We compared the cost-effectiveness of government-funded influenza vaccination (fully-funded policy) with the status quo (self-paid policy) for children aged 6 months to 14 years in Chinese mainland from the societal perspective. In our study, we made the assumption that government-funded influenza vaccination would be free and optional for the pediatric population. This study was reported according to the updated Consolidated Health Economic Evaluation Reporting Standards Statement recommendations for reporting health economic evaluations.

A static decision-tree model (Fig. 1) was developed to estimate the cost and health outcomes that would result from using the alternative policy. The model was built using TreeAge Pro 2019 (TreeAge Software, Inc., Williamstown, MA, USA). In the model, children who are vaccinated are assumed to be at lower risk of developing influenza than unvaccinated children. Children who are vaccinated against influenza are at risk of developing side effects, including fever, site reactions, and anaphylaxis [24]. Of those children who are infected with influenza virus and become symptomatic, a proportion seek healthcare, including self-medication, outpatient visits, and hospitalization [16, 25]. Potential complications include pneumonia, neurological disorders, and death following hospitalization.

Simplified Decision Tree. Chance nodes labelled with the same number have the same subtree

The time horizon of one influenza season (one year, starting in the 14th week of each year and ending in the 13th week of the following year) [26] was used in the model because most costs and outcomes caused by influenza, other than death due to influenza or its complications, occur within one influenza season. All life-years lost due to influenza-related deaths were included in the analysis. The unit costs were valued in 2019 Chinese Yuan (CNY). Where appropriate, unit costs were adjusted to 2019 values using the Consumer Price Index in China, then converted into 2019 US dollars (USD) (1 USD = 6.908 CNY) [27, 28]. Costs and quality-adjusted life-years (QALYs) were not discounted due to the short time horizon.

The US Centers for Disease Control and Prevention Advisory Committee on Immunization Practices has identified children aged < 5 years as being particularly vulnerable to influenza complications [24]. In China, different influenza vaccines are given to children aged < 3 years and ≥ 3 years [13]. The vaccine given to children aged < 3 years is named the “children’s type” and the vaccine given to children aged ≥ 3 years is named the “adults’ type.” We thus divided children under 5 years: 6 months to 2 years and 3–4 years to avoid the impact of differences of vaccines’ prices. These two age groups shared the same cost and epidemiological data except cost of vaccine. The population size of each age group was obtained from the National Bureau of Statistics in China [29]. Additionally, children were stratified according to urban and rural area of residence, in consideration of urban–rural differences in economic status and healthcare-seeking behaviors [16]. The proportion of children living in urban areas was obtained from the 2020 Population Census of China [30]. Population data are provided in the Additional file 1: Tables S1, S2.

According to the WHO influenza vaccination guidelines, children with underlying medical conditions, such as chronic respiratory disease and chronic cardiac disease, are at increased risk of hospitalization and death from influenza [31]. Hence, children were grouped into high-risk and low-risk groups in our model. The risk proportion was estimated using the method suggested by Clark et al., using data on the prevalence of each disease from the Global Burden of Diseases, Injuries, and Risk Factors Study 2017, to estimate the proportion of children with at least one underlying condition [32]. The detailed methods are reported in the Additional file 1: eMethods 1 and Tables S3).

Recently, Wang et al. estimated that, between 2010 and 2020, the mean incidence of influenza infection and symptomatic illness among children aged 0–14 years was 15.86 and 10.50 per 1000 person-seasons, respectively [11]. We applied this method to estimate rates of symptomatic influenza by age group and province in the model. The symptomatic rates for children aged < 5 years and aged ≥ 5 years were estimated to be 0.0586 and 0.0155, respectively, in the 2019–2020 season in China. Further details are provided in the Additional file 1: eMethods 2 and Table S4.

The healthcare-seeking rate among symptomatic cases was derived from a survey conducted in eastern China between 2011 and 2014 [25]. We used a healthcare-seeking rate of 84.4% in municipal districts as a proxy of that rate in urban areas, and a rate of 79.1% in counties as a proxy in rural areas. The proportions of different healthcare-seeking behaviors were obtained from a national survey conducted in 2017–2018 [33]. The proportions of complications after hospitalization were derived from two epidemiological surveys [34, 35]. Li et al. reported the influenza-associated excess respiratory mortality by provinces in China [36]. The case fatality ratio of hospitalization was calculated using influenza-associated mortality and other parameters. Detailed description was provided in the Additional file 1: eMethods 3 and Table S5.

According to one systematic review, children with influenza and underlying conditions have an increased risk of hospitalization [odds ratio (OR) = 3.39] and death (OR: = 2.04) compared to children with influenza without underlying conditions [37].

The cost of vaccination included the cost of vaccines, cost of administration, and cost of parent’s time taking children to be vaccinated [24, 38]. We searched the price of influenza vaccines on national and provincial official procurement websites from 2018 to 2021 (Additional file 1: Table S6). The prices of the child and adult influenza vaccine were estimated to be 4.56 USD and 6.66 USD, respectively, using bootstrap sampling of the data [16]. The cost of administration was derived from a national survey [39]. Additionally, the economic loss for parents due to taking their children to be vaccinated included productivity loss and transportation costs [39]. Productivity loss was estimated through multiplying the mean hourly wage of Chinese workers by average hour (1.43 h) spent [24, 39]. Detailed data regarding this calculation are provided in the supplementary material (Additional file 1: Table S7). We used the clinical effectiveness of influenza vaccine estimates of Tricco et al. in the model [40]. In China, most child and adult vaccines are inactivated split vaccines [13]. The odds ratios of the matched and mismatched trivalent inactivated influenza vaccine (TIV) effectiveness among the population were estimated to be 0.35 and 0.44, respectively. To obtain a conservative estimate of the effectiveness of vaccination, we used mismatched TIV effectiveness data among the general population as a proxy of effectiveness data for children.

Side-effect data were derived from the Chinese national surveillance system of adverse events of seasonal influenza vaccine during the 2015–2018 influenza season [41]. The cost of fever was assumed to be equal to the cost of self-medication. It was assumed that fever and site reaction do not cause health utility loss because of their short duration. The cost and utility loss due to anaphylaxis was obtained from published literature [24].

According to Yang et al. [17], we estimated influenza vacciantion coverage among children using number of vaccine doses supply (Additional file 1: eMethods 4 and Table S8). The influenza vaccination coverage among children in 2019–2020 season was estimated to 0.0695. Extrapolating from the experience in Beijing, vaccination coverage under the fully-funded policy was assumed to be 0.40.

The cost of self-medication for pediatric influenza was derived from a survey in Jiangsu Province, China [42]. We assumed the cost of self-medication is the same for children aged < 5 years and ≥ 5 years. The cost of outpatient and inpatient services were based on a national survey, and included direct and indirect medical costs [43]. The cost of self-medication, outpatient services, and inpatient services for other provinces and at the national level were adjusted using the local ratio of gross domestic product (GDP) per capita in 2019.

The national- and provincial-level costs of influenza-related complications were obtained from a previous study [38]. The cost per inpatient case of Hib pneumonia was used as a proxy of the cost of an inpatient case of influenza pneumonia, and the cost per inpatient case of meningitis was used as a proxy of the cost of per inpatient case of neurologic disorder. The cost of death was assumed to be ten times the cost of one inpatient stay, according to a previous study [24]. The lifetime productivity loss caused by death was estimated using the human capita method [38]. The retirement age was set at 60 years. An annual discount rate of 3% was used in the estimation of lifetime productivity (Additional file 1: Table S9) [44].

The healthy utility loss for outpatients and inpatients was calculated using the method suggested by Yang et al. [16, 45]:

$$} = \, \left( }}} \right) \, \times \, \left( }/.} \right).$$

The utility of the general population was obtained from the National Health Services Surveys between 2008 and 2013 [46]. The utility of outpatients and inpatients with influenza aged < 5 years were estimated to be 0.6286 and 0.5900, respectively; those aged ≥ 5 years were estimated to be 0.6216 and 0.6132, respectively [45]. The mean duration of an influenza episode for outpatients and inpatients was assumed to be 6.2 days and 11.8 days, respectively [45]. The QALY loss for self-medicated patients was assumed to be 0.005. The QALY losses for pneumonia and neurologic disorders were derived from published literature [24].

The primary outcomes of this study were total cost, effectiveness (QALY gained), and cost-effectiveness (incremental cost per QALY gained). The incremental cost-effectiveness ratio (ICER), defined as the incremental costs per QALY gained, was used to compare the fully-funded policy with the self-paid policy at the national and provincial levels (Additional file 1: eMethods 5). In the base-case analysis, the willingness-to-pay (WTP) threshold was set to USD 10,144, the GDP per capita in 2019 [47]. The GDP of each province is provided in the Additional file 1: Table S1. Additionally, we tested a WTP threshold estimated by University of York for China, which is between USD 1162 and USD 4595 per QALY [48].

To explore the drivers of the results, deterministic sensitivity analyses were performed of the base-case scenario at a national level. Probabilistic sensitivity analyses (PSA) were performed to examine the joint impact of parameter uncertainty on ICER using Monte Carlo simulation. The median values and the 95% uncertainty range (UR) (centiles 2.5–97.5) were estimated based on 10,000 simulations. The distributions of parameters are shown in Table 1. The cost-effectiveness acceptability curves were constructed under various WTP thresholds at a national and provincial level.

Additionally, we explored various scenarios in sensitivity analyses. In Scenario 1, we estimated the indirect effect of providing children with influenza vaccination based on previous epidemiological and modelling studies [49,50,51,52]. We used a conservative assumption that, when compared to a 0.0695 coverage (self-paid policy), symptomatic cases among children who were unvaccinated would decrease by 4% due to the indirect effect of a 40% vaccination coverage (fully-funded policy). We also analyzed the outcomes using a range of possible indirect effect values in the sensitivity analysis (1% and 10%). In Scenario 2, we used a conservative (30%) estimate of vaccination coverage under the fully-funded policy. In Scenario 3, we tested a higher probability of adverse events of vaccination based on a study conducted in the United States [24]. In Scenario 4, we tested the impact of switching to a healthcare sector perspective, as opposed to the societal perspective used in the base-case analysis. The influenza-related cost only included direct medical costs. The cost of parents taking their children to be vaccinated and the lifetime productivity loss were not considered in this scenario. In Scenario 5, we estimated the clinical effectiveness of vaccination based on the assumption of matched, rather than mismatched vaccines. In Scenario 6, we tested the joint impact of the indirect effect, higher probability of side effects, and mismatched vaccine effectiveness. A detailed description of the different scenarios is shown in Additional file 1: Table S10.