Christinah Chiyaka

A systematic review of mathematical models of mosquito-borne pathogen transmission: 1970-2010

Mathematical models of mosquito-borne pathogen transmission originated in the early twentieth century to provide insights into how to most effectively combat malaria. The foundations of the Ross–Macdonald theory were established by 1970. Since then, there has been a growing interest in reducing the public health burden of mosquito-borne pathogens and an expanding use of models to guide their control. To assess how theory has changed to confront evolving public health challenges, we compiled a bibliography of 325 publications from 1970 through 2010 that included at least one mathematical model of mosquito-borne pathogen transmission and then used a 79-part questionnaire to classify each of 388 associated models according to its biological assumptions. As a composite measure to interpret the multidimensional results of our survey, we assigned a numerical value to each model that measured its similarity to 15 core assumptions of the Ross–Macdonald model. Although the analysis illustrated a growing acknowledgement of geographical, ecological and epidemiological complexities in modelling transmission, most models during the past 40 years closely resemble the Ross–Macdonald model. Modern theory would benefit from an expansion around the concepts of heterogeneous mosquito biting, poorly mixed mosquito-host encounters, spatial heterogeneity and temporal variation in the transmission process.

Recasting the theory of mosquito-borne pathogen transmission dynamics and control

Mosquito-borne diseases pose some of the greatest challenges in public health, especially in tropical and sub-tropical regions of the world. Efforts to control these diseases have been underpinned by a theoretical framework developed for malaria by Ross and Macdonald, including models, metrics for measuring transmission, and theory of control that identifies key vulnerabilities in the transmission cycle. That framework, especially Macdonalds formula for R0 and its entomological derivative, vectorial capacity, are now used to study dynamics and design interventions for many mosquito-borne diseases. A systematic review of 388 models published between 1970 and 2010 found that the vast majority adopted the Ross–Macdonald assumption of homogeneous transmission in a well-mixed population. Studies comparing models and data question these assumptions and point to the capacity to model heterogeneous, focal transmission as the most important but relatively unexplored component in current theory. Fine-scale heterogeneity causes transmission dynamics to be nonlinear, and poses problems for modeling, epidemiology and measurement. Novel mathematical approaches show how heterogeneity arises from the biology and the landscape on which the processes of mosquito biting and pathogen transmission unfold. Emerging theory focuses attention on the ecological and social context for mosquito blood feeding, the movement of both hosts and mosquitoes, and the relevant spatial scales for measuring transmission and for modeling dynamics and control.

A quantitative analysis of transmission efficiency versus intensity for malaria.

The relationship between malaria transmission intensity and efficiency is important for malaria epidemiology, for the design of randomized control trials that measure transmission or incidence as end points, and for measuring and modelling malaria transmission and control. Five kinds of studies published over the past century were assembled and reanalysed to quantify malaria transmission efficiency and describe its relation to transmission intensity, to understand the causes of inefficient transmission and to identify functions suitable for modelling mosquito-borne disease transmission. In this study, we show that these studies trace a strongly nonlinear relationship between malaria transmission intensity and efficiency that is parsimoniously described by a model of heterogeneous biting. When many infectious bites are concentrated on a few people, infections and parasite population structure will be highly aggregated affecting the immunoepidemiology of malaria, the evolutionary ecology of parasite life history traits and the measurement and stratification of transmission for control using entomological and epidemiological data.

A mathematical analysis of the effects of control strategies on the transmission dynamics of malaria.

We formulate a deterministic model with two latent periods in the non-constant host and vector populations, in order to theoretically assess the potential impact of personal protection, treatment and possible vaccination strategies on the transmission dynamics of malaria. The thresholds and equilibria for the model are determined. The model is analysed qualitatively to determine criteria for control of a malaria epidemic and is used to compute the threshold vaccination and treatment rates necessary for community-wide control of malaria. In addition to having a disease-free equilibrium, which is locally asymptotically stable when the basic reproductive number is less than unity, the model exhibits the phenomenon of backward bifurcation where a stable disease-free equilibrium coexists with a stable endemic equilibrium for a certain range of associated reproductive number less than one. From the analysis we deduce that personal protection has a positive impact on disease control but to eradicate the disease in the absence of any other control measures the efficacy and compliance should be very high. Our results show that vaccination and personal protection can suppress the transmission rates of the parasite from human to vector and vice-versa. If the treated populations are infectious then certain conditions should be satisfied for treatment to reduce the spread of malaria in a community. Among the interesting dynamical behaviours of the model, numerical simulations show a backward bifurcation which gives a challenge to the designing of effective control measures.

A sticky situation: the unexpected stability of malaria elimination

Malaria eradication involves eliminating malaria from every country where transmission occurs. Current theory suggests that the post-elimination challenges of remaining malaria-free by stopping transmission from imported malaria will have onerous operational and financial requirements. Although resurgent malaria has occurred in a majority of countries that tried but failed to eliminate malaria, a review of resurgence in countries that successfully eliminated finds only four such failures out of 50 successful programmes. Data documenting malaria importation and onwards transmission in these countries suggests malaria transmission potential has declined by more than 50-fold (i.e. more than 98%) since before elimination. These outcomes suggest that elimination is a surprisingly stable state. Eliminations ‘stickiness’ must be explained either by eliminating countries starting off qualitatively different from non-eliminating countries or becoming different once elimination was achieved. Countries that successfully eliminated were wealthier and had lower baseline endemicity than those that were unsuccessful, but our analysis shows that those same variables were at best incomplete predictors of the patterns of resurgence. Stability is reinforced by the loss of immunity to disease and by the health systems increasing capacity to control malaria transmission after elimination through routine treatment of cases with antimalarial drugs supplemented by malaria outbreak control. Human travel patterns reinforce these patterns; as malaria recedes, fewer people carry malaria from remote endemic areas to remote areas where transmission potential remains high. Establishment of an international resource with backup capacity to control large outbreaks can make elimination stickier, increase the incentives for countries to eliminate, and ensure steady progress towards global eradication. Although available evidence supports malaria eliminations stickiness at moderate-to-low transmission in areas with well-developed health systems, it is not yet clear if such patterns will hold in all areas. The sticky endpoint changes the projected costs of maintaining elimination and makes it substantially more attractive for countries acting alone, and it makes spatially progressive elimination a sensible strategy for a malaria eradication endgame.

Modeling huanglongbing transmission within a citrus tree

The citrus disease huanglongbing (HLB), associated with an uncultured bacterial pathogen, is threatening the citrus industry worldwide. A mathematical model of the transmission of HLB between its psyllid vector and citrus host has been developed to characterize the dynamics of the vector and disease development, focusing on the spread of the pathogen from flush to flush (a newly developing cluster of very young leaves on the expanding terminal end of a shoot) within a tree. This approach differs from that of prior models for vector-transmitted plant diseases where the entire plant is the unit of analysis. Dynamics of vector and host populations are simulated realistically as the flush population approaches complete infection. Model analysis indicates that vector activity is essential for initial infection but is not necessary for continued infection because infection can occur from flush to flush through internal movement in the tree. Flush production, within-tree spread, and latent period are the most important parameters influencing HLB development. The model shows that the effect of spraying of psyllids depends on time of initial spraying, frequency, and efficacy of the insecticides. Similarly, effects of removal of symptomatic flush depend on the frequency of removal and the time of initiation of this practice since the start of the epidemic. Within-tree resistance to spread, possibly affected by inherent or induced resistance, is a major factor affecting epidemic development, supporting the notion that alternate routes of transmission besides that by the vector can be important for epidemic development.

Infectious disease. The stability of malaria elimination.

Eradication may not be necessary before countries can eliminate, scale back control, and rely on health systems. When the Global Malaria Eradication Programme (GMEP) was launched in 1955 (1, 2), all malaria-endemic countries outside of Africa were (or would soon be) eliminating malaria (3). The GMEPs design was based on a theory of malaria transmission dynamics and control that has become the standard for malaria elimination decisions today (4–6). When financial support for the GMEP collapsed in 1969, participating countries were caught at different stages of progress toward elimination (1). Examining their fate in the decades that followed provides a natural experiment that tests the theory. With a rise in funding (7) and renewed interest in eradication (8, 9), there is now a need to revisit the lessons learned from the GMEP. We identify changes in the epidemiology of malaria when elimination is reached that could explain its stability and discuss how this calls for a reassessment of strategies for eradication.

Effects of treatment and drug resistance on the transmission dynamics of malaria in endemic areas

We present a mathematical model for malaria treatment and spread of drug resistance in an endemic population. The model considers treated humans that remain infectious for some time and partially immune humans who are also infectious to mosquitoes although their infectiousness is always less than their non immune counterparts. The model is formulated by considering delays in the latent periods in both mosquito and human populations and in the period within which partial immunity is lost. Qualitative analysis of the model including positivity and boundedness of solutions is performed. Analysis of the reproductive numbers shows that if the treated humans become immediately uninfectious to mosquitoes then treatment will always reduce the number of sensitive infections. If however treated humans are infectious then for treatment to effectively reduce the number of sensitive infections, the ratio of the infectious period of the treated humans to the infectious period of the untreated humans multiplied by the ratio of the transmission rate from a treated human to the transmission rate of an untreated human should be less than one. Our results show that the spread of drug resistance with treatment as a control strategy depends on the ratio of the infectious periods of treated and untreated humans and on the transmission rates from infectious humans with resistant and sensitive infections. Numerical analysis is performed to assess the effects of treatment on the spread of resistance and infection. The study provides insight into the possible intervention strategies to be employed in malaria endemic populations with resistant parasites by identifying important parameters.

Modelling Immune Response and Drug Therapy in Human Malaria Infection

A new intra-host model of malaria that describes the dynamics of the blood stages of the parasite and its interaction with red blood cells and immune effectors is proposed. Local and global stability of the disease free equilibrium are investigated. Conditions for existence and uniqueness of the endemic equilibrium are derived. An intra-host basic reproductive number is identified. We deduce that drugs based on inhibiting parasite production are more effective than those based on inhibiting merozoite invasion of erythrocytes. We extend the model to incorporate, in addition to immune response, drug therapy, following treatment with antimalarial drugs. Using stability analysis of the model, it is shown that infection can be eradicated within the host if the drug efficacy level exceeds a certain threshold value. It will persist if the efficacy is below this threshold. Numerical simulations are done to verify the analytic results and illustrate possible behaviour of the models.

Modelling and analysis of the effects of malnutrition in the spread of cholera

Although cholera has existed for ages, it has continued to plague many parts of the world. In this study, a deterministic model for cholera in a community is presented and rigorously analysed in order to determine the effects of malnutrition in the spread of the disease. The important mathematical features of the cholera model are thoroughly investigated. The epidemic threshold known as the basic reproductive number and equilibria for the model are determined, and stabilities are investigated. The disease-free equilibrium is shown to be globally asymptotically stable. Local stability of the endemic equilibrium is determined using centre manifold theory and conditions for its global stability are derived using a suitable Lyapunov function. Numerical simulations suggest that an increase in susceptibility to cholera due to malnutrition results in an increase in the number of cholera infected individuals in a community. The results suggest that nutritional issues should be addressed in impoverished communities affected by cholera in order to reduce the burden of the disease.