Periodic Reporting for period 4 - COSMIC (Commitment, maturation and infectivity of sexual stage malaria parasites in natural infections) Berichtszeitraum: 2020-01-01 bis 2020-06-30 Zusammenfassung vom Kontext und den Gesamtzielen des Projekts 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. Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse 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. We analysed samples from previously completed controlled human malaria infections (CHMI) for the presence of mature gametocytes by molecular methods. In a CHMI study that was specifically designed to induce gametocytes using subcurative doses of sulphadoxine-pyrimethamine and piperaquine , we successfully induced gametocytes in all volunteers who were inoculated by malaria-infected mosquito bites. Infectious male and female gametocytes were observed in a subset of volunteers. The first appearance of male and female gametocytes (8.5-12 days after the first asexual parasites), indicates that gametocyte commitment appears very early in infections, during the first wave of asexual parasites.Objective 2: To determine commitment and maturation of gametocytes in natural infectionsUnder this objective we analyzed gametocyte prevalence, density and infectivity in populations of clinical malaria patients and asymptomatically infected individuals. In settings across Africa, we observed a very modest contribution of clinical malaria patients to mosquito infections compared to asymptomatic infections. To examine the timing of gametocyte production and infectivity in relation to the time since infection and time of occurrence of symptoms, we designed a cohort study in Burkina Faso to directly compare incident and chronic infections in partially immune children where we prospectively monitored acute and chronic infections to study the dynamics of gametocyte commitment, maturation, sex-ratio and infectivity. We observed higher gametocyte production and infectivity in chronic infections as compared to acute, incident infections. Objective 3: To quantify ongoing gametocyte production and release from the bone marrow following antimalarial treatmentUnder 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 observed that conventional antimalarials have differential effect on gametocyte development and clearance. In trials in Burkina Faso and Mali, we demonstrated the potency of the gametocytocidal drugs primaquine and methylene blue in reducing gametocyte circulation times and preventing malaria transmission to mosquitoes. Next, we determined submicroscopic parasite persistence in three clinical trials conducted in Uganda, Burkina Faso and Mali. These trials provided evidence for our hypothesis that low densities of ring-stage parasites may survive treatment and that this ring-stage survival depends on the schizonticidal drug given. Objective 4: To study clustering and infectivity of mature gametocytes in the subdermal vasculatureUnder 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. Skin biopsy samples and venous and finger-prick blood samples were collected repeatedly and processed for immunohistochemistry and molecular parasite detection. In a separate study, a comparison of mosquito infection rates by direct skin feeding and membrane feeding was performed in adult gametocyte carriers using laboratory reared An. coluzzii mosquitoes. We observed no significant clustering of gametocytes in skin tissue. Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts) 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 and contributed to the design of a new project on P.falciparum infection dynamics and transmission to inform elimination (INDIE) that was awarded in August 2017. In October 2017, a meeting on the importance of low-density infections for malaria elimination was organized at the World Health Organization in Geneva. The necessity to understand malaria transmission dynamics in settings of different malaria transmission intensities is receiving increasing interest, both by malaria policy makers and researchers. The COSMIC project has played a relevant role in stimulating this research, as well as making relevant tools available to study gametocyte dynamics, sex ratio and infectivity. 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 in 2017. 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. In 2017, the applicant also received the Eijkman Medal for contributions to research in Tropical Medicine and, in 2019, the KNAW-AMMODO award for basic research.