Background: The distribution of malaria in sub-Saharan Africa is determined largely by climatic influences on the development and survival of P. falciparum and its Anopheline vectors. This inter-relationship has been exploited in developing a limited number of predictive maps of malaria's distribution but these climate maps have limitations. Climate alone does not fully describe the complex dynamics of transmission and, in particular, human influences such as urbanization and the use of widespread anti-malarial interventions. The improved accuracy and validation of solely climatedriven maps relies on the availability of robust malariometric training data. To date, such data have been scarce. This study redresses several deficiencies of existing malaria maps for Africa through the collation of an extensive database of empirical P. falciparum prevalence data, the investigation of the relationship between prevalence and a widely-used climate-driven map, an assessment of the influence of urbanization on prevalence and finally, through the use of empirical training data to develop an improved malaria map for Kenya, Tanzania and Uganda. Methods: An extensive published and grey-literature search was conducted between 1996 and 2004 and identified 2003 P. falciparum prevalence surveys conducted among childhood populations across East Africa between 1927 and 2003. Stringent criteria were applied to select the best sample data; only randomly sampled community-based surveys, surveys with samples >=50 children, surveys conducted between 1980-2004 and children aged 0-14 years, and surveys which were spatially and temporally unique. The selected data were used to investigate the association between P. falciparum prevalence and a fuzzy logic climatic suitability (PCS) map of malaria transmission, the effect of urbanization on prevalence and to train Fourier-processed multi-temporal climate surrogate data derived from meteorological satellites in order to predict prevalence for un-sampled areas. Using discriminant analysis, the top ten climatic predictor variables that distinguished best between 4 categories of malaria prevalence (0-<5, 5-<25%, 25-<75% and >=75%) were selected and these used to develop a predictive transmission map.

In recent years there has been growing interest in applying frameworks from evolutionary ecology to understand infectious disease. It is becoming increasingly apparent that the interactions between parasites within the host environment can shape parasite phenotypes underlying infection dynamics and transmission. However, the spread of the disease will crucially depend on both within-host and between-host dynamics. Bridging these scales is challenging and for vector borne parasites, such as malaria and trypanosomes, will involve gaining a much better understanding of infection dynamics both within the host and vector. I apply evolutionary ecology frameworks including social evolution, life history theory, and phenotypic plasticity to investigate how parasite phenotypes are shaped by within-host and within-vector environments and examine the implications for inhost survival and between-host transmission. Specifically, I demonstrate that; 1. Within the host; i. In accordance with theory malaria parasites detect and respond to the presence of competitors by altering reproductive strategies to maximise in-host survival. Furthermore, these strategies are fine tuned in response to variation in the within-host environment, including the availability of resources. ii. The reproductive investment strategies of malaria parasites can be applied to explain the transmission strategies of African trypanosomes. This shows how general evolutionary frameworks can be applied to a novel parasite species and demonstrates the explanatory power of an evolutionary approach. iii. The complexity of the within-host environment poses specific statistical challenges for examining the temporal dynamics of parasite life history traits that are often not adequately dealt with, potentially leading to type 1 errors. Methods to evaluate levels of autocorrelation and how to deal with it are applied to datasets of within-infection dynamics. 2. Within the vector; i. Malaria parasites undergo programmed, apoptotic cell death. The occurrence of, and putative explanation for, apoptosis in protozoan parasites is controversial. I demonstrate the importance of quantitative methods and parasite ecology in testing the evolutionary explanations for parasite apoptosis. ii. The links between within-host dynamics and within-vector dynamics are complex and can lead to counter-intuitive implications for the success of between-host transmission. Density-dependent processes result in diverse fitness costs to parasites of crowding. More broadly, these processes could explain why parasites undergo apoptosis. In general my results demonstrate, across vertebrate hosts and insect vectors, how the interactions between parasites and with their environment shapes traits important for the transmission of infectious disease.

Malaria is a debilitating and deadly disease that afflicts over 200 million people and kills over 600 thousand each year. Due to quickly evolving drug resistance and lack of an affordable vaccine, novel interventions are needed to fight the Plasmodium parasites that cause malaria. Targeting Plasmodium inside their mosquito hosts is one approach that could complement other preventative and medicinal interventions by reducing the ability of the mosquitoes to transmit the disease to humans. The research presented here uses paratransgenesis, the genetic modification of symbiotic bacteria within the mosquito midgut, to provide antimalarial protein to the mosquito and to interfere with the life cycle of Plasmodium within the insect host. &lt;br&gt;This research has produced three new antimalarial paratransgenic tools. The first tool is a set of new antimalarial effector proteins that were constructed by converting anti-Plasmodium mouse antibodies into single-chain variable fragment (scFv) versions for expression by bacteria. These antibodies bind to Plasmodium surface proteins and interfere with critical steps in the parasite life cycle. The second tool is a modified bacterial species, Pantoea agglomerans , which was engineered to secrete diverse antimalarial proteins via the hemolysin secretion pathway. Modified P. agglomerans were fed to mosquitoes and were capable of inhibiting the invasion of Plasmodium within the midgut. The third tool is another modified bacterial species, Asaia sp. SF2.1. Native Type II secretion signals were discovered that enable the creation of paratransgenic strains of these bacteria. Modified strains of Asaia sp. SF2.1 were also demonstrated to interfere with the invasion of Plasmodium within the mosquito. &lt;br&gt;These tools have laid the groundwork for the future use of paratransgenic bacteria to combat malaria in the wild. Asaia sp. SF2.1 bacteria, in particular, are capable of spreading throughout mosquito populations, so they provide their own drive mechanism to establish themselves within the mosquito vectors of malaria. While further modifications will be required to make these bacteria ready for field use, the findings of this research provide proof of concept that the bacteria are suitable for eventual use in malaria transmission-blocking interventions. / Bayer School of Natural and Environmental Sciences; / Biological Sciences / PhD; / Dissertation;

Foi feito o estudo da Bromélia-Malária no Brasil, e de acordo com os dados disponíveis foi reconstituída a distribuição geográfica e evidenciada a incidência dessa enfermidade entre nós. Para o levantamento do estado atual dispusemos de dados inéditos referentes a São Paulo e a Santa catarina, nestes últimos, englobados também os referentes ao Rio Grande do Sul. Pudemos verificar que nessas áreas em diferentes estágios de erradicação, São Paulo, cujo plano de erradicação quase concluído, luta para não ser restabelecida a transmissão, e Santa Catarina, ainda com uma grande parte a ser concluída, luta não só para interromper a transmissão nas áreas ainda maláricas, como para não ser restabelecida, ou mesmo estabelecida a transmissão nas áreas não maláricas. / Actualized data about Bromelia-Malaria in Brazil, are presentedthrough a reconstituted geographic distribution and new records about the disease incidence. New data are related to São Paulo and Santa Catarina States, including the ones belonging to Rio Grande do Sul. There are several areas in different erradication stages. In São Paulo, it is almost concluded and struggle is against the menace of a transmission restablishment. At other places there are a quite different picture because the transmission in malaria areas but also for to avoid its introduction in disease - cleaned ones.

The thesis is based on the use of mathematical modeling and analysis to gain insightinto the transmission dynamics of malaria in a community. A new deterministic model for assessing the role of age-structure on the disease dynamics is designed. The model undergoes backward bifurcation, a dynamic phenomenon characterized by the co-existence of a stable disease-free and an endemic equilibrium of the model when the associated reproduction number is less than unity. It is shown that adding age-structure to the basic model for malaria transmission does not alter its essential qualitative dynamics. The study is extended to incorporate the use of anti-malaria drugs. Numerical simulations of the extended model suggest that for the case when treatment does not cause drug resistance (and the reproduction number of each of the two strains exceed unity), the model undergoes competitive exclusion. The impact of various effectiveness levels of the treatment strategy is assessed.

The thesis is based on the use of mathematical modeling and analysis to gain insightinto the transmission dynamics of malaria in a community. A new deterministic model for assessing the role of age-structure on the disease dynamics is designed. The model undergoes backward bifurcation, a dynamic phenomenon characterized by the co-existence of a stable disease-free and an endemic equilibrium of the model when the associated reproduction number is less than unity. It is shown that adding age-structure to the basic model for malaria transmission does not alter its essential qualitative dynamics. The study is extended to incorporate the use of anti-malaria drugs. Numerical simulations of the extended model suggest that for the case when treatment does not cause drug resistance (and the reproduction number of each of the two strains exceed unity), the model undergoes competitive exclusion. The impact of various effectiveness levels of the treatment strategy is assessed.

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.

Foi feito o estudo da Bromélia-Malária no Brasil, e de acordo com os dados disponíveis foi reconstituída a distribuição geográfica e evidenciada a incidência dessa enfermidade entre nós. Para o levantamento do estado atual dispusemos de dados inéditos referentes a São Paulo e a Santa catarina, nestes últimos, englobados também os referentes ao Rio Grande do Sul. Pudemos verificar que nessas áreas em diferentes estágios de erradicação, São Paulo, cujo plano de erradicação quase concluído, luta para não ser restabelecida a transmissão, e Santa Catarina, ainda com uma grande parte a ser concluída, luta não só para interromper a transmissão nas áreas ainda maláricas, como para não ser restabelecida, ou mesmo estabelecida a transmissão nas áreas não maláricas. / Actualized data about Bromelia-Malaria in Brazil, are presentedthrough a reconstituted geographic distribution and new records about the disease incidence. New data are related to São Paulo and Santa Catarina States, including the ones belonging to Rio Grande do Sul. There are several areas in different erradication stages. In São Paulo, it is almost concluded and struggle is against the menace of a transmission restablishment. At other places there are a quite different picture because the transmission in malaria areas but also for to avoid its introduction in disease - cleaned ones.

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.

Malaria is a serious and life-threatening mosquito-borne disease that every year affects over 200 million individuals and causes 400,00 deaths. An additional 0.5 billion people globally are at risk of malaria infection. The unique role of climate in influencing malaria transmission outcomes across individual communities by acting on multiple dimensions of the malaria vector and parasite ecology has been long recognized. This recognition has led to the development of explicit and implicit climate-driven models of malaria transmission designed to better understand and predict patterns of population vulnerability and uncover potential challenges to malaria control. However, existing implicitly-forced process-based models of malaria have relied on indirectly correlated predictors of malaria transmission, instead of direct relationships among climate, vector entomology and parasite ecology. The lack of biologically-motivated modulation of malaria transmission compromises meaningful interpretation of the ecological role played by climate in malaria transmission. Similarly, the specific influence of climate on vector and parasite dynamics is obscured, limiting the utility of these simple and powerful model forms. This dissertation focuses on elaborating the direct ecological relationships between climate, the malaria vector and parasite to enhance the ecological utility of lower dimensional mathematical models of malaria transmission. In the 2nd chapter of this thesis, a climate-driven entomological modeling framework is developed, consisting of a simple dynamic model that explicitly tracks malaria transmission in human populations and implicitly represents the malaria force of infection through climate-regulation of multiple aspects of the Entomological Inoculation Rate (EIR). The EIR-model construct is found to accurately capture seasonal malaria dynamics under free-simulation, when coupled to local rainfall and temperature climatology across multiple local regions in Rwanda. Furthermore, local rainfall modulation of sub-adult survivorship is found to be a more critical driver of seasonal malaria dynamics than other environmentally-regulated components of EIR. In chapter 3, the model framework is paired with data assimilation methods to dynamically simulate interannual malaria incidence in Rwanda, infer parameters of malaria transmission and validate the malaria model. Results indicate that the implicitly-forced transmission model is able to reproduce interannual and seasonal malaria incidence at regional and local scales. However, accuracy of model description of malaria incidence is more varied at the more resolved local level. Intensified malaria control efforts during the later years of the study are suspected to increase the discrepancy between the vector and parasite dynamics dictated by climate and the observed widespread decline in malaria activity in the region. Nonetheless, the parameters of transmission identified across populations in Rwanda were comparable to existing estimates of malaria, further validating the transmission model and data assimilation approach. For the 4th chapter, a state-of-the-art Bayesian inference forecasting system for the EIR-model framework is developed, as well as a multi-model forecasting system consisting of weighted-average predictions from the dynamic malaria model and historical expectance predictions. Retrospective forecasts of four years of malaria data from 42 regions in Rwanda indicate that the model-inference forecasting system predicts malaria incidence more accurately than historical expectance alone, particularly for predictions with 1-6 weeks lead times. Although slightly less skillful, the multi-model system was found to substantively enhance forecast reliability of the EIR-model system, bolstering the utility of the malaria model as a robust forecaster of malaria in the region. The concluding chapter describes areas for improving the specification of the parsimonious model construct. The need to include malaria control coverage data as exogenous forces of transmission, non-climate drivers and alternate sources of climate exposure that support transmission are highlighted. Future works on forecast calibration needed to improve model performance for real-time prediction are also detailed. In addition, areas for application within information systems for evaluating malaria risk and for advising malaria control efforts, specifically relating to local variability in malaria burden and characterization of entomological drivers of local malaria, are identified and further discussed. The model systems developed in this thesis advance the capabilities of lower dimension dynamic models to connect the ecological drivers of malaria transmission to climate variation. Such process-based formulations could provide better climate-driven descriptions of malaria, while limiting model complexity, without compromising representation of entomological relationships that are potentially valuable for improved understanding and control of malaria transmission.