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Research article

Mathematical analysis and optimal control of an epidemic model with vaccination and different infectivity


  • Received: 09 August 2023 Revised: 27 October 2023 Accepted: 31 October 2023 Published: 20 November 2023
  • This paper aims to explore the complex dynamics and impact of vaccinations on controlling epidemic outbreaks. An epidemic transmission model which considers vaccinations and two different infection statuses with different infectivity is developed. In terms of a dynamic analysis, we calculate the basic reproduction number and control reproduction number and discuss the stability of the disease-free equilibrium. Additionally, a numerical simulation is performed to explore the effects of vaccination rate, immune waning rate and vaccine ineffective rate on the epidemic transmission. Finally, a sensitivity analysis revealed three factors that can influence the threshold: transmission rate, vaccination rate, and the hospitalized rate. In terms of optimal control, the following three time-related control variables are introduced to reconstruct the corresponding control problem: reducing social distance, enhancing vaccination rates, and enhancing the hospitalized rates. Moreover, the characteristic expression of optimal control problem. Four different control combinations are designed, and comparative studies on control effectiveness and cost effectiveness are conducted by numerical simulations. The results showed that Strategy C (including all the three controls) is the most effective strategy to reduce the number of symptomatic infections and Strategy A (including reducing social distance and enhancing vaccination rate) is the most cost-effective among the three strategies.

    Citation: Lili Liu, Xi Wang, Yazhi Li. Mathematical analysis and optimal control of an epidemic model with vaccination and different infectivity[J]. Mathematical Biosciences and Engineering, 2023, 20(12): 20914-20938. doi: 10.3934/mbe.2023925

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  • This paper aims to explore the complex dynamics and impact of vaccinations on controlling epidemic outbreaks. An epidemic transmission model which considers vaccinations and two different infection statuses with different infectivity is developed. In terms of a dynamic analysis, we calculate the basic reproduction number and control reproduction number and discuss the stability of the disease-free equilibrium. Additionally, a numerical simulation is performed to explore the effects of vaccination rate, immune waning rate and vaccine ineffective rate on the epidemic transmission. Finally, a sensitivity analysis revealed three factors that can influence the threshold: transmission rate, vaccination rate, and the hospitalized rate. In terms of optimal control, the following three time-related control variables are introduced to reconstruct the corresponding control problem: reducing social distance, enhancing vaccination rates, and enhancing the hospitalized rates. Moreover, the characteristic expression of optimal control problem. Four different control combinations are designed, and comparative studies on control effectiveness and cost effectiveness are conducted by numerical simulations. The results showed that Strategy C (including all the three controls) is the most effective strategy to reduce the number of symptomatic infections and Strategy A (including reducing social distance and enhancing vaccination rate) is the most cost-effective among the three strategies.



    Infectious diseases have always been an important part of human history, where various societies and countries have all witnessed devastating epidemics that resulted in millions of casualties. A notable example is the Spanish flu, which originated in Spain in 1918 and claimed the lives of around 40 million people. The COVID-19 pandemic, which began at the close of 2019, was declared a major global public health concern by the World Health Organization (WHO). Due to the virus's rapid global transmission, it has reached over 200 countries. As of July 22, 2023, there have been approximately 760 million confirmed cases of the virus worldwide, with approximately 6.9 million reported deaths. This has posed a significant threat to the well-being of humans, giving rise to major public health challenges and economic crises [1,2]. Furthermore, it has placed additional strain on global healthcare systems [3].

    Vaccinations stand as the most effective approach for curtailing the transmission of diseases within a population, thus representing a long-term strategy in disease prevention. The introduction of vaccines has played a pivotal role in effectively managing several infectious diseases, including smallpox, cholera, and plague. Notably, the oral polio vaccine, often referred to as the sugar pill, has been instrumental in halting the spread of indigenous wild poliovirus, thereby safeguarding thousands of children from physical disabilities. The field of mathematical epidemiology has witnessed significant and remarkable advancements in modeling vaccination strategies. Lhimn et al. [4] developed a two-group Susceptible-Infected-Recovered (SIR) mathematical model to assess the effectiveness of split-dose vaccines in disease control. Their findings indicated that when vaccine efficacy reaches a certain threshold, vaccines exhibit a positive impact on both reducing the size of epidemics and delay the peak outbreak timing. Gao et al. [5] employed a two-sex mathematical model to assess the impact of vaccinations on Human Papilloma Virus (HPV) infection. Their research demonstrated that implementing a variable vaccination strategy could substantially contribute to reducing HPV prevalence.

    Along with the successful development of the COVID-19 vaccine, many authors have assessed its impact on the transmission of novel coronaviruses. Thompson et al. [6] proposed a detailed mathematical model to study the impact of various preventive and control measures and vaccinations on the spread of COVID-19. Harizi et al. [7] used data from Canada to discuss the impact of universal vaccinations on the transmission of COVID-19. Diagne et al. [8] developed a mathematical model to discuss the effect of the vaccination rate and vaccine inefficiency on the spread of epidemic. Paul et al. [9] used a six-compartment Susceptible-Vaccinated-Exposed-Infected-Hospitalized-Recovered (SVEIHR) model to analyze the effect of vaccines on the spread of COVID-19, and showed that vaccination can help to reduce social stress, which, in turn helps to strengthen the immune system. Rocha et al. [10] used an expanded version of the Susceptible-Infected-Recovered-Death (SIRD) model, including the vaccination effect, to study the impact of vaccines on COVID-19 transmission and concluded that vaccination results in a 5% relative reduction in the total number of deaths. Makhoul et al. [11] evaluated the effect of vaccines against infection and disease and concluded that an increased vaccination rate plays an important role in controlling the spread of the disease. Furthermore, several studies have used mathematical models to explore optimized vaccine distribution [12,13]. Brody et al. showed that the best strategy is to prioritize for older adults and high-exposure populations [14]. Li et al. [15] illustrated that universal booster injections are a cost-effective strategy in fully vaccinated persons aged 65 years.

    Optimal control theory encompasses several crucial principles for guiding the management of epidemic spread through practical control measures. Numerous researchers have applied this theory to explore the optimal strategy for epidemic models. Alrabaiah et al. [16] developed an optimized control model with three control variables and found that an integrated control strategy, including isolation, treatment and vaccination, is the most effective in eradicating Hepatitis B virus (HBV). Odionyenma et al. [17] employed optimal control theory to conclude that a control strategy combining treatment and prevention is the most cost-effective approach in controlling Chlamydia trachomatis, as per a cost-effectiveness analysis.

    However, upon reviewing the aforementioned literature, it becomes apparent that most works tend to focus on either vaccine failure rates or vaccine-induced immune decline while neglecting the possibility of asymptomatic infections progressing to symptomatic ones. Furthermore, there is limited research on optimal comprehensive control strategies that consider multiple factors. In light of these considerations, our study concentrates on evaluating the effects of reducing social distancing, increasing vaccination rates, and enhancing hospitalization rates on an epidemic spread within the population. We establish a transmission model that accounts for vaccination, distinct infection states, and varying infectivity. Through an exploration of its dynamic behavior and numerical simulations, we propose prevention and control strategies for infectious diseases with similar characteristics.

    The structure of this paper is as follows. In Section 2, we mainly make some basic assumptions and introduce the model. In Section 3, we discuss the stability of the disease-free equilibrium, and then conduct numerical simulations to discuss the effects of vaccine-related parameters on the control reproduction number and the spread of an epidemic. In Section 4, we perform sensitivity analyses of a control reproduction number, vaccinated individuals (V), and symptomatic infections (I) to derive three parameters that influence most on-disease transmission. In Section 5, the corresponding optimal control problem is considered, and several different control combinations are compared in terms of the control effectiveness and the cost effectiveness. This paper ends with the conclusion and discussion.

    Assuming that the vaccine, which is available and is partially effective on preventing infection, we divide the total population (N) into susceptible (S), vaccinated (V), exposed (E), asymptomatic (A), symptomatic (I), hospitalized (H), and recovered (R). Based on the divided compartments, we will formulate a transmission epidemic model.

    It is assumed that susceptible individuals are recruited into the population at rate Λ, and receive vaccinations at rate φ. Symptomatic and asymptomatic infections can transmit a disease at rates βεI and βεA, respectively, where β is the basic transmission rate, and εI and εA are adjusted factors for the transmission ability of symptomatic and asymptomatic infections, respectively. Although the hospitalized cases are infectious, we assume that they will not reinfect others due to the increased isolation conditions. We assume that the vaccine may not offer complete protection and vaccinated individuals can become infected with a rate σβ, where σ[0,1] is the modified factor and denote ¯σ=1σ. The vaccinated individuals can return to be susceptible after the vaccine-induced immunity wanes at a rate θ. After contact with infectious individuals, they will enter into an exposed compartment and experience an exposed period (1/α). Due to individual heterogeneity, exposed individuals with a fraction p develop to be asymptomatically infectious while others with a fraction 1p become symptomatically infectious. Furthermore, asymptomatic infections progress to symptomatic infections at a rate δ. The asymptomatic and symptomatic infections can naturally recover at rates rA and rI, respectively. We assume that asymptomatic infections do not need hospitalization and cannot cause an additional death. Alternatively, symptomatic infections require hospitalization at a rate k, and has an additional death at a rate dI. The hospitalized individuals can recover and may die at rates rH and dH, respectively. All recovered individuals enter the recovered compartment and have no secondary infections. Moreover, individuals in all compartments have a natural death rate d. The detailed schematic diagram is shown in Figure 1. Table 1 summarizes the model parameters. Based on the aforementioned assumptions and Figure 1, we formulate the following transmission epidemic model in the form of a nonlinear differential equations given by the following:

    {dSdt=Λ+θVβ(εAA+εII)SN(φ+d)S,dVdt=φSσβ(εAA+εII)VN(θ+d)V,dEdt=β(εAA+εII)SN+σβ(εAA+εII)VN(α+d)E,dAdt=pαE(rA+δ+d)A,dIdt=(1p)αE+δA(rI+k+dI+d)I,dHdt=kI(rH+dH+d)H,dRdt=rAA+rII+rHHdR, (2.1)

    with initial conditions ¯X0=(S(0),V(0),E(0),A(0),I(0),H(0),R(0)), where S(0) is positive and the other initial values are non-negative. For simplicity, we introduce the notations in model (2.1) as follows:

    ι=β(εAA+εII)N,ϕ1=φ+d,ϕ2=θ+d,ϕ3=α+d,ϕ4=rA+δ+d,ϕ5=rI+k+dI+d.
    Figure 1.  Schematic diagram of model (2.1).
    Table 1.  Summary of parameters for the epidemics model.
    Parameter Definition Values Reference
    Λ The recruitment rate of susceptible individuals 50 [18]
    β Transmission rate 2.55 [19]
    ¯σ/εA/εI Modification factor 0.88/0.4775/0.695 [20]/[21]/[21]
    φ Vaccination rate 0.038 [22]
    θ The waning rate of vaccine-induced immunity 0.0057 [22]
    1/α Exposed period 1/5 [23]
    p Proportion of exposed to asymptomatic infections 0.5028 [24]
    δ Transition rate of asymptomatic to symptomatic infections 0.078 [25]
    rA/ rI/ rH Recovery rate 0.165/0.21/0.27 [26]/[27]/[28]
    d Natural death rate 3.5×105 [29]
    dI/ dH Disease-induced death rate 6.248×104 [26]
    k Hospitalization rate 0.4 Asummed

     | Show Table
    DownLoad: CSV

    It should be noted that H and R are independent of the other equations in model (2.1). Therefore, we will focus on the following subsystem:

    {dSdt=Λ+θVιSϕ1S,dVdt=φSσιVϕ2V,dEdt=ιS+σιVϕ3E,dAdt=pαEϕ4A,dIdt=(1p)αE+δAϕ5I, (2.2)

    Denote the initial value of system (2.2) as X(0)=(S(0),V(0),E(0),A(0),I(0)).

    In this section, we will focus on the mathematical analysis of model (2.2) and the associated simulations to explore the influences of vaccine-related parameters on the spread of an epidemic.

    Clearly, system (2.2) with the non-negative initial conditions is wellposed. It is easy to check that the solution of system (2.2) is always unique and non-negative in the region Ω={(S,V,E,A,I)R5+:0<NΛ/d} for all time t0.

    Lemma 3.1. The region Ω is positively invariant of model (2.2).

    It follows from model (2.2) that we can add all the equations and observe that the total population satisfies dN/dt=ΛdN(dII+dHH)ΛdN, which implies that NΛ/d.

    Clearly, model (2.2) has a unique disease-free equilibrium E0=(S0,V0,0,0,0), where S0=Λϕ2/dD1, V0=Λφ/dD1 and D1=ϕ2+φ.

    By the next generation matrix approach [30,31], we obtain the following two matrices:

    F=(ι(S+σV)00) and V=(ϕ3EpαE+ϕ4A(1p)αEδA+ϕ5I).

    Furthermore, linearizing system (2.2) at E0 produces the following two sensitivity matrixes of F and V:

    F=(0βεAD2D1βεID2D1000000) and V=(ϕ300pαϕ40(1p)αδϕ5),

    where D2=ϕ2+σφ. The V is obtained by the spectral radius of the next generation matrix (FV1) with the following expression:

    V=ρ(FV1)=D2D1(pαβεAϕ3ϕ4+(1p)αβεIϕ3ϕ5+pαδβεIϕ3ϕ4ϕ5).

    It can be seen that D1 and D2 are vaccine-related parameters. If we do not take the vaccination strategy into account, that is, φ=σ=θ=0, we have D1=D2=d. In this case, we can obtain the corresponding basic reproduction number, denoted by 0, as follows:

    0=βεApαϕ31ϕ4EA+βεIpαϕ3δϕ41ϕ5EAI+βεI(1p)αϕ31ϕ5EI.

    Clearly, 0 consists of three parts, which implies that there are three transmission routes. Specifically, the first item denotes the number of new, asymptomatic infections during his/her duration period. βεA is the transmission rate of asymptomatic infections. The probability of survival and transfer from exposed individuals to asymptomatic infections is pα/ϕ3, whereas 1/ϕ4 refers to the average duration of transmission in asymptomatic infections. The second and third items denote the number of new, symptomatic infections during his/her average duration period. There are two ways. βεI is the infection rate of symptomatic infections. First, survival and transmission from exposed individuals to asymptomatic infections is pα/ϕ3, and then transmission from asymptomatic infections to symptomatic infections is δ/ϕ4. Alternatively, survival and transmission from exposed individuals to symptomatic infections is (1p)α/ϕ3. 1/ϕ5 is the mean infection duration of symptomatic infections.

    Theorem 3.1. The disease-free equilibrium E0 is globally asymptotically stable if V<1 and σ=1.

    Proof. Step1. Local stability.

    The Jacobian of model (2.2) at E0 is as follows:

    J(E0)=(ϕ1θ0βεAϕ2D1βεIϕ2D1φϕ20σβεAφD1σβεIφD100ϕ3βεAD2D1βεID2D100pαϕ4000(1p)αδϕ5).

    The associated characteristic equation of E0 is given by C(λ)=(λ+d)(λ+D2)f(λ)=0, where f(λ)=λ3+Ψ1λ2+Ψ2λ+Ψ3 with

    Ψ1=ϕ3+ϕ4+ϕ5>0,Ψ2=ϕ3ϕ5+ϕ4ϕ5+ϕ3ϕ4αβD2D1[(1p)εI+pεA],Ψ3=ϕ3ϕ4ϕ5(1V)>0ifV<1.

    Clearly, λ1=d and λ2=D2 are two negative roots of C(λ)=0, and the other three roots are determined by f(λ)=0. Now, we focus on f(λ)=0. From V<1, one can obtain the following:

    ϕ3ϕ4>αβD2D1(pεA+(1p)εIϕ4ϕ5+pεIδϕ5),ϕ3ϕ5>αβD2D1((1p)εI+pεIδϕ4+pεAϕ5ϕ4).

    Thus, Ψ2>0. Since the only negative item ϕ3ϕ4ϕ5 can be counterbalanced by one of items in Ψ1Ψ2, Ψ1Ψ2Ψ3>0 holds.

    By Hurwitz criteria, one has that all eigenvalues of f(λ)=0 have negative real parts. Moreover, C(λ)=0 has five roots with negative real parts. Hence, E0 is locally asymptotically stable if V<1.

    Step2. Globally stability.

    Define the Lyapunov function as follows:

    L=p1E+p2A+p3I,

    where

    p1=ϕ5pαεA+ϕ4(1p)αεI+pαδεI,p2=ϕ3(εAϕ5+εIδ),p3=ϕ3ϕ4εI.

    It is easily seen that L is non-negative in Ω. The time differentiation of L along with the solution of model (2.2) gives the following:

    dLdt=p1dEdt+p2dAdt+p3dIdt=(pαεAϕ5+(1p)αεIϕ4+pαεIδ)(β(εAA+εII)S+σVNϕ3E)+ϕ3(εAϕ5+εIδ)(pαEϕ4A)+ϕ3εIϕ4((1p)αE+δAϕ5I)=(εAA+εII)ϕ3ϕ4ϕ5([pαβεAϕ3ϕ4+(1p)αβεIϕ3ϕ5+pϕ3δβεIϕ3ϕ4ϕ5]S+σVN1)=(εAA+εII)ϕ3ϕ4ϕ5(0S+σVN1).

    Obviously, V=0 if σ=1. Hence, one has

    dLdt=(εAA+εII)ϕ3ϕ4ϕ5(VS+VN1)(εAA+εII)ϕ3ϕ4ϕ5(V1)<0,

    if V<1. Moreover dL/dt=0 only if A=I=0. By LaSalle's invariance principle, E0 is globally asymptotically stable if V<1 and σ=1.

    In this section, based on the parameter values in Table 1, we perform several numerical simulations to explore how the vaccine influences the control reproduction number and the infection size of the epidemic.

    First, Figure 2 shows the influence of vaccines on the control reproduction number. From Figure 2, one can observe the control reproduction number is positively correlated with the immune waning rate, and negatively correlated with the effectiveness rate of the vaccine. Figure 2(a) implies that solely increasing vaccination rate cannot reduce the value of V to below 1. A clear observation is that the vaccine effectiveness rate is more sensitive than the vaccination rate, as shown in Figure 2(b). Concretely, when the value of the vaccination rate is fixed, the value of the control production number decreases linearly with the increasing effectiveness of the vaccine. This suggests that promoting the development of more effective and less wanning vaccines is a more important way to cope with the epidemic.

    Figure 2.  The influences of vaccine-related parameters on the control reproduction number. (a) Interpretation of φ and θ on V. (b) Interpretation of φ and ¯σ on V.

    Next, Figure 3 shows how the vaccination rate influences the finial size of vaccinated individuals and symptomatic infections. In Figure 3, we set φ=0.038 as the baseline value. We observe the changes in behavior by increasing φ by 30%, 60% and 90%, which are summarized in Table 2. From Figure 3, we observe that the finial size of vaccinated individuals increases as the vaccination rate is enhanced, while the size of symptomatic infections does the opposite. Specially, a clear comparison from Table 2 shows that a 30% increase in the vaccination rate leads to a 17.57% increase in the peak value of vaccinated individuals and a 15.73% decrease in the peak value of symptomatic infections; however, if the vaccination rate increases by 90%, the peak value of vaccinated individuals will increase by 47.2% and the peak value of symptomatic infections will decrease by 41.39%. Therefore, additional measures, such as extensively advertising and more encouraging policies, are taken to increase the vaccination rate, which will effectively reduce the peak value of infections and contribute to alleviating the epidemic.

    Figure 3.  The influence of vaccination rate on the size of vaccinated individuals (V) and symptomatic infections (I).
    Table 2.  The peak values of V and I under different scenarios.
    Parameter V I
    φ=0.0380 (baseline value) 252,170 102,070
    30% increment in φ 296,490 86,9010
    60% increment in φ 336,100 71,950
    90% increment in φ 371,190 59,820
    θ=0.0057 (baseline value) 252,170 102,070
    30% reduction in θ 256,040 100,450
    60% reduction in θ 260,050 98,790
    90% reduction in θ 264,190 97,100

     | Show Table
    DownLoad: CSV

    Finally, Figure 4 shows the influences of the immune waning rate on the finial size of epidemic. To do so, we set θ=0.0057 as the baseline value, and observe the changes by reducing θ by 30%, 60% and 90%. Figure 4 shows that the effects on the peak value of vaccinated individuals and symptomatic infections are not so significant. The additional simulation values are summarized in Table 2, which shows that if the immune waning rate is reduced by 90%, the peak value of vaccinated individuals will increase by 4.77% and the peak value of symptomatic infections will decrease by 4.87%. Comparing Figure 3(b) and Figure 4(b), one can conclude that improving the vaccination rate is a more conductive and effective measure to control the epidemic.

    Figure 4.  The influence of the immune waning rate on the size of vaccinated individuals (V) and symptomatic infections (I).

    A sensitivity analysis shows the importance of parameters in relation to disease transmission. This information is essential not only for experimental design, but also for the reduction of complex non-linear models. Two types of sensitivity analyses are used, namely local and global sensitivity analyses. The local sensitivity analysis technique examines the local response of the output by changing one input parameter at a time and keeping the other parameters at their central values [32]. The global sensitivity analysis perturbs the input parameters of the model on a large scale to quantify the overall impact of the model inputs on the model output [33,34]. In this section, we employ a sensitivity analysis to explore how parameters influence the control reproduction number. To do so, we only select eight key parameters, β, σ, θ, α, rI, rA, φ and k, which can be interpreted by some actual measurements.

    The local sensitivity analysis can be quantified by the sensitivity index, which is defined as the forward sensitivity index [33] calculated by γRVξ=RVξξRV.

    The analytical expressions of each parameter sensitivity index for V are as follows:

    γVβ=1,γVα=dϕ3,γVφ=(1σ)ϕ2φD1D2,γVθ=(1σ)φθD1D2,γVk=pkεAϑkϕ5,γVσ=σφD1,γVrA=(1p)εIrAD3rAϕ4,γVrI=prIεAD3rIϕ5,

    with D3=pεAϕ5+(1p)εIϕ4+pεIδ.

    It should be noted that some sensitivity indicators depend on one or more parameters, while partial sensitivity indicators are constant and do not depend on any parameter value. Based on the parameter values in Table 1, the calculated indicators are shown in Table 3 and the absolute sensitivity indicators are shown in Figure 5(a).

    Table 3.  Sensitivity indicators of the control reproduction number.
    Parameter Sensitivity index Parameter Sensitivity index
    β 1 rI -0.2773
    σ 0.4468 φ -0.3600
    θ 0.4233 rA -0.4576
    α 0.00017 k -0.5269

     | Show Table
    DownLoad: CSV
    Figure 5.  (a) Radar plot of the absolute sensitivity index of V. (b) PRCC of V evaluated at the baseline parameter values given in Table 1.

    From Table 3, the parameters with positive sensitivity indicators are β, σ, θ, and α, which means that they have a positive effect on V, that is, the value of the control reproduction number will increase/decrease as parameters β, σ, θ, and α increase/decrease. Furthermore, the sensitivity indicators show that the transmission rate β is the most sensitive positive parameter. The parameters with negative sensitivity indicators are rI, rA, φ and k, which means that they have a negative effect on V, that is, the increase of these parameters will decrease the value of V, and vice versa. Sensitivity indicators show that the hospitalization rate k is the most sensitive negative parameter.

    Compared to the local sensitivity analysis, the global sensitivity analysis extends the range of model input parameters. A global sensitivity analysis is performed by calculating the partial rank correction coefficient (PRCC) [35,36] to sample by the Latin hypercube sampling (LHS) method.

    The PRCC of the control reproduction number is described in Figure 5(b). One can observe that the parameters β, σ, θ, and α are positively correlated with V, and the parameters k, φ, rA and rI are negatively correlated with V. We can further find that the transmission rate β is the most sensitive positive indicator, and the hospitalization rate k and the vaccination rate φ are the most sensitive negative indicators. Therefore, in order to effectively reduce the value of the control reproduction number, it is necessary to carry out control measures to deduce the transmission rate, and increase the hospitalization and vaccination rates, which is consistent with the results of the local sensitivity analysis.

    To assess the importance of parameters on the entire duration of the epidemic, we focus on the state variables V and I. Based on the parameter values in Table 1, we chose a time range from 0 to 100 for the PRCCs, which is plotted in Figure 6, where the gray region indicates that there is no significant difference from zero.

    Figure 6.  Time-varying PRCCs sensitivity indexes of V and I.

    From Figure 6(a), one can observe that the parameters fall into three categories. The parameters φ and β belong to the first category, where φ is always positively correlated with V and β is always negatively correlated with V. The parameter θ belongs to the second category, where θ is negatively correlated with V at the beginning, then enters the grey region and leaves it again as time changes, and finally remains negatively correlated with V and eventually stabilizes. Any additional parameters fall into the third category, where they start in the gray region, either increase or decrease over time, then leave the gray region and eventually stabilize.

    From Figure 6(b), the parameters are also divided into three categories. The first category includes β, α, rI and k, where β is always positively correlated with I and parameters rI, α and k are always negatively correlated with I. The second category contains σ, θ and rA, which start in the gray region, either increase or decrease over time, and then leave the gray region. The third category is the parameter φ, which is initially negatively correlated with I and moves into the grey region over time and is uncorrelated with I.

    From the above analysis, we can observe that the three most important parameters affecting the transmission threshold are the transmission rate β, the vaccination rate φ and the hospitalization rate k. Thus, an optimal control problem to mitigate the COVID-19 epidemic is proposed by introducing three time-varying control measures denoted by ui(t) (i=1,2,3), where u1(t) denotes reducing social distance to decrease the transmission ability, u2(t) denotes enhancing the vaccination rate, u3(t) denotes enhancing the hospitalization rate. Thus, the transmission rate is reduced to (1u1(t))β, the vaccination rate is increased to (1+u2(t))φ and the hospitalization rate is adjusted as (1+u3(t))k. Therefore, model (2.1) with an integrated control strategy is given by the following system:

    {dSdt=Λ+θV(1u1(t))ιS(1+u2(t))φSdS,dVdt=(1+u2(t))φS(1u1(t))σιVϕ2V,dEdt=(1u1(t))ιS+(1u1(t))σιVϕ3E,dAdt=pαEϕ4A,dIdt=(1p)αE+δA¯ϕ5I(1+u3(t))kI,dHdt=(1+u3(t))kIϕ6H,dRdt=rAA+rII+rHHdR, (5.1)

    where ¯ϕ5=rI+dI+d. Denote three control measures as U(t)=(u1(t),u2(t),u3(t)) and the control set as Θ={ui()(L[0,T],R)|0ui(t)1,i=1,2,3}. Thus, we define the objective functional as follows:

    J(U)=tf0L(A,I,u1(t),u2(t),u3(t))dt,

    where the integrand function is given by the following:

    L(A(t),I(t),u1(t),u2(t))=A1A(t)+A2I(t)+12(B1u21(t)+B2u22(t)+B3u23(t)).

    The objective of optimal control is to find the optimal control U such that the number of infections (asymptomatic and symptomatic) is minimized with the smallest cost of the control measures. Here, A1 and A2 represent the weights of asymptomatic and symptomatic infections, respectively. Bi (i=1,2,3) denote the weight coefficients standing for the cost associated with the control variables ui(t) (i=1,2,3), respectively.

    In the following, we will analyze the existence of optimal control and its characteristics by Pontryagin's Maximum Principle [38,39].

    Theorem 5.1. There exists an optimal control U=(u1,u2,u3)Θ such that J(U)=minUΘJ(U).

    Proof. Note that following: (i) the state variables and control variables are non-negative; (ii) the control set Θ is closed and convex; (iii) the optimal system is bounded, which implies the compactness of the optimal control; (iv) the integrand of the objective functional J(U) is convex on Θ; and (v) there exist constants a1,a2>0 and q>1 such that J(U) satisfies the following:

    J(U)a1(|u1|2+|u2|2+|u3|2)q+a2.

    Therefore, it follows from the results in [37] that system (5.1) exists an optimal control U=(u1,u2,u3)Θ such that J(U)=minUΘJ(U).

    To find the characteristic express of optimal control, we denote X=(S,V,E,A,I,H,R)T and λ=(λ1,...,λ7) and then define the Hamiltonian function as follows:

    G(X,λ)=L+7i=1λidXdt. (5.2)

    Here, λi is called to be adjoint functions. When taking the state system (5.1) with Hamiltonian function (5.2) together, the adjoint system is derived by dλi/dt=λi/Xi (i=1,2...,7), that is

    dλ1dt=GS=λ1[(1u1(t))ι(1SN)+(1+u2(t))φ+d]λ2[(1+u2(t))φ+(1u1(t))ισVN]λ3(1u1(t))ι(1S+σVN),dλ2dt=GV=λ1[θ+(1u1(t))ιSN]+λ2[(1u1(t))σι(1VN)+ϕ2]λ3[(1u1(t))ι(σS+σVN)],dλ3dt=GE=λ1(1u1(t))ιSNλ2(1u1(t))ισVN+λ3[(1u1(t))ιS+σVN+ϕ3]λ4pαλ5(1p)α,dλ4dt=GA=A1+λ1(1u1(t))S(βεANιN)+λ2(1u1(t))σV(βεANιN)λ3(1u1(t))(S+σV)(βεANιN)+λ4ϕ4λ5δλ7rA,dλ5dt=GI=A2+λ1(1u1(t))S(βεINιN)+λ2(1u1(t))σV(βεINιN)λ3(1u1(t))(S+σV)(βεINιN)+λ5((1+u3(t))k+¯ϕ5)λ6(1+u3(t))kλ7rI,dλ6dt=GH=λ1(1u1(t))ιSNλ2(1u1(t))ισVN+λ3(1u1(t))ιS+σVN+λ6ϕ6λ7rH,dλ7dt=GR=λ1(1u1(t))ιSNλ2(1u1(t))ισVN+λ3(1u1(t))ιS+σVN+λ7d. (5.3)

    The transversality conditions are as follows:

    λi(T)=0,i=1,...,7. (5.4)

    Combining system (5.1), adjoint system (5.3) and transversality conditions (5.4) forms an optimal control problem. By Pontryagin's Maximum Principle, one can have the following theorem.

    Theorem 5.2. For any optimal control UΘ and solution of system (5.1), the optimal control solution of optimal control problem can be obtained as follows:

    ui=min{1,max{0,uci}},i=1,2,3,

    where

    uc1=λ3λ1B1ιS+λ3λ2B1σιV,uc2=λ1λ2B2φS,uc3=λ5λ6B3kI.

    Proof. The optimal control solution can be obtained by solving the following equations:

    Gu1=B1u1(t)+λ1ιS+λ2ισVλ3ι(S+σV)=0,Gu2=B2u2(t)λ1φS+λ2φS=0,Gu3=B3u3(t)λ5kI+λ6kI=0.

    Thus, one has the following:

    uc1=λ3λ1B1ιS+λ3λ2B1ισV,uc2=λ1λ2B2φS,uc3=λ5λ6B3kI,

    which, together with the upper and the lower bounds of ui(t) (i=1,2,3), derive the characteristic expression of the optimal control solution.

    All parameter values are shown in Table 1 and the control period is set as 80 days. Furthermore, we assume that the values of the weight coefficients are A1=20, A2=50, B1=10, B2=20 and B3=30. The initial state variables are chosen as S(0)=500,000, V(0)=80,000, E(0)=140, A(0)=40, I(0)=28, H(0)=19 and R(0)=0.

    To better visualise the dependence of peak value and peak timing of vaccinated individuals and symptomatic infections on three constant controls, we designed four different constant values for ui (i=1,2,3): (1) no control u1=u2=u3=0; (2) weak control u1=u2=u3=0.1; (3) moderate control u1=u2=u3=0.2; and (4) strong control u1=u2=u3=0.3. Figure 7 illustrates the effect of the different control intensities on the peak value and peak timing of vaccinated individuals and symptomatic infections, where the numerical results summarized in Table 4. As can be seen in Figure 7 and Table 4, the peak value of vaccinated individuals significantly increases with increasing control intensity, whereas the peak value of symptomatic infections significantly decreases. Additionally, it can be seen that the peak timing of vaccinated individuals and symptomatic infections gradually increases as the control intensity increases. Specifically, for the peak value of vaccinated individuals (symptomatic infections), there is an increase (decrease) about 13.2% (26.1%) for weak control, 28.8% (68.9%) for moderate control, and 47.5% (71.9%) for strong control. In addition, with the increase of control intensity, the peak timing of vaccinated individuals and symptomatic infections are delayed.

    Figure 7.  The influence of constant controls on the peak value and peak timing of vaccinated individuals (V) and symptomatic infections (I).
    Table 4.  The comparison of the spread of COVID-19 under different control strengths.
    Control No Weak Medium Strong
    Peak Value V 252,170 285,390 324,690 371,890
    I 102,070 75,380 50,550 28,670
    Peak timing V 15 17 21 27
    I 20 23 26 39

     | Show Table
    DownLoad: CSV

    In this section, we combine the forward-backward sweep method [40] and the Runge-Kutta scheme to conduct a numerical simulation of the control problem. To investigate the effectiveness of control strategies, we designed four different strategies:

    ● Strategy A: (u1,u2).

    ● Strategy B: (u1,u3).

    ● Strategy C: (u1,u2,u3).

    ● Strategy D: Black group (No control).

    Strategy A includes the control combination of reducing social distance and improving the vaccination rate. Figure 8(a) shows the optimal curve of Strategy A, where both u1 and u2 are at their maximum values at the beginning, and u1 and u2 decreases from day 64 and day 24, respectively. As shown in Table 5, a comparison between Strategy A and D shows that Strategy A can significantly reduce the peak value of symptomatic infections by 99.91% and shorten the peak timing of symptomatic infections from 20 days to 4 days.

    Figure 8.  The time series of Strategies (A)–(C) and their effects on the number of symptomatic infections.
    Table 5.  The comparison of different strategies.
    Strategies A B C D
    Peak value of I 91 62 58 102,070
    Peak timing of I 4 2.4 2 20

     | Show Table
    DownLoad: CSV

    Strategy B combines reducing social distance and improving the hospitalization rate. It follows from Figure 8(b) that both u1 and u3 display the maximum intensity for about 64 days and 38 days, respectively, and then gradually and slowly decrease till they hit 0. Using data from Table 5 to compare Strategy B and D, the results show that Strategy B significantly reduces the peak value of symptomatic infections by 99.93% and shortens the peak timing to 2.4 days.

    Strategy C contains three control measures. In the beginning, u1 is at its maximum value for 56 days and then starts to decrease, u2 is at its maximum value only for 18 days and then begins to decrease slowly, and u3 remains at its maximum value for 37 days and then begins to decrease. From Table 5, one can see that Strategy C has the best effect on reducing the peak value and delaying the peak timing of symptomatic infections.

    The comparison between the control effects of Strategies A–C is shown in Figure 8(d). Compared to both Strategies A and B, Strategy B has a better effect on reducing the peak value of symptomatic infections. This implies that improving the hospitalization rate is more important than enhancing the vaccination rate. If the effectiveness of the vaccine can be greatly raised and the vaccine immunity waning can be enormously lowered, the situations may undergo completely different changes. Compared to both Strategies A and C, Strategy C adds the control measure of improving the hospitalization rate control measure and has a lower peak value of symptomatic infections. Compared to both Strategies B and C, Strategy C adds the control measure of improving the vaccination rate, in which one can see the peak value of symptomatic infections is reduced but not significantly changed. This shows that increasing the hospitalization rate has a more remarkable impaction on curbing the spread of the epidemic. The more effective vaccine should be quickly developed to improve the role of epidemic prevention. Thus, Strategy C is the most effective strategy to reduce the number of symptomatic infections.

    The impact of an intervention should not only refer to its effectiveness, but also the corresponding control cost. Hence, to further quantify the benefits of different strategies, we introduce the incremental cost-effectiveness ratio (ICER) [41,42], which is defined as ICER(Y)=Δ1/Δ2, where Δ1 = Cost of Strategy Y Cost of Strategy X, and Δ2 = Number of infections averted under Strategy Y Number of infections averted under Strategy X.

    Furthermore, the cost of the strategy can be calculated by tf0(B1u1+B2u2+B3u3)dt, and the number of symptomatic infections averted is tf0(I˜I)dt, where ˜I is the optimal solution under the corresponding strategy. Based on the numerical simulation results, the difference in the number of symptomatic infections averted and the cost are shown in Tables 6 and 7.

    Table 6.  Total costs and averted infections for Strategies A and B.
    Strategy Controls Total infections averted Total costs ICER
    A u1, u2 1,772,784 1,214,700 0.685
    B u1, u3 1,773,322 1,978,800 1420

     | Show Table
    DownLoad: CSV
    Table 7.  Total costs and averted infections for Strategies A and C.
    Strategy Controls Total infections averted Total costs ICER
    A u1, u2 1,772,784 1,214,700 0.685
    C u1, u2, u3 1,773,532 2,351,000 1519

     | Show Table
    DownLoad: CSV

    A clear observation from Table 6 is that if ICER(A) < ICER(B), then Strategy B is less effective than Strategy A. Moreover, Strategy B has a higher cost and a lower benefit compared to Strategy A. Therefore, Strategy B is excluded.

    The next step is a comparison of the ICER values for Strategy A and Strategy C. From Table 7, one can have ICER(A) < ICER(C). Therefore, Strategy C is excluded and Strategy A is more effective.

    From the aforementioned comparisons, we can conclude that Strategy A is the most cost-effective among the three strategies.

    To investigate the impacts of vaccinations and varying infectivity across different infection statuses, we developed a mathematical epidemic model and conducted a comprehensive mathematical analysis of its dynamic behaviors and optimal control. This involved establishing the well-posedness of the solution, deriving the expression for the control reproduction number, and demonstrating the existence and global stability of the disease-free equilibrium.

    Furthermore, we conducted two types of sensitivity analyses to identify which parameters have the most significant influence on the threshold and the spread of infections. This information serves as the theoretical foundation for devising corresponding control strategies. Notably, the top three parameters found to be most influential are the transmission rate, the vaccination rate, and the hospitalization rate. Consequently, we proposed and rigorously analyzed a time-varying optimal control problem, thus providing specific expressions for optimal control strategies. These strategies hold the potential to assist public health efforts in effectively preventing and controlling epidemics.

    Our findings indicated that the control reproduction number plays a pivotal role in determining the global stability of the disease-free equilibrium. The results of the sensitivity analyses are valuable for guiding the control strategy implementation. When controls remain constant, higher control intensities lead to larger final sizes of vaccinated individuals, thus suggesting that a robust control strategy offers the most effective means of reducing the peak value and delaying the peak timing of infections. In the case of time-varying controls, we compared various optimal control combinations in terms of minimizing control costs. The results underscore the effectiveness of an integrated control strategy in curtailing epidemics, with increased vaccine protection rates significantly hastening the suppression of infections. Additionally, we conducted a cost-effectiveness analysis to identify the most economically efficient strategy, which involves a combination of reducing social distance and enhancing vaccination rates, which is distinct from the integrated optimal control strategy. This discovery guides devising strategies that align with limited resources and economic considerations.

    In this section, we will discuss the influence of several key factors. As for model (2.1), it incorporates the natural births and deaths (NBD), while ignoring natural-immunity waning (NIW). If either ignoring NBD or considering NIW, one must discover what changes will occur in the long-term dynamic behavior. To understand the influences of such factors, we set the following four cases to perform the numeral simulations:

    ● Case 1: Model (2.1)

    ● Case 2: Model (2.1) without NBD

    ● Case 3: Model (2.1) without NIW

    ● Case 4: Model (2.1) without NIW and with NBD

    First, we compare Case 1 and Case 2 to explore the influence of NBD on the long-term dynamics. Based on the parameter values in Table 1, we can observe from Figure 9 that NBD takes a slight influence in the time-horizon of an epidemic. To be specific, there are some little changes in the peak value of each compartment. When considering NBD, the peak values of each compartment (except S) are higher than those not considered, which is consistent with the reality for the long-time behavior.

    Figure 9.  The influence of NBD on the long-term dynamics.

    Then, we compare Case 1 and Case 3 to understand how NIW affects the dynamical behavior. Based on the previous work in [46], we set the NIW rate as 0.005. Combined with the parameter values in Table 1, we plotted the time series diagrams of each subpopulation. From Figure 10, one can observe that NIW can obviously influence the long-time behavior of susceptible and vaccinated populations, but only has a slight influence on the other populations. It is undeniable that considering NIW within the model will cause non-monotonicity in the proposed system, which will make the analysis on the global dynamical behavior difficult. Our future work will include how to deeply analyze the impact of NIW on the global dynamical behavior.

    Figure 10.  The influence of NIW on the long-term dynamics.

    Finally, we compare Case 1 and Case 4 to investigate the joint influence of NBD and NIW. It follows from Figure 11 that there is an obvious influence on the dynamic behavior of each subpopulation. In the absence of NBD, NIW has the most obvious impact on susceptible and vaccinated individuals, whose numbers significantly increase in the later stage of the epidemic; however, there was a slight influence on the number of other populations (i.e., exposed, asymptomatic, symptomatic, and hospitalized). Furthermore, comparing Figure 10 and Figure 11, one can observe that NBD still has little influence on disease transmission, even in the presence of NIW. This implies that NBD can only slightly affect the long-term dynamic behavior, and perhaps this phenomenon is related with either the proposed model or the parameter values.

    Figure 11.  The joint influence of NBD and NIW on the long-term dynamics.

    Dynamical systems have consistently served as valuable tools in the advancement of life sciences and infectious disease research [43,44,45]. Nonetheless, several complex issues warrant deeper consideration. (ⅰ) The formulation of suitable Lyapunov functions and the application of LaSalle's invariant principle demonstrate the global stability of the endemic equilibrium when the control reproduction number exceeds one. (ⅱ) The impact of virus mutations leading to either multiple or super-infections and the modeling of vaccines with varying protection rates against different virus variants. (ⅲ) In the case of diseases like COVID-19, where vaccines may render a significant proportion of individuals as asymptomatic carriers, it is essential to develop a more detailed description and model of this phenomenon. (ⅳ) Acknowledging that both vaccinated and unvaccinated individuals experience natural immune waning after a certain period of recovery from infection, we must explore how secondary infections among the population influence vaccine scheduling, resource allocation, and control strategies. These considerations represent potential directions for future research and analyses.

    The authors declare they have not used Artificial Intelligence (AI) tools in the creation of this article.

    We are grateful to the editors and referees for their careful reading and valuable comments which have led to a great improvement of this paper. The authors thank Zhen Jin from Shanxi University for his useful suggestions, and Yiwen Tao from Zhengzhou University for improving English writing. This work was supported by the National Natural Science Foundation of China (Nos. 12126349, 12361102, 11901326, 12071382), Natural Science Foundation of Guizhou Province (No. QianKeHe Jichu-ZK[2021] Yiban002), Guizhou Provincial Department of Education Innovation Group Project (No. Qian Jiao He KY Zi[2019]067).

    The authors declare there is no conflict of interest.



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