Pneumococcal Vaccination for Children in Asian Countries: A Systematic Review of Economic Evaluation Studies

Background: Evidence on costs and health benefits of pneumococcal conjugate vaccine (PCV) for children in Asian countries is limited but growing. As a region with a considerably high burden of pneumococcal disease, it is prominent to have a comprehensive overview on the cost-effectiveness of implementing and adopting a PCV vaccination program. Methods: We conducted a systematic review from Pubmed and Embase to identify economic evaluation studies of PCV for children in Asian countries up to May 2020. Data extraction included specific characteristics of the study, input parameters, cost elements, cost-effectiveness results, and key drivers of uncertainty. The Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statement was followed for this systematic review. The reporting quality of the included studies was evaluated using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. Results: After the screening process on both the title and abstract and full text of 518 records, a total of 25 studies fulfilled the inclusion criteria, and were included in the review. The majority of included studies demonstrates that PCV for children is cost-effective in most of the Asian region, and even cost-saving in some countries. Most of the included studies implemented cost utility analysis (CUA) using either quality-adjusted life years (QALYs) or disability-adjusted life years (DALYs). Overall, the main drivers affecting the cost effectiveness were vaccine price, burden regarding pneumonia-related parameters, and the inclusion of herd effects. Conclusion: The children pneumococcal vaccination program appears to be a cost-effective intervention in Asia, and even cost-saving in certain conditions. Vaccine price, pneumonia-related disease burden, and the inclusion of the herd effect are observed as important key drivers in estimating cost-effectiveness in this region. Incorporating PCV in vaccination programs in this region was found to be highly favorable.


Introduction
Pneumococcal disease (PD), which is caused by Streptococcus pneumoniae (SP), remains to be a globally problematic burden, accounting for 16% of deaths in children less than five years of age [1,2]. SP is transmitted through the exposure to airborne droplets, when there is direct individual-to-individual contact. The carriage of SP is more prevalent in children compared to adults, with increasing colonization rates observed from birth until the age of 1-2 years [3,4]. Its manifestation includes invasive PD (IPD), such as meningitis, bacteremia, and sepsis, and non-invasive PD (NIPD), such as acute otitis media (AOM), pneumonia, bronchitis, and sinusitis [5][6][7].
Complexity in early diagnosis and the growing incidence of SP penicillin-resistant strains has complicated management of PD, contributing to a substantial clinical and economic burden on the health care system and in society [8][9][10]. Vaccination remains the cornerstone in reducing PD rates. Among 90 known serotypes of SP, various serotypes can lead to PD [2]. Protection against seven SP serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) is provided by the first pneumococcal conjugate vaccine (PCV) developed, a seven-valent PCV (PCV7). A significant reduction of PD incidence rates was associated with the use of this vaccine [11,12]. The licensure of newer versions of PCV, a 10-valent PCV (PCV-10) and a 13-valent PCV (PCV-13), which consist of an additional three (1, 5, 7F) and six (1, 3, 5, 6A, 7F, 19A) serotypes' antigens, respectively, were assessed based on noninferiority efficacy comparison with PCV-7 [13,14]. With the proven effectiveness of PCV, the World Health Organization (WHO) encourages the prioritization of the inclusion of PCV in national universal immunization programs, worldwide [15].
The burden of PD is considerably high in the Asian region. Asian countries are among the countries with the highest number of deaths associated with PD. The incidences of PD is concentrated particularly in South Asia [2,16]. However, within Asian countries, only few countries, such as Pakistan and the Philippines, have already included PCV in their universal vaccination programs [17,18]. The exact policies in pneumococcal vaccination programs are usually determined on multiple factors, including (availability of) prevalence data, perception of vaccine effectiveness, and national budgets [18][19][20]. The role of a health-economic evaluation is prominent in the decision-making process related to public health interventions. It provides the evidence to ensure efficient allocation of scarce healthcare resources [19]. Such information may contribute to the evidence-based policy formulation related to PCV and help policy makers in the decision on the possible introduction of a universal PCV immunization program in the region. Considering the high burden of PD in Asia and the lack of a comprehensive review on a health-economic evaluation of PCV in this region, we aimed to summarize potential health and economic benefits of PCV for children in Asian countries.

Methods
The Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statement was used for this systematic review [21].

Search Strategy
The systematic search was conducted in two electronic databases (Pubmed and EMBASE) to identify all economic evaluation studies of PCV for children in Asian countries. The following keywords were used for the search: (

Study Selection
The initial search records from electronic databases were exported to Mendeley reference manager and checked for duplicates. The title and abstracts were then screened for relevance. The full texts of the included records were retrieved and reviewed. The screening process was performed by two reviewers (NZ and WNI) with the following inclusion criteria: Study design should be a complete economic evaluation classified in one of the formal health-economic study categories, including cost-minimization analysis (CMA), cost-effectiveness analysis (CEA), cost-utility analysis (CUA), or cost-benefit analysis (CBA); and the intervention should be a universal PCV immunization program for children in Asian countries. Any disagreements were resolved by discussions with a third reviewer (AAS).
We excluded multi-country economic evaluation studies without specific analysis per country, systematic review, experimental and observational studies, conference abstracts, and non-English studies.

Data Extraction
From each included study, we extracted data regarding study characteristics (author, year of publication, country, study objectives, detailed analysis, type of study), study design (methods, perspectives, herd effect, time horizon, discount rate, outcomes, and sensitivity analysis), and cost elements. Economic results from the analysis were converted to 2018 International $ using purchasing power parity (PPP) and gross domestic product (GDP) deflators [22,23]. If a study did not state the year of costing, it was estimated that the costing year was similar to the year of publication.

Quality Assessment
The quality of reporting was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. It provides a set of recommendations, including a checklist, to facilitate adequate reporting of economic evaluation studies. The checklist consisted of 24 items classified in 6 categories, namely title and abstract, introduction, methods, results, discussion, and others. The compliance to each of the criteria was assessed for each study and categorized as follows: Complied completely, partially, or not at all [24].

Systematic Search
The initial search identified 518 records in Pubmed and Embase. After removing 35 duplicates, 483 articles were screened by title and abstract, excluding 442 records. Forty-three records screened on full text, of which 16 articles were excluded due to the study being conducted in adults (n = 16) and multi-country studies without a specific analysis per country (n = 2). Two extra additional articles were identified from snowballing on references during full-text screening, resulting in the final inclusion of 25 studies (Figure 1) [20,.

Study Findings
The majority of the studies (n = 22) confirmed that pneumococcal vaccination would be a cost-effective intervention [20,[25][26][27][28][29][30][31][33][34][35][36][37][38][39][40][41][42][43][44][45]48]. Only three studies showed that PCV-7, PCV-10, and PCV-13 would not be cost-effective [32,46,47]. There were conflicting results with regards to the benefits of PCV-10 and PCV-13. Five studies showed that PCV-10 would be cost-saving compared to PCV-13 [25,34,36,42,44], while another five studies found the opposite result [20,26,31,37,42]. Four studies confirmed that PCV-7 would be cost-effective compared with no vaccination, of which one study also showed that it would be cost-saving [27,29,30]. PCV-13 was assessed in six studies, with cost-effective findings observed in all studies [35,38,40,41,43,45], with an additional condition observed in a Japanese study showing that PCV-13 would be a socially acceptable option compared to current PCV-7 vaccination if it had additional protection against AOM compared to PCV-7, and the cost of PCV-13 per dose is 1.7 times less than that of PCV-7. Four BIAs showed conflicting results, in which two studies showed the introduction of PCV-13 would reduce healthcare costs as well as societal costs [37,45], while the other two showed that the cost of a universal PCV immunization program was higher than the current healthcare budget, which was only sufficient to provide PCV vaccination for 25% of the cohort [31] and either the no co-payment or co-payment vaccination program appears to not be budget saving for the first six years [39].
Findings on a favorable cost-effectiveness are related with the threshold of willingness to pay (WTP) to define cost-effectiveness. The majority of the studies (n = 17) used the WHO criteria [26,27,29,30,32,[34][35][36][37][38][39][40][41][42][43][44]48], namely that vaccination would be considered cost-effective if the incremental cost-effectiveness ratio (ICER) was not more than three times the gross domestic product (GDP) per capita and cost-saving if it was not more than one time GDP per capita [52]. Five other studies used more conservative approaches, in which cost-effectiveness was defined as the ICER not exceeding one time GDP per capita [25,28,31,45,47]. One study explicitly stated the WTP threshold based on a national pharmacoeconomic guideline [20], while the other one synthesized a range of WTP thresholds based on an acceptability curve of vaccination with various vaccine prices per dose and dosing schedules [46].

Quality of Reporting
Fulfilment of the reporting criteria based on the CHEERS checklist varied among the sections. Sections that were sufficiently reported by all studies included the introduction, study perspective, setting, and comparator. In the abstract section, almost one-third of the articles failed to report brief results of the sensitivity analysis. Most articles described the target population and time horizon for vaccination, but the reason for choosing such a group and time range were partly reported. The discount rate for both vaccine price and efficacy were sufficiently reported by most studies. CHEERS recommends the reporting of the outcomes and the reason for choosing the measure. The latter criterion was not sufficiently reported. Most studies reported the source of costs estimation, such as from the authority data and published studies. The currency used was provided in all studies, but the year of costing and conversion were not fully reported. Measurement and valuation of preference-based outcomes, such as health-related quality of life (HRQoL), were another criterion that was poorly reported by relevant articles. Furthermore, we found that although most studies reported the choice of economic models, only a few reported the rationale to use such a model. In the discussion section, most studies reported information related to the generalizability and study limitations. The source of funding was reported in most studies, but not all studies described the role of the funder. A summary of the results from the CHEERS checklist is provided in Figure 2.

Discussion
This systematic review demonstrated that a pneumococcal vaccination program for children would be a cost-effective intervention in most Asian countries (in 22 of 25 studies), and even cost-saving in certain conditions. Potentially comparable benefits were shown by PCV-10 and PCV-13, with five studies showing that PCV-10 would be cost-saving compared to PCV-13 [25,34,36,42,44], and another five studies favoring PCV-13 [20,26,31,37,42]. The findings were sensitive to vaccine price, AOM, and other diseases' burden regarding pneumonia-related parameters, and the inclusion of the herd effect.
Most of the decision analytic models used in this review were static models. Herd effects could have a significant impact on health economic analysis of PCV. In this review, most studies considered herd effects, although the majority of studies incorporated this effect in a static model, and only one study assessed it in a dynamic model. The application of a dynamic model allows better estimation of disease exposure that is related to the development of the herd effect. In countries where the vaccine coverage is particularly high, a static model may be sufficient due to a lack of further herd immunity benefits since most individuals are already vaccinated [53][54][55]. However, as most Asian countries have considerably low PVC coverage [17], incorporating a dynamic model, where disease transmission is comprehensively taken into account by indirect effects, such as herd protection, can better capture the benefit of PCV in a population. Real-world herd effects following the introduction of PCV-13 on IPD were observed in different regions, such as in the USA, Denmark, France, and the UK, where high coverage of the vaccine was observed [56].
Costs related to PCV, as one of the driving factors of cost-effectiveness, varied across the countries in the included studies. Multiple factors can influence vaccine prices, including regulation for procuring vaccines, public health value, and the extent of the government's commitment related to coverage of the vaccine for the population [57]. In several Asian countries, PCV is only available on the private market, such as in Malaysia and China, resulting in a higher price of PCV [28,42]. In a Chinese study showing that PCV-7 would not be cost-effective, the price of PCV was even more expensive than in European vaccination programs [32,58]. Although in most studies the PCV was proven to be cost-effective, we observed in several countries that the additional budget to healthcare should be allocated to allow the inclusion of PCV in their universal immunization program [26,31]. It was estimated that PCV would cost more than any other vaccines in such a program [38]. Negotiations with manufacturers should be initiated to obtain better pricing, enabling better immunization coverage and greater market sustainability of PCV.
One of the major contributing factors in PD burden are related to AOM. Previous studies indicated that the burden and expenses for AOM treatment could exceed that of IPD [59]. Although AOM is not life-threatening, it is highly prevalent and its treatment, including the sequelae, requires a substantial amount of costs due to the high volume of patient consultation, myringotomy/tympanostomy tube surgical procedure, and utilization of antibiotics [59,60]. Vaccine protection against AOM and pneumonia was also frequently reported as an influential parameter on PCV cost-effectiveness [20,25,28,44].
A previous systematic review on the cost-effectiveness of pneumococcal vaccination in children in low-and middle-income countries (LMICs) suggested that PCV vaccination in children was considered to be a cost-effective intervention in most LMICs. Similar to our results, the key drivers of cost-effectiveness results were vaccine price, burden concerning pneumonia-related parameters, and vaccine efficacy [61]. Among 22 included studies in the aforementioned review, only 7 Asian countries were included. Considering that the burden of PD is considered high in the Asia region, our current review can complement the results from a previous systematic review to inform decisions makers on the costs and benefits of introducing PCV vaccination in a country's immunization program.
A global modelling analysis assessing both the effect and cost-effectiveness of PCV vaccination predicted that the introduction of PCV vaccination was estimated to be the most effective in averting disability-adjusted life years (DALYs) in Asia and Africa [62], which is probably due to the high burden of pneumonia-related diseases in both regions. The ICER for PCV introduction was also estimated to be cost-effective in the majority of countries worldwide [62], as indicated by cost-effectiveness thresholds, such as GDP per capita, and a more stringent one using the country-level opportunity cost of health expenditure [63]. Nevertheless, PCV is one of the most expensive vaccines, which can hamper its introduction, especially in countries with limited resources. Vaccine price remains one of the important key drivers of cost-effectiveness in many countries [61,63]; therefore, reviving joint efforts, especially on PCV introduction with affordable prices, is necessary, especially for underprivileged populations [62]. This review indicates that a comparable cost-effectiveness is observed among PCV-10 and PCV-13 in several different settings, suggesting that a country's decision to incorporate PCV into its immunization program should also evaluate the interchangeability of the vaccine by considering benefits in terms of both the cost and effectiveness. This could enable policymakers to make an informed decision while choosing the most appropriate vaccine according to the country's epidemiological and immunization program [64].
In this review, the CHEERS checklist was used to assess the quality of reporting in the included studies. The quality of reporting is one of the prominent aspects of economic evaluation studies, as it provides transparency. Although most of the studies were already adequately complied with the standards in the checklist, there were some points there were poorly fulfilled by the majority of studies, e.g., the rationale to use the chosen decision modeling and the details or description of the role of the funder. Previous studies observed that health economic evaluation funded by pharmaceutical companies tends to have favorable results compared to noncommercially funded studies, thus the reporting of the source of funding and its role in the study is important to allow better assessment of study credibility [65,66].
To the best of our knowledge, this is the first systematically performed review on PCV with the focus on Asia. Systematic approaches were taken in identifying relevant studies from electronic databases. Furthermore, the initial and full-text screening process were carried out by two researchers independently using prespecified inclusion and exclusion criteria, therefore reducing potential bias.
Inevitably, this review has some potential limitations. Although systematic approaches were applied in both the literature search and screening, there is a possibility that some studies may were missed as we focused more on studies in peer-reviewed journals, published in the English language. CHEERS checklist was used to assess the reporting format of the included studies, and the compliance to each criteria in the checklist was categorized as complete, partial, or not at all. However, in the end, the classification and also interpretation were based solely on the reviewers, who did do their utmost best to be highly objective in their task.

Conclusions
As pneumococcal infections result in a considerable burden in the Asian region, the control of PD with vaccination is of utmost importance. Some prominent parameters, such as the vaccine price, pneumonia-related burden of disease, and the inclusion of the herd effect in the analysis, were observed as key drivers for estimating the cost-effectiveness in this region. A pneumococcal vaccination program for children appeared to be a cost-effective intervention in the Asian region, and even cost-saving under certain conditions.

Conflicts of Interest:
Maarten J. Postma received grants and honoraria from various pharmaceutical companies, inclusive all those developing, producing and marketing pneumococcal vaccines. Other authors report no conflicts of interest that are relevant to the content of this article.