Controlling and eliminating malaria in Indonesia is a challenging endeavour. Evidence-based strategic plans should be critically formulated to overcome a complex mosaic of infection risk across the 5000-km-long archipelago of thousand islands and distinctive habitats. This project aimed to thoroughly explore the challenges and opportunities for controlling/eliminating malaria and present the application of malaria cartographic tools to allow malaria control agencies and their partners to comprehensively assess the prospects for reaching pre-elimination, monitor and evaluate the effectiveness of future strategies against the baseline generated. First, the historical context of malaria in Indonesia and important methods of control and their impact in the context of the political systems that supported them was comprehensively described. A series of distribution maps of twenty Anopheles malaria vector mosquitoes in Indonesia were also produced, supported by comprehensive reviews of each species’ bionomics and susceptibility to insecticides. Then, the application of malaria cartographic tools for malaria control/elimination in Indonesia was explored. The first high spatial resolution (1 x 1 km) baseline endemicity maps of Plasmodium falciparum and P. vivax malaria were generated, together with corresponding estimates of population at risk and clinical burdens of each species in 2010. Low malaria prevalences of these parasites were predicted in western areas, with high prevalences in eastern Indonesia. Over 132 million people in Indonesia lived at risk of P. falciparum transmission with 70% of them in areas of unstable transmission and 30% in stable transmission. There were an estimated 7.7 million P. falciparum clinical cases across the populations at risk. Meanwhile, nearly 130 million people lived at risk of P. vivax malaria with 79% living in unstable and 21% in stable transmission areas. This infection caused 1.5 million estimated clinical cases in 2010. Both estimates were 30-fold and 6-fold higher than routinely reported numbers, respectively. Finally, this project revealed the substantial multi-faced problems that impede current efforts towards the pre-elimination agenda. High rates of undiagnosed clinical cases, insufficient competence of malaria microscopy, inadequate primaquine dosing against P. vivax malaria infections, insufficient evidence of vector control interventions, wide diversities of vector mosquitoes and their bionomics, mosquito resistance against insecticides and inadequate malaria surveillance systems are challenging the task of controlling and eliminating malaria. A diverse range of strategies enabling locally-specific approaches must be implemented for controlling and eliminating malaria in Indonesia. Strategic recommendations are listed and future research priorities are proposed for further study.

Malaria is a disease that causes great burden in public health worldwide. It was estimated that in 2011 there were 3.3 billion people at risk of acquiring malaria. According to data from the Ministry of Public Health of Ecuador, malaria incidence has shown a 99.9% steady decrease since year 2000. This study evaluated the effect of timely treatment on circulating gametocyte and malaria incidence rates. All cases reported in the province of Esmeraldas, Ecuador from July 2012 to March 2015 and to the national headquarters between February 2012 and December 2014 were studied. The effect of early treatment on: 1) follow-up gametocytemia at an individual level (cases reported in Esmeraldas); and, 2) incidence rates at a population level (within Esmeraldas and within Ecuador) was evaluated using a retrospective cohort and an ecologic study design, respectively. A total of 193 cases from the province of Esmeraldas were included in the retrospective cohort study. Patients were classified into three groups depending on time to treatment (i.e. how many days elapsed from symptoms onset to treatment) as follows: 1) early treatment for those treated within 2 days; 2) late treatment for those treated between 3 to 7 days; and, 3) extremely late for those receiving treatment after 7 days. A consistent association between time to treatment and follow-up gametocytemia was found in different regression models including logistic (adjusted OR = 0.20 and 0.28 for early and late treatment, respectively, p < 0.05), linear (parameter estimate = 0.018, p < 0.05) Poisson log linear (parameter estimate 0.103, p < 0.05), and negative binomial (parameter estimate = 0.111, p < 0.05). Extremely late patients had higher follow-up gametocytemia levels during follow-up visits 1 and 2. A survival analysis showed that extremely late treated patients tend to clear gametocytes later than the other two treatment arms (p > 0.05). Finally, there was a positive association between time to treatment and a period of transmisibiltiy, which was estimated based on the potential number of days that a patient has gametocytemia (p < 0.05). Population-level associations between time to treatment and malaria incidence rates were assessed through a two-tiered ecologic study: nationwide for Ecuador and provincewide for Esmeraldas.. A parish-level anlaysis of malaria among all parishes in the province of Esmeraldas revealed that malaria transmission differs widely within each population-level treatment arm classification group. A repeated measures negative binomial regression showed that there is a positive association between malaria incidence rate in subsequent periods and mean time to treatment, follow-up gametocytemia and a negative association with malaria incidence rate in the previous period (p < 0.05 for all associations). The nationwide analysis confirmed that there is wide variation in malaria incidence rate within each population-level treatment arm classification group. Although the World Health Organization (WHO) recommends timely malaria treatment there seems to be lack of peer-reviewed published evidence evaluating the association of time to malaria treatment with follow-up gametocytemia and incidence rates, especially in Latin America. This study has important public health implications. Firstly, there seems to be no clear definition for early malaria treatment. In this study, consistent evidence of the association between time to treatment and, specifically, early malaria treatment (i.e. malaria within 2 days of symptoms onset) with follow-up gametocytemia and period of transmissibliity is provided. Evidence provided here can serve as a basis for future research in other countreis facing similar conditions. Additionally, this information can serve to better inform public health policy, especially regarding the definition of early treatment and, thus, setting goals to accomplish early treatment among malaria infected patients. Noteworthy, Esmeraldas and Ecuador face significant challenges not only to achieve but to maintain malaria elimination, if achieved. These challenges arise from favorable local environmental conditions and to certain vulnerabilities like proximity to neibhoring areas with high malaria incidence, susceptibility to receive migration, specially refugees fleeing armed conflict, socio-economic disadvantages and remoteness of some parishes were malaria remains active. Moreover, the integration of the current national malaria control program into the organizational strucutre of the Ministry of Health may impose additional challenges like: 1) differential prioritization of other diseases, 2) lack of clear guidance about the role of the current malaria-dedicated personnel in the MoH strucutre; and, 3) lack of specification about on whom would accountability for malaria control rely. All these vulnerabilities should be properly addressed if malaria elimination is to be achieved in Ecuador. Finally, further research is required to confirm whether these trends and association are replicable across different populations, countries and continents. If these associations are similar or even stronger in other populations, then better malaria control programs informed in evidence-based definition of early malaria treatment could certainly be planned and implemented to achieve malaria elimination and control in other regions of the world.

Le paludisme a déjà sévi dans 80% des pays chinois. Après plusieurs décennies d’efforts, la prévalence du paludisme a considérablement diminué et la Chine est sur le point de l’éliminer dans tout le pays. Les informations sur les vecteurs du paludisme ne sont toujours pas bien documentées, ce qui pourrait entraver l'élaboration de stratégies de surveillance appropriées et la certification par l'OMS. Le principal risque pour l'élimination du paludisme est la réintroduction de la maladie à partir de cas de paludisme importés. De plus en plus de cas de paludisme importés sont causés par des citoyens chinois revenant récemment de pays touchés par le paludisme. Les informations sur leurs personnages, leurs conducteurs et leur voie d’introduction dans différentes zones fourniront aux décideurs politiques des données factuelles où et quand effectuer les interventions. Avec plus de 1,3 milliard d’habitants et un territoire couvrant différentes zones climatiques, les enseignements tirés de l’élimination du paludisme en Chine pourraient servir de référence à d’autres pays. Selon les initiatives Belt and Road, la Chine participera plus globalement aux activités liées à la gouvernance. Les partenaires et les parties prenantes de la campagne mondiale pour l’élimination du paludisme s'intéressent aux opportunités futures et aux domaines potentiels qui impliqueraient une expertise chinoise. 1.Une analyse récapitulative a été réalisée sur la distribution à l'échelle nationale des vecteurs du paludisme, leurs caractéristiques bionomiques, leurs mesures de contrôle et les études connexes. La distribution en Chine des principaux vecteurs du paludisme a été réduite. Anopheles sinensis, qui avait déjà été signalé comme étant moins efficace dans la transmission du paludisme, est en train de devenir l’espèce prédominante dans le sud-ouest de la Chine. Les résultats de l'échantillonnage sur le terrain ont indiqué l'existence de vecteurs du paludisme hautement efficaces, par ex. An. minimus et An. harrisoni à la frontière Sino-Birmane. De plus, des taux élevés de piqûres humaines, des densités élevées d'adultes et de larves et des taux de parous ont été observés chez An. sinensis et An. harrisoni, qui révèlent une très grande réceptivité et un risque élevé de réintroduction du paludisme le long de la frontière Sino-Birmane. 2. L'analyse comparative des cas importés de paludisme signalés dans d'anciennes zones non endémiques et d'anciennes zones endémiques en Chine a montré que toutes les anciennes zones non endémiques signalaient désormais des cas importés de paludisme. 3. Une analyse résumée des progrès accomplis en matière d'élimination du paludisme depuis 2010 a été réalisée, avec un accent particulier sur la cartographie des foyers de paludisme résiduels et la répartition des cas de paludisme en Chine. L'incidence du paludisme contracté localement a fortement diminué, parallèlement à la diminution concomitante des zones d'endémie palustre de 762 comtés signalant le paludisme en 2010 à seulement deux comtés adjacents aux zones frontalières (Province du Yunnan: Chine-Myanmar et Tibet, Chine-Inde). En 2017, la Chine a atteint pour la première fois zéro cas de paludisme autochtone. En conclusion, la Chine est sur la voie de l’élimination du paludisme d’ici 2020. Le risque de réintroduction lié à l’émergence de cas importés de paludisme et à la présence de vecteurs du paludisme hautement efficaces présents dans le pays reste la cible de la surveillance du paludisme. Afin de maintenir l'élimination du paludisme, une collaboration internationale intensifiée, axée sur les zones transfrontalières et la population mobile / migrante, est appelée à prendre des mesures. Les études pilotes sur la manière de présenter les leçons tirées de l'élimination du paludisme en Chine et l'expertise Chinoise sont sur la liste des mesures à prendre, qui harmoniseraient l'aide de la Chine à l'élimination du paludisme dans les pays cibles. / Malaria has occurred in 80% of the counties in China in the past. After several decades of effort, malaria prevalence decreased drastically and China is currently approaching elimination throughout the country. Information on malaria vectors is still found not well documented, which could hinder the development of appropriate surveillance strategies and WHO certification. The major risk to malaria elimination is the re-introduction of the disease from imported malaria cases. There are an increasing number of imported malaria cases caused by Chinese citizens returning from malaria-affected countries recently. The information about their characters, drivers and route of introduction in different areas will provide evidence-based data to policy makers where and when to carry out the interventions. This will in turn allow them to develop efficient guidelines for risk-assessment of malaria re-introduction and for allocating appropriate resources. As a country with over 1.3 billion population and a territory covering different climatic zones, lessons learnt from malaria elimination in China that could serve as references to other countries. According to the Belt and Road initiatives, China will participate more globally to governance related activities. Partners and stakeholders within Global malaria elimination campaign are interested to the future opportunity and potential fields that would involve Chinese expertise. 1.A summary analysis was conducted on the nationwide distribution of malaria vectors, their bionomic characteristics, control measures and related studies. The distribution in China of the principal malaria vectors was found reduced, in particular for Anopheles lesteri and Anopheles dirus s.l., including the two main malaria vector species, An. dirus and An. baimaii, which nearly disappeared after several years of malaria control effort. Anopheles sinensis, which was previously reported to be less efficient in malaria transmission, is becoming the predominant species in Southwestern China. The field sampling results indicated the existence of high efficient malaria vectors, e.g. An. minimus and An. harrisoni at the China-Myanmar border. In addition, elevated human-biting rates, high adult and larval densities, and parous rates were found in both An. sinensis and An. harrisoni, which reveal a very high receptivity and risk of malaria re-introduction along the China–Myanmar border. 2.The comparative analysis of imported malaria cases reported from former non-endemic areas and former endemic areas in China showed that all former non-endemic areas are now reporting imported malaria cases. 3. A summary analysis on malaria elimination progress since 2010, was carried out with specific focus on mapping the residual malaria foci and the distribution of malaria cases in China. The incidence of locally acquired malaria has declined sharply along with the concomitant decrease of malaria-endemic areas from 762 counties reporting malaria in 2010 to just two counties adjacent to border areas (Yunnan Province: China-Myanmar and Tibet, China-India) in 2016. In 2017, China achieved zero indigenous malaria case report for the first time. In conclusion, China is on the track to achieve malaria elimination by 2020. The risk of re-introduction caused by the emergence of imported malaria cases and the occurrence of highly efficient malaria vectors present in the country is still the target of malaria surveillance. To maintain malaria elimination, intensified international collaboration with specific focus on cross-border areas and mobile/migrant population is called to take actions. The pilot studies on how to introduce the lessons learned from malaria elimination in China and the Chinese expertise are on the list to take action in future, which would harmonize the China aid to malaria elimination in the target countries.

Dans la première partie de cette thèse, nous avons mis en place un métamodèle de transmission du paludisme basé sur la modélisation compartimentale susceptible-infecté-résistant (SIR) et prenant en compte les flux de mobilité humaine entre différents villages du Centre Sénégal. Les stratégies d’intervention géographiquement ciblées, s’étaient avérées efficaces pour réduire l’incidence du paludisme aussi bien dans les zones d’intervention qu’à l’extérieur de ces zones. Cependant, des actions combinées ciblant à la fois le vecteur et l’hôte, coordonnées à large échelle sont nécessaires dans les régions et pays visant l’élimination du paludisme à court/moyen terme.Dans la deuxième partie nous avons évalué différentes méthodes d’estimation de la mobilité humaine en l’absence de données individuelles. Ces méthodes incluaient la traçabilité spatio-temporelle des téléphones mobiles ainsi que les modèles mathématiques de gravité et de radiation. Le transport de l’agent pathogène dans l’espace géographique, par la mobilité d’un sujet infecté est un déterminant majeur de la vitesse de propagation d’une épidémie. Nous avons introduit le modèle d’impédance qui minimise l’erreur quadratique moyen sur les estimations de mobilité, en particulier dans les contextes où les ensembles de population sont caractérisés par leurs tailles hétérogènes.Nous avons enfin élargi le cadre des hypothèses sous-jacentes à la calibration des modèles de gravité de la mobilité humaine. L’hypothèse d’une distribution avec excès de zéros a fourni un meilleur ajustement et une meilleure prédictibilité, comparée aux hypothèses classiques n’assumant pas un excès de zéros : Poisson, Quasipoisson. / In the first part of this thesis, we have developed a malaria transmission metamodel based on the susceptible-infected-resistant compartmental modeling framework (SIR) and taking into consideration human mobility flows between different villages in the Center of Senegal. Geographically targeted intervention strategies had been shown to be effective in reducing the incidence of malaria both within and outside of intervention areas. However, combined interventions targeting both vector and host, coordinated on a large scale are needed in regions and countries aiming to achieve malaria elimination in the short/medium term.In the second part we have evaluated different methods of estimating human mobility in the absence of real data. These methods included spatio-temporal traceability of mobile phones, mathematical models of gravity and radiation. The transport of the pathogen through the geographical space via the mobility of an infected subject is a major determinant of the spread of an epidemic. We introduced the impedance model that minimized the mean square error on mobility estimates, especially in contexts where population sets are characterized by their heterogeneous sizes.Finally, we have expanded the framework of assumptions underlying the calibration of the gravity models of human mobility. The hypothesis of a zero inflated distribution provided a better fit and a better predictability, compared to the classical approach not assuming an excess of zeros: Poisson, Quasipoisson.