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COSMIC Report Summary

Project ID: 639776
Funded under: H2020-EU.1.1.

Periodic Reporting for period 1 - COSMIC (Commitment, maturation and infectivity of sexual stage malaria parasites in natural infections)

Reporting period: 2015-07-01 to 2016-12-31

Summary of the context and overall objectives of the project

The burden of malaria has declined considerably in recent years as a consequence of wide-scale use of insecticide treated bednets and improved access to malaria diagnosis and treatment . Despite this positive trend, recent gains are threatened by the emergence of insecticide and antimalarial resistance. Moreover, malaria elimination is unlikely to be achieved with the currently available tools. Both resistance containment and elimination initiatives require a thorough understanding of how malaria spreads in communities. Malaria-transmitting mosquitoes become infected with malaria after biting humans that carry malaria transmission stages, gametocytes. It is currently unclear when gametocytes first arise during infections and when individuals are first infectious to mosquitoes. The COSMIC project determines gametocyte commitment, maturation and infectivity in experimental and natural malaria infections. During field activities in Mali, Burkina Faso and Uganda, the contribution of different populations to malaria transmission is determined and a long-standing hypothesis of gametocyte sequestration in skin tissue is addressed. Specific objectives are to i) determine gametocyte commitment and maturation after controlled human malaria infections ; ii) determine commitment and maturation of gametocytes in natural infections; iii) quantify ongoing gametocyte production and release from the bone marrow following antimalarial treatment; iv) study clustering and infectivity of mature gametocytes in the subdermal vasculature. The COSMIC project will thus contribute to our understanding of the epidemiology of malaria and support evidence-based interventions to reduce and ultimately prevent the spread of malaria in communities.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Objective 1: To determine gametocyte commitment and maturation after controlled human malaria infections (CHMI)
Under this objective, we aimed to provide the first conclusive evidence on gametocyte commitment and maturation during the first rounds of parasite multiplication in primary infections. In the current reporting period, we analysed RNA samples from previously completed controlled human malaria infections (CHMI) for the presence of mature gametocytes by Pfs25 mRNA quantitative reverse-transcriptase PCR (qRT-PCR). In CHMI experiments that treated infections early with artemisinin-combination therapy (ACT), we observed no gametocyte maturation. We subsequently designed a CHMI model for gametocyte induction using subcurative doses of sulphadoxine-pyrimethamine and piperaquine ( NCT02836002). The CHMI trial for gametocyte-induction is currently ongoing and has gametocyte densities and sex-ratio as endpoints .

Objective 2: To determine commitment and maturation of gametocytes in natural infections
Under this objective we proposed to recruit cohorts of children and adults to study the dynamics of natural malaria infections in relation to gametocyte commitment, maturation and infectivity. In 2015 and 2016 we conducted a field study in two phases in Burkina Faso. We monitored acute and chronic infections in children aged 5-10 years for gametocyte production, sex-ratio and infectivity by membrane feeding assays.

Objective 3: To quantify ongoing gametocyte production and release from the bone marrow following antimalarial treatment
Under this objective, we aimed to assess in detail the dynamics of gametocyte decay and production following antimalarial treatment. We hypothesized that low levels of asexual parasites persist after apparently successful antimalarial treatment and may give rise to gametocyte production. We further hypothesized that antimalarial drugs will differ in their activity against asexual stage parasites, developing gametocytes and mature gametocytes. In the first of the COSMIC activities under this objective, we conducted a large pooled analysis on the effect of ACTs on gametocyte dynamics, using individual patient level data, revealing that ACTs have differential effect on gametocyte development and clearance. We further determined submicroscopic parasite persistence in two clinical trials conducted in Uganda and Burkina Faso. Both trials used a potent artemisinin-combination therapy alone or in combination with the gametocytocidal drug primaquine. We demonstrated that primaquine reduces gametocyte carriage in a dose-dependent and provided evidence for our hypothesis that low densities of ring-stage parasites survive treatment. Ring-stage specific mRNA persisted in a fraction of individuals until day 14 after treatment. The duration of follow-up of these two trials was too short to allow an assessment of the consequences of persisting ring-stage RNA for the individual patient (in terms of recrudescent infections) or the population (in terms of gametocyte production or infectivity)
We subsequently conducted a clinical trial with mosquito feeding endpoints (NCT02831023) and a 42-day follow-up period. The fieldwork for this trial was completed in 2016. Gametocyte sex-ratio in relation to mosquito infection rates will be a key outcome measure of this trial, together with longitudinal assessments of asexual parasite carriage following treatment in relation to later treatment failure or gametocyte production.

Objective 4: To study clustering and infectivity of mature gametocytes in the subdermal vasculature
Under this objective, we proposed to test a long-standing hypothesis on subdermal clustering of mature gametocytes as contributor to the apparent transmission success of P. falciparum. Recruitment of adult gametocyte carriers started in 2016. Skin biopsy samples and venous and finger-prick blood samples were collected repeatedly and processed for immunohistochemistry and molecular paras

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The findings from the COSMIC project have immediate relevance for malaria control and elimination strategies. The World Health Organization and the Gates Foundation are two parties that play important roles in implementing and funding malaria elimination research and public health interventions. Preliminary results of the COSMIC project were presented at a strategic meeting of the Bill & Melinda Gates Foundation on understanding the infectious reservoir for malaria. In May 2017, a meeting on the importance of low-density infections for malaria elimination will be organized at the World Health Organization in Geneva. The applicant is one of the organizers of this meeting and will present preliminary results of the COSMIC study to policy makers.
In addition to immediate health policy consequences, malaria research offers a viable opportunity to raise awareness about the necessity of and fascination for infectious disease research. The applicant was shortlisted as New Scientist Talent 2015 for The Netherlands and Belgium. This event generated media attention for malaria in general and malaria transmission research in particular. The applicant was further awarded the Radboud Science Award. As part of this award, a program was developed for primary schools (10-12 year old pupils) that uses COSMIC findings on the transmission of infectious diseases as an example to stimulate classroom scientific projects.
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