly repetitive DNA markers and highly expressed stage-specific transcripts. Ultra-low density infections will be studied in different endemic settings and age groups, For P. vivax we compare PNG (high transmission), Thailand (low transmission) and Brazil (close to elimination), for P. falciparum 4 regions in Tanzania differing in endemicity. Gametocyte detection and genotyping in both species will be used for estimating the transmission potential and trans-mission dynamics. The transcriptome of P. vivax gametocytes will be mined to develop new assays for determination of sex ratios and new highly sensitive assays for genotyping P. vivax gametocytes. Expected outcomes: ¦ Basic epidemiological knowledge on so-far undetectable malaria infections gained from endemic areas world-wide. In the context of malaria elimination this information is a key priority. ¦ Improved sensitivity of malaria diagnosis on population level suitable for surveillance and assessing the impact of interventions and more accurate data for modeling infection dynamics.¦ Demonstrating that ultra-low density infections either do or do not contribute to the infectious reservoir will inform surveillance strategies and treatment policies. Results should assist policy makers in deciding on approaches to malaria control and elimination, i.e. mass treatment campaigns to clear all potential infections versus targeted treatment following diagnostic screening.
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