Em epidemiologia matemática, muitos modelos de propagação de doenças infecciosas em populações têm sido analisados matematicamente e aplicados para doenças específicas. Neste trabalho um modelo de propagação de dengue é analisado considerando-se diferentes hipóteses sobre o tamanho da população humana. Mais precisamente, estamos interessados em verificar o impacto das variações populacionais a longo prazo no cálculo do parâmetro Ro e no equilíbrio endêmico. Vamos discutir algumas ideias que nortearam o processo de definição do parâmetro Ro a partir da construção do Operador de Próxima Geração. Através de um estudo qualitativo do modelo matemático, obtivemos que o equilíbrio livre de doença é globalmente assintoticamente estável se Ro é menor ou igual a 1 e instável se Ro>1. Para Ro>1, a estabilidade global do equilíbrio endêmico é provada usando um critério geral para estabilidade orbital de órbitas periódicas associadas a sistemas autônomos não lineares de altas ordens e resultados da teoria de sistemas competitivos para equações diferenciais ordinárias. Também foi desenvolvida uma análise de sensibilidade do Ro e do equilíbrio endêmico com relação aos parâmetros do modelo de propagação. Diversos cenários foram simulados a partir dos índices de sensibilidade obtidos nesta análise. Os resultados demonstram que, de forma geral, o parâmetro Ro e o equilíbrio endêmico apresentam considerável sensibilidade a taxa de picadas do vetor e a taxa de mortalidade do vetor. / In mathematical epidemiology many models of spread of infectious diseases in populations have been analyzed mathematically and applied to specific diseases. In this work a dengue propagation model is analyzed considering different assumptions about the size of the human population. More precisely, we are interested to verify the impact of population long-term variations in the calculation of the parameter Ro and endemic equilibrium. We will discuss some ideas that guided the parameter setting process Ro from the construction of the Next Generation Operator. Through a qualitative study of the mathematical model, we found that the disease-free equilibrium is globally asymptotically stable if Ro is less or equal than 1 and unstable if Ro> 1. For Ro> 1 the global stability of the endemic equilibrium is proved using a general criterion for orbital stability of periodic orbits associated with nonlinear autonomous systems of higher orders and results of the theory of competitive systems for ordinary differential equations. Also a sensitivity analysis of the Ro and the endemic equilibrium with respect to the parameters of the propagation model was developed. Several scenarios were simulated from the sensitivity index obtained in this analysis. The results demonstrate that in general the parameter Ro and the endemic equilibrium are the most sensitive to the vector biting rate and the vector mortality rate.

O número de reprodutibilidade basal, R_0, é definido como o número esperado de casos secundários de uma doença produzidos por um indivíduo infectado em uma população suscetível durante seu período de infecciosidade. Tem-se que, para R_0 < 1 a doença não consegue se manter na população, e para R_0 >1 a doença irá se estabelecer. O cálculo do valor de R_0 pode ser feito de diversas maneiras, como por exemplo: a partir da análise de estabilidade de um modelo compartimental, através da matriz de próxima geração, da fase final de uma epidemia, entre outros. Neste trabalho foi estudado o cálculo de R_0 a partir da fase inicial de crescimento de um surto, em que ao fazer este cálculo não é suposto crescimento exponencial da doença, o que é proposto implicitamente na maior parte dos estudos. Foram estudadas as técnicas propostas por Nishiura, Ross-Macdonald e White e Pagano. O objetivo deste estudo foi comparar essas técnicas e avaliar como cada técnica estima o valor do número de reprodutibilidade basal, aplicando-as a doenças causadas por vetores, neste caso em particular foram utilizados dados de dengue. Foram utilizados dados da cidade de Ribeirão Preto nos períodos de 2009-2010 e 2010-2011, em ambos os casos a cidade apresentou um surto epidêmico. Os resultados apresentados pelos três métodos são numericamente diferentes. Pode-se concluir que todos os métodos acertam na previsão de que a dengue irá se propagar na cidade estudada, o que é verdade para os casos estudados, e que apesar de serem numericamente diferentes a análise semanal dos dados mostra que os valores calculados apresentam um mesmo padrão ao longo do tempo / The basic reproduction number,R_0, is defined as the expected number of secondary cases of a disease produced by a single infection in a susceptible population. If R_0 < 1 the disease cannot establish in the population, and if R_0 > 1 we expect the disease spread in the population. The value of R_0 can be estimated in several ways, for example, with the stability analysis of a compartmental model, through the matrix of next generation, using the final phase of an epidemic, etc. In this work we studied methods for estimating R_0 from the initial growth phase of the outbreak, without assuming exponential growth of cases, which is suggested in most studies. We used the methods proposed by Nishiura, Ross-Macdonald and White and Pagano. The objective of this work was to compare these techniques and to evaluate how these technique estimate the value of the basic reproduction number, applying them to diseases caused by vectors. In this particular case we used data of dengue. We used data from the city of Ribeirão Preto in the periods of 2009-2010 and 2010-2011, in both cases the city had an outbreak. The results obtained by the three methods are numerically different. We can conclude that all methods are correct in the sense that dengue will spread in the city studied, what is true for the cases studied, although they are numerically different. Weekly analysis of the data show that the estimated values have a same pattern over time

abstract: Rabies is an infectious viral disease. It is usually fatal if a victim reaches the rabid stage, which starts after the appearance of disease symptoms. The disease virus attacks the central nervous system, and then it migrates from peripheral nerves to the spinal cord and brain. At the time when the rabies virus reaches the brain, the incubation period is over and the symptoms of clinical disease appear on the victim. From the brain, the virus travels via nerves to the salivary glands and saliva. A mathematical model is developed for the spread of rabies in a spatially distributed fox population to model the spread of the rabies epizootic through middle Europe that occurred in the second half of the 20th century. The model considers both territorial and wandering rabid foxes and includes a latent period for the infection. Since the model assumes these two kinds of rabid foxes, it is a system of both partial differential and integral equations (with integration over space and, occasionally, also over time). To study the spreading speeds of the rabies epidemic, the model is reduced to a scalar Volterra-Hammerstein integral equation, and space-time Laplace transform of the integral equation is used to derive implicit formulas for the spreading speed. The spreading speeds are discussed and implicit formulas are given for latent periods of fixed length, exponentially distributed length, Gamma distributed length, and log-normally distributed length. A number of analytic and numerical results are shown pertaining to the spreading speeds. Further, a numerical algorithm is described for the simulation of the spread of rabies in a spatially distributed fox population on a bounded domain with Dirichlet boundary conditions. I propose the following methods for the numerical approximation of solutions. The partial differential and integral equations are discretized in the space variable by central differences of second order and by the composite trapezoidal rule. Next, the ordinary or delay differential equations that are obtained this way are discretized in time by explicit continuous Runge-Kutta methods of fourth order for ordinary and delay differential systems. My particular interest is in how the partition of rabid foxes into territorial and diffusing rabid foxes influences the spreading speed, a question that can be answered by purely analytic means only for small basic reproduction numbers. I will restrict the numerical analysis to latent periods of fixed length and to exponentially distributed latent periods. The results of the numerical calculations are compared for latent periods of fixed and exponentially distributed length and for various proportions of territorial and wandering rabid foxes. The speeds of spread observed in the simulations are compared to spreading speeds obtained by numerically solving the analytic formulas and to observed speeds of epizootic frontlines in the European rabies outbreak 1940 to 1980. / Dissertation/Thesis / Doctoral Dissertation Applied Mathematics 2018

<p><b>In this dissertation we present the quantitative response of an epidemic of the so-called SIR-type, in a population consisting of a local component and a migrant component. Each component can be divided into three classes, the susceptible individuals, usually denoted by S, who are uninfected but may contract the disease, infected individuals (I) who are infected and can spread the disease to the susceptible individuals and the class (R) of recovered individuals. If a susceptible individual becomes infected, it moves into the infected class. An infected individual, at recovery, moves to the class R. Firstly we develop a model describing two interacting populations with vaccination. Assuming the vaccination rate in both groups or components are constant, we calculate a threshold parameter and we call it a vaccination reproductive number. This invariant determines whether the disease will die out or becomes endemic on the (in particular, local) population. Then we present the stability analysis of equilibrium points and the effect of vaccination. Our primary finding is that the behaviour of the disease free equilibrium depend on the vaccination rates of the combined population. We show that the disease free equilibrium is locally asymptotically stable if the vaccination reproductive number is less than one. Also our stability analysis show that the global stability of the disease free equilibrium depends on the basic reproduction number, not the vaccination reproductive number. If the vaccination reproductive number is greater than one, then the disease free equilibrium is unstable and there exists three endemic equilibrium points in our model. Two of these three endemic equilibria are so-called boundary equilibrium points, which means that the infection is only in one group of the population. The third one which we focus on is the general endemic point for the whole system. We derive a threshold condition that determines whether the endemic equilibria is locally asymptotically stable or not. Secondly, by assuming that the rate of vaccination in the migrant population is constant, we apply optimal control theory to find an optimal vaccination strategy in the local population. Our numerical simulation shows the effectiveness of the control strategy. This model is suitable for modeling the real life situation to control many communicable diseases. Models similar to the model used in the main contribution of our dissertation do exist in the literature. In fact, our model can be regarded as being in-between those of [Jia et al., Theoretical Population Biology 73 (2008) 437-448] and [Piccolo and Billings, Mathematical and Computer Modeling 42 (2005) 291-299]. Nevertheless our stability analysis is original, and furthermore we perform an optimal control study whereas the two cited papers do not. The essence of chapter 5 and 6 of this dissertation is being prepared for publication.</b></p>

Infectious disease models with switching are constructed and investigated in detail. Modelling infectious diseases as switched systems, which are systems that combine continuous dynamics with discrete logic, allows for the use of methods from switched systems theory. These methods are used to analyze the stability and long-term behaviour of the proposed switched epidemiological models. Switching is first incorporated into epidemiological models by assuming the contact rate to be time-dependent and better approximated by a piecewise constant. Epidemiological models with switched incidence rates are also investigated. Threshold criteria are established that are sufficient for the eradication of the disease, and, hence, the stability of the disease-free solution. In the case of an endemic disease, some criteria are developed that establish the persistence of the disease. Lyapunov function techniques, as well as techniques for stability of impulsive or non-impulsive switched systems with both stable and unstable modes are used. These methods are first applied to switched epidemiological models which are intrinsically one-dimensional. Multi-dimensional disease models with switching are then investigated in detail. An important part of studying epidemiology is to construct control strategies in order to eradicate a disease, which would otherwise be persistent. Hence, the application of controls schemes to switched epidemiological models are investigated. Finally, epidemiological models with switched general nonlinear incidence rates are considered. Simulations are given throughout to illustrate our results, as well as to make some conjectures. Some conclusions are made and future directions are given.

Infectious disease models with switching are constructed and investigated in detail. Modelling infectious diseases as switched systems, which are systems that combine continuous dynamics with discrete logic, allows for the use of methods from switched systems theory. These methods are used to analyze the stability and long-term behaviour of the proposed switched epidemiological models. Switching is first incorporated into epidemiological models by assuming the contact rate to be time-dependent and better approximated by a piecewise constant. Epidemiological models with switched incidence rates are also investigated. Threshold criteria are established that are sufficient for the eradication of the disease, and, hence, the stability of the disease-free solution. In the case of an endemic disease, some criteria are developed that establish the persistence of the disease. Lyapunov function techniques, as well as techniques for stability of impulsive or non-impulsive switched systems with both stable and unstable modes are used. These methods are first applied to switched epidemiological models which are intrinsically one-dimensional. Multi-dimensional disease models with switching are then investigated in detail. An important part of studying epidemiology is to construct control strategies in order to eradicate a disease, which would otherwise be persistent. Hence, the application of controls schemes to switched epidemiological models are investigated. Finally, epidemiological models with switched general nonlinear incidence rates are considered. Simulations are given throughout to illustrate our results, as well as to make some conjectures. Some conclusions are made and future directions are given.

<p><b>In this dissertation we present the quantitative response of an epidemic of the so-called SIR-type, in a population consisting of a local component and a migrant component. Each component can be divided into three classes, the susceptible individuals, usually denoted by S, who are uninfected but may contract the disease, infected individuals (I) who are infected and can spread the disease to the susceptible individuals and the class (R) of recovered individuals. If a susceptible individual becomes infected, it moves into the infected class. An infected individual, at recovery, moves to the class R. Firstly we develop a model describing two interacting populations with vaccination. Assuming the vaccination rate in both groups or components are constant, we calculate a threshold parameter and we call it a vaccination reproductive number. This invariant determines whether the disease will die out or becomes endemic on the (in particular, local) population. Then we present the stability analysis of equilibrium points and the effect of vaccination. Our primary finding is that the behaviour of the disease free equilibrium depend on the vaccination rates of the combined population. We show that the disease free equilibrium is locally asymptotically stable if the vaccination reproductive number is less than one. Also our stability analysis show that the global stability of the disease free equilibrium depends on the basic reproduction number, not the vaccination reproductive number. If the vaccination reproductive number is greater than one, then the disease free equilibrium is unstable and there exists three endemic equilibrium points in our model. Two of these three endemic equilibria are so-called boundary equilibrium points, which means that the infection is only in one group of the population. The third one which we focus on is the general endemic point for the whole system. We derive a threshold condition that determines whether the endemic equilibria is locally asymptotically stable or not. Secondly, by assuming that the rate of vaccination in the migrant population is constant, we apply optimal control theory to find an optimal vaccination strategy in the local population. Our numerical simulation shows the effectiveness of the control strategy. This model is suitable for modeling the real life situation to control many communicable diseases. Models similar to the model used in the main contribution of our dissertation do exist in the literature. In fact, our model can be regarded as being in-between those of [Jia et al., Theoretical Population Biology 73 (2008) 437-448] and [Piccolo and Billings, Mathematical and Computer Modeling 42 (2005) 291-299]. Nevertheless our stability analysis is original, and furthermore we perform an optimal control study whereas the two cited papers do not. The essence of chapter 5 and 6 of this dissertation is being prepared for publication.</b></p>

The thesis is based on using dynamical systems theories and techniques to study the qualitative dynamics of herpes simplex virus type 2 (HSV-2), a sexually-transmitted disease of major public health significance. A deterministic model for the interaction of the virus with the immune system in the body of an infected individual (in vivo) is designed first of all. It is shown, using Lyapunov function and LaSalle's Invariance Principle, that the virus-free equilibrium of the model is globally-asymptotically stable whenever a certain biological threshold, known as the reproduction number, is less than unity. Furthermore, the model has at least one virus-present equilibrium when the threshold quantity exceeds unity. Using persistence theory, it is shown that the virus will always be present in vivo whenever the reproduction threshold exceeds unity. The analyses (theoretical and numerical) of this model show that a future HSV-2 vaccine that enhances cell-mediated immune response will be effective in curtailling HSV-2 burden in vivo. A new single-group model for the spread of HSV-2 in a homogenously-mixed sexually-active population is also designed. The disease-free equilibrium of the model is globally-asymptotically stable when its associated reproduction number is less than unity. The model has a unique endemic equilibrium, which is shown to be globally-stable for a special case, when the reproduction number exceeds unity. The model is extended to incorporate an imperfect vaccine with some therapeutic benefits. Using centre manifold theory, it is shown that the resulting vaccination model undergoes a vaccine-induced backward bifurcation (the epidemiological importance of the phenomenon of backward bifurcation is that the classical requirement of having the reproduction threshold less than unity is, although necessary, no longer sufficient for disease elimination. In such a case, disease elimination depends upon the initial sizes of the sub-populations of the model). Furthermore, it is shown that the use of such an imperfect vaccine could lead to a positive or detrimental population-level impact (depending on the sign of a certain threshold quantity). The model is extended to incorporate the effect of variability in HSV-2 susceptibility due to gender differences. The resulting two-group (sex-structured) model is shown to have essentially the same qualitative dynamics as the single-group model. Furthermore, it is shown that adding periodicity to the corresponding autonomous two-group model does not alter the dynamics of the autonomous two-group model (with respect to the elimination of the disease). The model is used to evaluate the impact of various anti-HSV control strategies. Finally, the two-group model is further extended to address the effect of risk structure (i.e., risk of acquiring or transmitting HSV-2). Unlike the two-group model described above, it is shown that the risk-structured model undergoes backward bifurcation under certain conditions (the backward bifurcation property can be removed if the susceptible population is not stratified according to the risk of acquiring infection). Thus, one of the main findings of this thesis is that risk structure can induce the phenomenon of backward bifurcation in the transmission dynamics of HSV-2 in a population.

The thesis is based on using dynamical systems theories and techniques to study the qualitative dynamics of herpes simplex virus type 2 (HSV-2), a sexually-transmitted disease of major public health significance. A deterministic model for the interaction of the virus with the immune system in the body of an infected individual (in vivo) is designed first of all. It is shown, using Lyapunov function and LaSalle's Invariance Principle, that the virus-free equilibrium of the model is globally-asymptotically stable whenever a certain biological threshold, known as the reproduction number, is less than unity. Furthermore, the model has at least one virus-present equilibrium when the threshold quantity exceeds unity. Using persistence theory, it is shown that the virus will always be present in vivo whenever the reproduction threshold exceeds unity. The analyses (theoretical and numerical) of this model show that a future HSV-2 vaccine that enhances cell-mediated immune response will be effective in curtailling HSV-2 burden in vivo. A new single-group model for the spread of HSV-2 in a homogenously-mixed sexually-active population is also designed. The disease-free equilibrium of the model is globally-asymptotically stable when its associated reproduction number is less than unity. The model has a unique endemic equilibrium, which is shown to be globally-stable for a special case, when the reproduction number exceeds unity. The model is extended to incorporate an imperfect vaccine with some therapeutic benefits. Using centre manifold theory, it is shown that the resulting vaccination model undergoes a vaccine-induced backward bifurcation (the epidemiological importance of the phenomenon of backward bifurcation is that the classical requirement of having the reproduction threshold less than unity is, although necessary, no longer sufficient for disease elimination. In such a case, disease elimination depends upon the initial sizes of the sub-populations of the model). Furthermore, it is shown that the use of such an imperfect vaccine could lead to a positive or detrimental population-level impact (depending on the sign of a certain threshold quantity). The model is extended to incorporate the effect of variability in HSV-2 susceptibility due to gender differences. The resulting two-group (sex-structured) model is shown to have essentially the same qualitative dynamics as the single-group model. Furthermore, it is shown that adding periodicity to the corresponding autonomous two-group model does not alter the dynamics of the autonomous two-group model (with respect to the elimination of the disease). The model is used to evaluate the impact of various anti-HSV control strategies. Finally, the two-group model is further extended to address the effect of risk structure (i.e., risk of acquiring or transmitting HSV-2). Unlike the two-group model described above, it is shown that the risk-structured model undergoes backward bifurcation under certain conditions (the backward bifurcation property can be removed if the susceptible population is not stratified according to the risk of acquiring infection). Thus, one of the main findings of this thesis is that risk structure can induce the phenomenon of backward bifurcation in the transmission dynamics of HSV-2 in a population.

>Magister Scientiae - MSc / In this dissertation we present the quantitative response of an epidemic of the so-called SIR-type, in a population consisting of a local component and a migrant component. Each component can be divided into three classes, the susceptible individuals, usually denoted by S, who are uninfected but may contract the disease, infected individuals (I) who are infected and can spread the disease to the susceptible individuals and the class (R) of recovered individuals. If a susceptible individual becomes infected, it moves into the infected class. An infected individual, at recovery, moves to the class R. Firstly we develop a model describing two interacting populations with vaccination. Assuming the vaccination rate in both groups or components are constant, we calculate a threshold parameter and we call it a vaccination reproductive number. This invariant determines whether the disease will die out or becomes endemic on the (in particular, local) population. Then we present the stability analysis of equilibrium points and the effect of vaccination. Our primary finding is that the behaviour of the disease free equilibrium depend on the vaccination rates of the combined population. We show that the disease free equilibrium is locally asymptotically stable if the vaccination reproductive number is less than one. Also our stability analysis show that the global stability of the disease free equilibrium depends on the basic reproduction number, not the vaccination reproductive number. If the vaccination reproductive number is greater than one, then the disease free equilibrium is unstable and there exists three endemic equilibrium points in our model. Two of these three endemic equilibria are so-called boundary equilibrium points, which means that the infection is only in one group of the population. The third one which we focus on is the general endemic point for the whole system. We derive a threshold condition that determines whether the endemic equilibria is locally asymptotically stable or not. Secondly, by assuming that the rate of vaccination in the migrant population is constant, we apply optimal control theory to find an optimal vaccination strategy in the local population. Our numerical simulation shows the effectiveness of the control strategy. This model is suitable for modeling the real life situation to control many communicable diseases. Models similar to the model used in the main contribution of our dissertation do exist in the literature. In fact, our model can be regarded as being in-between those of [Jia et al., Theoretical Population Biology 73 (2008) 437-448] and [Piccolo and Billings, Mathematical and Computer Modeling 42 (2005) 291-299]. Nevertheless our stability analysis is original, and furthermore we perform an optimal control study whereas the two cited papers do not. The essence of chapter 5 and 6 of this dissertation is being prepared for publication. / South Africa