Global Stability and Optimal Control Analysis of Malaria Dynamics in the Presence of Human Travelers

Department of Pure and Applied Mathematics, Ladoke Akintola University of Technology, Ogbomoso, Nigeria Department of Mathematics, Vaal University of Technology, Vanderbijlpark, South Africa Department of Mathematical Sciences, Redeemer’s University, Ede, Nigeria Department of Mathematics, University of Medical Sciences, Ondo, Nigeria Department of Education, Vaal University of Technology, Vanderbijlpark, South Africa


INTRODUCTION
Malaria is a vector-borne disease caused by parasites of genus Plasmodium whose life cycle depends on the asexual and sexual phases in humans and mosquitoes respectively [1]. The disease is transmitted to humans through the bites of infected female Anopheles mosquitoes. Of the five parasites species that affect humans, Plasmodium falciparum and Plasmodium vivax pose the greatest public health challenge [2]. It is estimated that 212 million cases of malaria occurred globally in the year 2015 with most cases and deaths in the WHO African, South-East Asia and Eastern Mediterranean Regions [3].
The spread of malaria disease in two interacting populations of humans and mosquitoes has been described mathematically via compartmental models governed by autonomous and non-autonomous systems of ordinary differential equations. These models have helped in facilitating the understanding of mechanisms involved in the transmission dynamics of malaria [4 -11] and some of the references therein. A comprehensive survey of malaria models starting from the basic Ross model [12] has been provided in Mandal et al., [13]. Particularly, the advent of the non-autonomous systems of ordinary differential equations in the description of malaria dynamics can be of great importance in assessing the impact of some intervention strategies, namely vector control, chemoprevention and case management on the disease transmission. Using optimal control theory, a number of studies of non-autonomous malaria models have been carried out. Blayneh et al., [14] presented an optimal control framework to examine the effects of time-dependent prevention and treatment efforts on malaria. Makinde and Okosun [15] analyzed the dynamics of malaria infection with infected immigrants by incorporating treatment of infectives and spray of insecticides as control functions.
In another development, Agusto et al., [16] applied optimal control theory to investigate optimal strategies for controlling the spread of malaria using treatment, insecticide treated bed nets and spray of mosquito insecticide as the system control variables, while Ozair et al., [17] analyzed the dynamics of vector-borne disease with nonlinear incidence using similar control variables. Lashari et al., [18] explored the impact of three control variables, namely vector-reduction, personal protection and blood screening strategies, on malaria dynamics with direct and indirect transmissions. Moreover, optimal vaccination and bed-net control efforts in populations with different levels of naturally acquired immunity were presented by Prosper et al., [19]. In Otiento et al., [20], the transmission dynamics of malaria was studied by considering four time-dependent control measures which include insecticide treated bed nets (ITNS), treatment, indoor residual spray (IRS), and intermittent preventive treatment of malaria in pregnancy (IPTp). This paper presents an optimal control framework that does not only consider treatment control measure aimed at the blood-stage infection of malaria in infectious human but also considers a prophylactic measure targeted at treating liver-stage infection in latently infected (exposed) human among other intervention measures, namely mosquitoreduction and personal protection efforts. A class of short term vigilant human travelers who adhere to these control measures are incorporated into the human population. Using stability theory of nonlinear ordinary differential equations, global dynamics of the autonomous version of the formulated model is rigorously analyzed. Optimal control analysis is carried out on the time-dependent model using Pontryagin's Maximum Principle in order to determine necessary conditions for the optimal strategies for controlling the spread of malaria.
The rest of this work is organized as follows. In Section 2, the model with four time-dependent control functions is presented and the qualitative analysis of its time-independent version is carried out. Further, in Section 2, optimal control analysis of the time-dependent model using Pontryagin's Maximum Principle and numerical simulations are performed. Section 3 discuses results by showing the significance of different combinations of the control measures on the malaria dynamics. The work is wrapped up by giving some concluding remarks.

Model Formulation
The model presented in this section takes into account time-dependent control functions such as personal protection, treatments (liver and blood stage therapies) and mosquito reduction intervention strategies. The total human population at time t, denoted by N h (t), is subdivided into susceptible S h (t) (number of individuals not yet infected with malaria parasite but are capable of being infected by infectious mosquitoes at time t; exposed E h (t) (number of individuals infected with parasite still at the liver stage but not yet infectious at time t; infectious I h (t) (number of individuals with malaria parasite at the blood stage and are capable of transmitting the disease to susceptible mosquitoes at time t; and vigilant V h (t) (comprises number of human travelers who are protected against malaria for the entire duration of their short stay in the community). Then, The total mosquito population at time t, denoted by N h (t), is subdivided into susceptible S m (t) (number of ℎ ( ) = ℎ ( ) + ℎ ( ) + ℎ ( ) + ℎ ( ) mosquitoes not yet infected with malaria parasite but are capable of being infected by infectious humans at time t); exposed E m (t) (those infected but not yet infectious at time t); infectious I m (t) (those that are capable of transmitting malaria parasite to the susceptible humans at time t), so that

(2)
It is assumed that new recruits enter human population by birth or immigration at the rate Λ h . A fraction (1 -τ) Λ h enters susceptible population while the remaining fraction τΛ h are short term travelers who enter the community taking antimalarial measures daily for the entire duration of their short stay and then leave without getting infected. This class of of short term travelers are assumed to be protected against malaria infection. The disease transmission terms for humans and mosquitoes populations given, respectively, by are reduced by a factor of (1 -u 1 (t)), where b is the biting rate of mosquitoes, β h (β m )represents the transmission probability in humans (mosquitoes) and represents control variable for personal protection using ITNs and mosquito repellent lotion.
Exposed human progresses at per capita rate α h either to become infectious or recovered due to chemo-prohylaxis (liver-stage therapy) and travel out of the community without re-infection. Thus, control variable u 2 (t) represents the use of liver-stage therapy which measures the level of effective treatment effort. It is worth stating that P. vivax malaria has ability to form dormant liver stages (hypnozoites) which often escape blood-stage therapy (WHO [2] and Howes et al., [21]). Hence, the need for the control variable u 2 (t). Infectious human joins the class of vigilant human travelers at per capita recovery rate u 3 (t)γ, where γ > 0 is a rate constant and 0 ≤ u 3 (t) ≤ 1 represents control on treatment of infectious human targeted at blood stage parasites. It is assumed that recovery of infected humans is not spontaneous but depends only on treatment (liver and blood stage therapies). Every treated individual who recovers is allowed to enter vigilant class and individuals in this class are protected against infection.
The descriptions of variables and parameters used for the model are given in Table 1. The recruitment rate of the mosquito population assumed susceptible, denoted by Λ m , is reduced by a factor (1 -u 4 (t)) and each class of the mosquitoes population is reduced at a rate u 4 (t)r, where r > 0 is a rate constant and u 4 (t) is the control function due to spray of insecticides. Exposed mosquito becomes infectious at per capita rate α m . The death rates of humans and mosquitoes populations are given by µ h and µ m respectively.
The transmission dynamics of the disease is described by the following non-autonomous system of differential equations: with initial data given at t = 0.

Global Dynamics of the Autonomous Version
In the absence of the four time-dependent control functions (i.e., when the non-autonomous model (3) becomes the following autonomous system of ordinary differential equations: The dynamics of system (4) is studied in the feasible region of the form: which can be shown to be positively invariant with respect to (4).

Global Stability of the Disease-Free Equilibrium (DFE)
The DFE of the model (4) is given by Using the next generation matrix method [22], the basic reproduction number of model (4) is given by Other methods for calculating are provided in van den Driessche [23]. Straightforward calculation shows that . This implies that if all individuals recruited into human population are vigilant, then there will not be malaria infection in the population. However, it is assumed that and all other parameters are positive. The dynamical behavior of autonomous system (4) as its solutions approach the disease-free is provided in Theorem 1.

Theorem 1: If,
≤ 1 then the DFE ε given by (5) is globally asymptotically stable in the region Ω.
Proof: Consider the constructed Lyapunov function of the form with the time derivative of along the solutions of system (4) given by Therefore, provided if and only if = 1 or I h = 0 and I m = 0. It follows that the largest invariant set in is the singleton {ε 0 }, and hence by LaSalle's invariance principle [24], the DFE {ε 0 } is globally asymptotically stable. This completes the proof.
The epidemiological implication of Theorem 1 is that malaria elimination is possible regardless of the initial sizes of the sub-populations of the model (4) whenever ≤ 1. This result is graphically illustrated in Fig. (7).

Global Stability of the Endemic Equilibrium
First, the existence of endemic equilibrium (where the components of the infected variables are non-zero) of the model (4) is explored. Let the endemic equilibrium be represented by and solving (4) at steady-state gives with forces of infection for humans and mosquitoes at steady-states given, respectively, by Substituting (10) and the expression for in (11) into the expression for in (11) gives the following linear equation: , ℱ ℎ * * = ℎ * * and ℱ * * = ℎ * * . ℱ * * ℱ ℎ * *

Global Stability and Optimal Control Analysis
The Open Infectious Diseases Journal, 2018, Volume 10 171 (12) where which is always positive since and . It is should be noted from (12) that and no endemic equilibrium exits. On the other hand . Thus, an endemic equilibrium exists only at > 1 and this result is summarized hereunder.

Theorem 2:
The autonomous model (4) has a unique endemic (positive) equilibrium whenever > 1, and no endemic equilibrium otherwise.
Next, the global stability property of the endemic equilibrium ε e of the model (4) is explored in Theorem 3 with graphical illustration given in Fig. (7).

Theorem 3:If
> 1, then the endemic equilibrium ε e , of the autonomous model (4), given by (9) is globally asymptotically stable in the interior of the region Ω.
Proof: The use is made of the following Goh-Volterra type Lyapunov function [25 -28].

(13)
with suitably determined coefficients, The time derivative of in (13) along the solutions of the model (4) is given by The following equilibrium relations hold from (4) at steady-state: Substituting appropriate equations of model (4) and the equilibrium relations (15) into (14) with algebraic simplification gives

(16)
Consequently, ℒ Finally, since arithmetic mean is greater than or equal to geometric mean, it follows that Therefore, since all the model parameters are positive, with if and only if It follows from this that V h → as t → ∞, and hence by LaSalle's invariance principle [24], the endemic equilibrium Ee is globally asymptotically stable whenever > 1. The proof is complete.
The epidemiological implication of the Theorem 3 is that malaria will establish itself in the community whenever > 1 irrespective of the initial sizes of the infectious individuals in the population.

Optimal Control Analysis
In this section, the detailed qualitative analysis of the non-autonomous model (3) is carried out using Pontryagin's Maximum Principle. The bulk of models in the literature of mathematical epidemiology that uses optimal control theory depends on the Pontryagin's Maximum Principle [29 -31]. This is so because necessary conditions for the optimal strategies aimed at controlling the disease spread can explicitly be derived using Pontryagin's Maximum Principle [32]. For a collection of these models, readers may check Sharomi and Malik [33]. The following objective functional is used to minimize the number of exposed human E h (t), infectious human I h (t) and total mosquito population N m (t) while keeping the costs of applying the controls u 1 (t), u 2 (t), u 3 (t) and u 4 (t) as low as possible.

(18)
where W 1 , W 2 , W 3 , C 1 , C 2 , C 3 and C 4 are positive weight constants. The terms represent the costs associated with personal protection efforts, liver-stage therapy, treatment of infectious human and spraying of insecticides respectively. The costs of controls have been chosen to be quadratic in accordance with the standard in the literature [33].
Thus, the goal is to seek an optimal control quadruple such that

(19)
where Lebesgue measurable is the control set. The Pontryagin's Maximum Principle [32] converts system (3), with (18) and (19) into a problem of minimizing pointwise a Hamiltonian H, with respect to where λ i , = 1, 2,...,7 are the adjoint variables. Using the existence result for the optimal control [34], the following theorem is obtained. Further, the optimal controls are given by

(23)
Proof: The existence of optimal control follows from Fleming and Rischel [34] due to convexity of the integrand of the objective functional in (18) with respect to u i i = 1,....,4, over a convex and closed control set , and system (3) satisfies the Lipschitz property with respect to the state variables since the state solutions are bounded. The differential equations (21) governing the adjoint variables λ i i = 1, 2,....,7, are obtained by partial differentiation of the Hamiltonian in (20) with respect to the corresponding state variables, so that with terminal conditions (22). The characterization of the optimal control given by (23) is derived by taking the partial derivative of Hamiltonian (20) with respect to each of the control u i , and solving . This ends the proof.

Numerical Simulations
The optimality system of fourteen-dimensional ordinary differential equations consisting the state and the adjoint equations (3) and (21) respectively is solved using an iterative method with Runge-Kutta fourth order scheme. The state equations are solved forward in time with an initial guess for the controls over the simulated time. Owing to the transversality conditions (22), the adjoint equations are solved backward in time using the current iteration solutions of the state equations. Then the controls are updated by using a convex combination of the previous controls and the value from the characterization (23). This process continues until the difference between the values of unknowns at the previous iteration and that of the present iteration is negligibly small [35].

e.
( 1 )   Fig. (1) illustrates the combined effects of the preventive control u 1 and liver-stage treatment control u 2 on malaria transmission within human and mosquito populations. It is observed that the sizes of exposed human, exposed and infectious mosquitoes with control diminish more rapidly than the case without control. The size of infectious human in Fig. (1b) with control is constantly maintained at the initial condition. The control profiles in Fig. (1e) shows that the optimal control is at the upper bound for 198 days before dropping to the lower bound while the control is at the upper bound until time t = 120 days before reducing gradually to the lower bound at the final time.

RESULTS AND DISCUSSION
As it can be seen in Fig. (2), combination of the treatment controls u 2 and causes a sharp decrease in the number of infectious human. The reduction in the sizes of other classes is not as sharp as when compared with scenario in Fig.  (1). The optimal controls and shown in Fig. (2a) are at the upper bound till about 125 days and 105 days respectively before dropping gradually until reaching the lower bound in the final time. Fig. (3) illustrates the combined effect of preventive and therapeutic controls on the dynamical spread of malaria. It can be observed that the numbers of exposed and infectious human and mosquito diminish more rapidly with controls than when there is no control.    In Fig. (5), the control profiles illustrating the combination of other optimal controls without blood-stage control u 3 are displayed. The behavior of the sizes of human and mosquito populations is similar to that in Fig. (1). However, it can be seen in Fig. (5a) Fig. (7a) depicts the global asymptotic behaviour of the infectious human at the disease-free equilibrium (5) using the parameter values in Table 2 except that µ h = 0.05, β m = 0.01, τ = 0.95 such that = 2.73496 x 10 -4 < 1 where the disease dies out regardless of large initial values of the infectious human population. On the other hand, Fig. (7b) shows the global asymptotic behaviour of the infectious human at the endemic equilibrium (9) using the same parameter values in Table 2 for which > 1 where the disease persists regardless of the initial sizes of the infectious human population.

b.
a.

Global Stability and Optimal Control Analysis
The Open Infectious Diseases Journal, 2018, Volume 10 183 Fig. (7). Global asymptotic dynamics of the disease-free and endemic equilibrium points.

CONCLUSION
The malaria transmission dynamics in the presence of human travelers who are protected against malaria has been analyzed both theoretically and quantitatively. The work is distributed in two parts; autonomous and non-autonomous systems of ordinary differential equations.
The global asymptotic properties of the autonomous version with respect to the disease-free and endemic equilibria are established. The disease-free equilibrium is shown to be globally asymptotically stable when < 1 and a uniquely determined endemic equilibrium of the autonomous system is shown to be globally asymptotically stable when > 1. This shows that the global dynamics of the autonomous model is completely determined by the epidemiological a.
b. In other words, our results ascertain that effective control or elimination in the community depends largely on the basic reproduction number and therefore, efforts that seek the reduction of this basic reproduction number should be encouraged in order to achieve a malaria-free population.
On the other hand, optimal control analysis is performed on the non-autonomous system which incorporates four time-dependent controls, namely liver and blood stage therapies as well as mosquito-reduction strategy using insecticide spray and personal protection effort using insecticide treated bed nets. The analysis made possible by Pontryagin's Maximum Principle coupled with numerical simulations reveal that the combination of the four control strategies may be adopted in curtailing the spread of malaria among the human and mosquito interacting populations.
Hence, individuals traveling into a malaria-endemic region for a short period of time are enjoined to be vigilant by taking into account the combination of the aforementioned control measures with a view to preventing further spread of the disease beyond the malaria endemic region.
It is worth mentioning that the present model is formulated under the assumption that treated individuals travel out of the community without getting re-infected due to strict adherence to control measures. However, further studies may consider re-infection of treated individuals as a result of imperfect treatment or human's failure to adhere strictly to the control measures.

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