Economic evaluations of 13-valent pneumococcal conjugate vaccine: a systematic review

ABSTRACT

Introduction

Studies on economic evaluations of the 13-valent pneumococcal conjugate vaccine (PCV13) have been increasing over the last decade. No systematic reviews have synthesized the evidence of economic evaluations of the PCV13.

Areas covered

We systematically searched the literature which published on peer-reviewed journals from January 2010 to June 2022. The literature search was conducted in the following electronic databases: PubMed, Web of Science, Embase, the Cochrane Library, CNKI, Wanfang database, VIP database. We identified 1827 records from the database search. After excluding 511 duplicates, 1314 records were screened, of which 156 records were retained for the full-text reviews. A total of 44 studies were included in the review. Among the included studies, 33 studies were economic evaluations of PCV13 among children, and 11 studies were conducted among adults. The literature search initiated in April, 2022, and updated in June 2022.

Expert opinion

Vaccination with PCV13 was found to significantly reduce the mortality and morbidity of pneumococcal diseases and was cost-effective compared to no vaccine or several other pneumococcal vaccines (e.g. PCV10, PPV23). Future research is advised to expand economic evaluations of PCV13 combined with dynamic model to enhance methodologic rigor and prediction accuracy.

KEYWORDS:

• 13-valent pneumococcal conjugate vaccine
• PCV13
• cost-effectiveness
• incremental cost-effectiveness ratio
• ICER
• quality-adjusted life-year
• QALY
• disability-adjusted life-year
• DALY
• systematic review

1. Introduction

Pneumococcal diseases (PDs) have become a serious public health problems around the world, and cause significant morbidity and mortality and a substantial burden for health care systems [1–3]. The Streptococcus Pneumoniae (SPn) or pneumococcus is acknowledged as the main cause of PDs, such as bacterial pneumonia, meningitis, acute otitis media (AOM), and bacteremia in children and adults [4]. It has been estimated that more than 300,000 children under 5 years old worldwide died every year from SPn infections [5]. Given the increasing resistance to antibiotics treatments for SPn, there is an urgent need to use vaccines to control PDs [6]. WHO recommends that all countries should incorporate pneumococcal conjugate vaccine (PCV) into their own National Immunization Programs (NIP), especially those countries with high childhood mortality [7].

13-valent pneumococcal conjugate vaccine (PCV13) is one of the major PCVs that has been used since 2010 for prevent PDs among children and adults [8]. In recent years, a number of studies have reported that the incidence of PDs, especially the invasive PDs in vaccinated populations decreased significantly with the use of the PCV13 [9–12]. However, there are significant differences across countries in terms of the income levels and the epidemic intensity of PDs. Based on income levels categorized by the World Bank, the countries and territories were stratified into four

groups, which classified as high-income countries (HICs), upper-middle income countries (UMCs), lower-middle income countries (LMCs), and low-income countries (LICs), respectively [13]. Health economic evaluation is a scientific method to evaluate cost-effectiveness or cost-benefits of health interventions, which can provide scientific evidence for health resource allocation and health care decision-making [14]. In the last decade, studies on economic evaluations of PCV13 have been increasing worldwide. However, the evidence-based cost-effectiveness of PCV13 is unclear. Some studies have demonstrated that PCV13 is more cost-effective relative to no vaccine or other pneumococcal vaccines [14,15], while other studies have shown that the PCV13 vaccine was not cost-effective [16–18]. There is a lack of evidence integration and systematic reviews of the economic evaluation studies for PCV13. No systematic reviews have summarized the cost-effectiveness results of PCV13 among populations of both children and adults in all countries, though a few systematic reviews examined cost-effectiveness of PCVs in children, or adults separately in some regions (e.g. in low- and middle-income countries) [19–21]. Further, no previous systematic reviews have included both English and Chinese language studies. A comprehensive systematic reviews of cost-effectiveness PCV13 is important to provide evidence-based information as decision-makers need to know whether the PCV13 vaccination is cost-effective, and how the vaccination impacts the economic budget.

This systematic review aimed to synthesize the individual studies on the economic evaluation of PCV13.

2. Methods

2.1. Protocol and reporting

This systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO) (registration no. CRD42022327,960), available from https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=327960. The review is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [22].

2.2. Eligibility criteria

Inclusion criteria: Studies were determined to be eligible if they met the following criteria: (1) economic evaluations that compared the PCV13 with other vaccines or no vaccination, including cost-effectiveness analysis, cost-utility analysis, cost-benefit analysis and cost-minimization analysis; (2) outcomes included quality-adjusted life-year (QALY), disability-adjusted life-year (DALY), and the study reported an incremental cost-effectiveness ratio (ICER), or incremental costs, incremental effectiveness; (3) the target populations included children and adults.

Exclusion criteria: (1) Studies describing vaccine effectiveness and immunogenicity; (2) no valid outcome data could be extracted from the studies; (3) studies on data duplication; (4) studies in multiple countries. (5) systematic review and meta-analysis studies, conference abstracts, articles and proceedings.

2.3. Information sources and search

We systematically searched the literature which published on peer-reviewed journals from January 2010 to June 2022. The literature search was conducted in the following electronic databases: PubMed, Web of Science, Embase, the Cochrane Library, CNKI, Wanfang database, VIP database. Search terms included ‘pneumococcal vaccines,’ ‘PCV13,’ ‘13-valent pneumococcal conjugate vaccine,’ ‘cost-benefit analysis,’ ‘cost-effectiveness analysis,’ ‘cost-utility analysis,’ ‘economic evaluation.’ We also screened the references in relevant reviews and meta-analyses to identify potential eligible studies. The search results from the databases were merged, and duplicates were removed. The literature search initiated in April, 2022, and updated in June 2022.

2.4. Selection of sources of evidence

According to inclusion and exclusion criteria, two authors independently conducted the study selection. The authors screened the titles and abstracts. If a decision could not be made based on the title and abstract, the full-text was retrieved for review to determine the eligibility. When there were disagreements on the eligibility of some studies between the two authors, the eligibility of the studies was resolved by discussion among all the authors.

2.5. Data charting process and data items

Subsequently, the full-text articles of all selected studies for the synthesis were retrieved for data extraction. Data were extracted by one author and checked by another author for accuracy and correction. We developed a customized data extraction sheet based on the WHO Guide for standardization of economic evaluations of immunization programs [23]. Extracted information included basic information (i.e. author, year of publication, country and target population), description of the interventions (i.e. types of interventions and comparisons), details of the economic evaluations (i.e. model, currency, type and perspective, time horizon, reference year, discounting and sensitivity analysis) and study findings (i.e. incremental costs, incremental effects and incremental cost-effectiveness ratios).

2.6. Assessment of risk of bias

We used the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement to evaluate risk of bias of the included studies [24]. The CHEERS statement is a report checklist with 24 items developed to assess methodological quality of economic evaluations. Each question was answered with ‘yes,’ ‘no,’ or ‘not clear.’ The question was assigned one score if a confirmative answer ‘yes’ was appropriate for the study, indicating that the study met the quality criteria. If the answer to the question was ‘no’ or ‘not clear,’ it was assigned a score of zero, indicating that the study did not entirely fulfill the quality criteria. The total score was computed as a sum of the score for each question. The quality of the selected studies was determined by the percentage of items that fulfilled the quality criteria. Studies were classified as ‘excellent,’ ‘good,’ ‘fair’ and ‘poor’ quality if they fulfilled 100% of the items, between >75% and <100% of the items, between >50% and ≤75% of the items, and ≤50% of the items respectively [25,26].

2.7. Synthesis of results

Narrative synthesis was used to summarize the findings of individual studies. The main findings of individual studies were presented using descriptive tables for qualitative comparisons.

3. Results

We identified 1827 records from the database search. After excluding 511 duplicates, 1314 records were screened, of which 156 records were retained for the full-text reviews. A total of 44 studies were included in the review. Study selection is shown in Figure 1.

Figure 1. Flow chart for selection of the studies in the systematic review.

3.1. Characteristics of reviewed studies

The characteristics of included studies are presented in Table 1–1 and Table 2. The studies were published between 2010 and 2021, and were conducted among 31 countries. Two studies in Chinese language were PhD and Master degree students’ theses [27,28]. Among the included studies, 33 studies were economic evaluations of PCV13 among children [14,16–18,27–55], and most of these studies included children less than 5 years old. These studies included 7 HICs [29,38,41,49–52], 19 UMCs [14,16–18,27,28,30,32–34,37,40,42,43,45–47,53,54], 5 LMCs [31,35,39,44,48] and 2 LICs [36,55]. Eleven studies were conducted among adults [15,56–65], where 10 studies selected adults aged 50 years older, and one study targeted adults > 18 years of age [58]. Eleven studies were all HICs. All studies performed cost-effectiveness analysis. Twenty-five studies used a 3% discount rate for outcomes. All studies applied health economic models, and 13 studies applied a model time horizon of 5 years. Markov model (n = 22) and decision tree model were the most commonly used models in the included studies. Other models (i.e. TRIVAC model) were also used in some studies [29,34,41–43,54]. In terms of perspectives, 15 studies used the societal perspective, followed by the payer perspective (n = 8), healthcare perspective (n = 5), and government perspective (n = 4). Two studies did not report the perspective [29,59].

Table 1. Characteristics of the included studies.

Author (Year)	Ref	Regions	Country	Target Population	Study Type	Modeling Approach	Time Horizon	Discount Rate	Currency/Year	Perspective	Sensitivity Analysis
Li Y et al, 2021	[14]	UMCs	China	Children	CEA	Decision tree	1	5%	¥/2019	Payer	1 Way, scenario
Bakir M et al, 2012	[16]	UMCs	Turkey	Children	CEA	Decision tree	1	_	US$/2010	HCS	1 Way, PSA
Mo X et al, 2016	[17]	UMCs	China	Children	CEA	Markov	100	3%	US$/2015	societal	1 Way, PSA
Zhou H et al, 2018	[18]	UMCs	China	Children	CEA	Markov	Lifetime	5%	US$/2016	HCS, societal	1 Way, PSA
Kim HY et al, 2021	[29]	HICs	South Korea	Children	CEA	Epidemiologic forecasting model	5	5%	US$/2018		1 Way, PSA
Perdrizet J et al, 2021	[30]	UMCs	Brazil	Children	CEA	Decision tree	5	5%	$BRL/2019	Payer, government	Scenario
Perdrizet J et al, 2021	[31]	LMCs	Filipino	Children	CEA	Decision tree	10	7%	PHP/2020	Societal	Scenario
Wang CX et al, 2021	[32]	UMCs	China	Children	CEA	Markov	5	5%	US$/2019	Societal	1 Way, PSA
Lin L, 2020	[28]	UMCs	China	Children	CEA	Markov	5	5%	¥/2018	Payer	1 Way, PSA
Dilokthornsakul P et al, 2019	[33]	UMCs	Thai	Children	CEA	Markov	5	3%	THB/2018	Societal	Multivariate, PSA, scenario
Ezoji K et al, 2019	[34]	UMCs	Iran	Children	CEA	TRIVAC model	10	3%	US$/2014	Government, societal	Scenario
Krishnamoorthy Y et al, 2019	[35]	LMCs	India	Children	CEA	Static cohort model	10	3%	US$/2017	Government	PSA, scenario
Dorji K et al, 2018	[36]	LICs	Bhutan	Children	CEA	Markov	Lifetime	3%	US$/2017	Government	1 Way, PSA
Shen KL et al, 2018	[37]	UMCs	China	Children	CEA	Decision tree	1	3%	¥/2015	Payer	1 Way, scenario
Kuhlmann A et al, 2017	[38]	HICs	Germany	Children	CEA	Markov	50	3%	EUR/2013	HCS, societal	1 Way, PSA
Sundaram N et al, 2017	[39]	LMCs	Mongolia	Children	CEA	Static cohort model	30	3%	US$/2014	HCS, societal	Scenario
Ning GJ, 2017	[27]	UMCs	China	Children	CEA/CBA/CUA	Markov	5	5%, 3%-8%	¥/2015	Societal	1 Way, PSA
Maurer KA et al, 2016	[40]	UMCs	China	Children	CEA	Markov	5	3%	US$/2014	Societal	1 Way, 2 Way, PSA
Vucina VV et al, 2015	[41]	HICs	Croatia	Children	CEA	TRIVAC model	20	3%	US$/2014	Government, societal	Univariate, multivariate scenario, threshold
Mezones-Holguin E et al, 2015	[42]	UMCs	Peru	Children	CEA	TRIVAC model	20	3%	US$/2012	Government	1 Way, scenario
Kieninger MP et al, 2015	[43]	UMCs	Paraguay	Children	CEA	TRIVAC model	10	3%	US$/2009	Government, societal	Scenario
Sibak M et al, 2015	[44]	LMCs	Egypt	Children	CEA	Static cohort model	10	3%	US$/2012	Government, provider	Multivariate
Mezones-Holguin E et al, 2014	[45]	UMCs	Peru	Children	CEA	Decision tree	3	3%	US$/2011	Government	PSA
Gomez JA et al, 2013	[46]	UMCs	Peru	Children	CEA/CUA	Markov	Lifetime	3.50%	US$/2009	Payer	1 Way, PSA, Scenario
Kulpeng W et al, 2013	[47]	UMCs	Thai	Children	CUA	Markov	Lifetime	3%	THB/2010	Societal	1 Way, PSA
Ayieko P et al, 2013	[48]	LMCs	Kenya	Children	CEA	Static cohort model	5	3%	US$/2010	Societal	PSA, multivariate
Hoshi SL et al, 2013	[49]	HICs	Japan	Children	CEA	Markov	5	3%	¥/2010	Societal	1 Way, PSA, scenario
Earnshaw SR et al, 2012	[50]	HICs	Canada	Children	CEA	Decision tree	Lifetime	_	C$/2010	HCS	Scenario
Díez-Domingo J et al, 2011	[51]	HICs	Spain	Children	CEA	Decision tree	Lifetime	3%	EUR/2009	Payer	1 Way, deterministic, scenario
Robberstad B et al, 2011	[52]	HICs	Norway	Children	CEA	Markov	Lifetime	4%	NOK/2009	Societal	1 Way, PSA, scenario
Mucino-Ortega E et al, 2011	[53]	UMCs	Mexico	Children	CEA	Decision tree	Lifetime	5%	US$/2010	Payer	1 Way
Uruena A et al, 2011	[54]	UMCs	Argentina	Children	CEA	TRIVAC model	20	3%	US$/2009	HCS, societal	Scenario
Kim SY et al, 2010	[55]	LICs	Gambia	Children	CEA	Markov	5	3%	US$/2005	Societal	1 Way, PSA, scenario

HICs: high-income countries. UMCs: upper-middle income countries. LMCs: lower-middle income countries. LICs: low-income countries. CEA: Cost-Effectiveness Analysis. CBA: Cost-Benefit Analysis. CUA: Cost-Utility Analysis. HCS: Health Care System. 1Way: One way sensitivity analyses. PSA: probabilistic sensitivity analyses.

Table 2. Characteristics of the included studies.

Author (Year)	Ref	Regions	Country	Target Population	Study Type	Modeling Approach	Time Horizon	Discount Rate	Currency/Year	Perspective	Sensitivity Analysis
Igarashi A et al, 2021	[56]	HICs	Japan	Adults	CEA	A natural history model	Lifetime	2%	JPY/2019	Payer, societal	PSA, scenario
Gouveia M et al, 2019	[57]	HICs	Portugal	Adults	CEA	Markov	Lifetime	5%	€/2013	Social	1 Way, PSA
Biagini L et al, 2018	[58]	HICs	Chile	Adults	CEA/CUA	Markov	10	3%	US$/2014	Payer	PSA
Chen C et al, 2018	[59]	HICs	Australia	Adults	CEA	Markov	5	5%	$AU/2016		_
Marbaix S et al, 2018	[60]	HICs	Belgium	Adults	CEA	A cohort model	Lifetime	3%	€/2016	Payer	1 Way, PSA, scenario
Boccalini S et al, 2017	[61]	HICs	Italy	Adults	CEA	Decision tree	5	3%	EUR/2015	HCS	1 Way, multivariate
Heo JY et al, 2017	[62]	HICs	South Korea	Adults	CEA	Markov	15	5%	US$/2015	Societal	1 Way, PSA
Dirmesropian S et al, 2017	[63]	HICs	Australia	Adults	CEA	Markov	1	5%	$AU/2016	HCS	1 Way, PSA, scenario
Rodríguez González-Moro JM et al, 2016	[64]	HICs	Spain	Adults	CEA	Markov	5	3%	€/2015	HCS	1 Way, PSA
Mangen MJJ et al, 2015	[15]	HICs	Netherlands	Adults	CEA	Markov	Lifetime	4%	€/2012	Societal	1 Way, multiway, scenario
Smith KJ et al, 2012	[65]	HICs	United States	Adults	CEA	Markov	Lifetime	3%	US$/2008	Societal	Scenario, PSA

HICs: high-income countries. CEA: Cost-Effectiveness Analysis. CBA: Cost-Benefit Analysis. CUA: Cost-Utility Analysis. HCS: Health Care System. 1Way: One way sensitivity analyses. PSA: probabilistic sensitivity analyses.

Table 3 and Table 4 show characteristics of interventions and economic evaluations. In studies of children, 17 studies used three doses of PCV13 [30,31,34,36,39,41–46,48,50–53,55], 15 studies used four doses of PCV13 [16–18,27–29,32,33,35,37,38,40,47,49,54], and one study used three and four doses of PCV13 [14]. In studies of adults, one dose of PCV13 was used in all studies. The vaccine coverage varied from country to country, and the coverage of PCV13 was assumed to be the same as diphtheria, tetanus toxoids, and pertussis vaccine coverage in some countries [16,18,27–29,35,37,38,50,55].

Table 3. Characteristics of interventions and economic evaluations.

Author (Year)	Ref	Regions	Country	Intervention	Comparator	No. of Doses		Vaccine Coverage %	Incremental cost	Incremental effect	ICER	Unit of ICER	Conclusion of EE study
Li Y et al, 2021	[14]	UMCs	China	PCV13	NV	3, 4	70%		Beijing:¥49,160,000	Beijing: 12,010	Beijing:¥4,093	/QALYs	cost-effective
									Shanghai:¥28,650,000	Shanghai: 14,880	Shanghai:¥1,925
									Shenzhen:¥8,760,000	Shenzhen: 7660	Shenzhen:¥1,145
									Chengdu:¥113,550,000	Chengdu: 9710	Chengdu:¥11,693
									Karamay:¥4,060,000	Karamay: 270	Karamay:¥15,132
									Qingdao:¥83,710,000	Qingdao: 5430	Qingdao:¥15,422
									Suzhou:¥60,920,000	Suzhou: 6870	Suzhou:¥8,862
Bakir M et al, 2012	[16]	UMCs	Turkey	PCV13	PHiD-CV	4	84%		$8,235,010	933	_	/QALYs	not cost-effective
Mo X et al, 2016	[17]	UMCs	China	PCV13	NV	4	20%		$21.76	0.000738	$29,460.16	/QALYs	not cost-effective
Zhou H et al, 2018	[18]	UMCs	China	PCV13	NV	4	83.27%		HCS: $189	0.009	HCS: $20,709	/QALYs	not cost-effective
									Societal: $169		Societal: $18,483
Kim HY et al, 2021	[29]	HICs	South Korea	PCV13	PCV10	4	88.60%		$47,419,598	6537	_	/QALYs	cost-effective
Perdrizet J et al, 2021	[30]	UMCs	Brazil	PCV13	PCV10	3	95%		$172,101,081	20,317	_	/QALYs	cost-effective
Perdrizet J et al, 2021	[31]	LMCs	Filipino	PCV13	PCV10	3	90%		PHP12,274,777,282	153,349	_	/QALYs	cost-effective
Wang CX et al, 2021	[32]	UMCs	China	PCV13	NV	4	90%		$15,173,252	986	$15,394	/QALYs	cost-effective
Lin L, 2020	[28]	UMCs	China	PCV13	NV	4	85%		¥631,263,862	5383	¥117,274	/QALYs	highly cost-effective
Dilokthornsakul P et al, 2019	[33]	UMCs	Thai	PCV13	NV	4	_		THB3693	0.038	THB97,269	/QALYs	cost-effective
Ezoji K et al, 2019	[34]	UMCs	Iran	PCV13	NV	3	Various		Government:$573,310,000	Government:303.34	Government: US $1,890	/DALYs	cost-effective
									Society:$466,530,000	Society:303.34	Society: US$1,538
Krishnamoorthy Y et al, 2019	[35]	LMCs	India	PCV13	NV	4	88%		$4,739,655,686.00	10,159,402	$467	/DALYs	highly cost-effective
Dorji K et al, 2018	[36]	LICs	Bhutan	PCV13	NV	3	97%		$0.03	0.0007	$40	/QALYs	cost-effective
Shen KL et al, 2018	[37]	UMCs	China	PCV13	NV	4	85%		¥29,362,300,000.00	370,300	¥79,304	/QALYs	cost-effective
Kuhlmann A et al, 2017	[38]	HICs	Germany	PCV13	PCV10	4	90%		HCS: EUR140,971,958	HCS: 41,859	HCS: EUR3,368	/QALYs	cost-effective
									Societal: EUR454,679,978	Societal: 41,859	Societal: EUR9,826
Sundaram N et al, 2017	[39]	LMCs	Mongolia	PCV13	NV	3	97.60%		$6,250,000	121,000	$52	/DALYs	highly cost-effective
Ning GJ, 2017	[27]	UMCs	China	PCV13	NV	4	90%		¥2,236,679,210,000.00	121	¥1,860,500	/QALYs	not cost-effective
Maurer KA et al, 2016	[40]	UMCs	China	PCV13	NV	4	near 100%		$99.20	0.01	$11,463.60	/QALYs	cost-effective
Vucina VV et al, 2015	[41]	HICs	Croatia	PCV13	NV	3	95%		Government: $49,233,621	Government: 643	Government: US $76,557	/DALYs	unlikely to be cost-effective
									Societal: $45,001,682	Societal: 643	Societal: US $69,977
Mezones-Holguin E et al, 2015	[42]	UMCs	Peru	PCV13	NV	3	Various		$408,260,000	313,119	$1,304	/DALYs	cost-effective
Kieninger MP et al, 2015	[43]	UMCs	Paraguay	PCV13	NV	3	>95%		$69,126,188	14,106	$4,901	/DALYs	cost-effective
Sibak M et al, 2015	[44]	LMCs	Egypt	PCV13	NV	3	96.50%		$1,068,599,533	272,878	$3,916	/DALYs	cost-effective
Mezones-Holguin E et al, 2014	[45]	UMCs	Peru	PCV13	PCV10	3	100%		$514	40.94	$13	/QALYs	more cost-effective
Gomez JA et al, 2013	[46]	UMCs	Peru	PCV13	NV	3	95%		$23,381,588	4389	$5,327	/QALYs	cost-effective
Kulpeng W et al, 2013	[47]	UMCs	Thai	PCV13	NV	4	Almost 100%		THB8,048	0.0044	THB183,0716	/QALYs	not cost-effective
Ayieko P et al, 2013	[48]	LMCs	Kenya	PCV13	NV	3	_		$11,681,790	248,094	$47	/DALYs	highly cost-effective
Hoshi SL et al, 2013	[49]	HICs	Japan	PCV13	NV	4	76.10%		¥10,933	0.0024	¥4,495,903	/QALYs	cost-effective
Earnshaw SR et al, 2012	[50]	HICs	Canada	PCV13	PCV10	3	91%		$132,823,511	13,828	_	/QALYs	cost-effective
Díez-Domingo J et al, 2011	[51]	HICs	Spain	PCV13	NV	3	95%		€ 34,911,853.00	3354	€ 10,407.00	/QALYs	cost-effective
Robberstad B et al, 2011	[52]	HICs	Norway	PCV13	PHiD-CV	3	_		NOK24,239,000	50	_	/QALYs	not cost-effective
Mucino-Ortega E et al, 2011	[53]	UMCs	Mexico	PCV13	NV	3	_		$2,430,534,394.00	332,006	_	/QALYs	more cost-effective
Uruena A et al, 2011	[54]	UMCs	Argentina	PCV13	PCV10	4	99%		HCS: $207,609,804	HCS:7376	HCS: $28,147	/DALYs	cost-effective
									Social: $20,367,859	Social:7376	Social: $27,614
Kim SY et al, 2010	[55]	LICs	Gambia	PCV13	NV	3	90%		$666,180	1180	$570	/DALYs	cost-effective

HICs: high-income countries. UMCs: upper-middle income countries. LMCs: lower-middle income countries. LICs: low-income countries. PCV13: 13-valent pneumococcal conjugate vaccine. PCV10: 10-valent pneumococcal conjugate vaccine. PPV23: 23-valent Pneumococcal Polysaccharide Vaccine. PHiD-CV: pneumococcal non-typeable Haemophilus influenzae protein-D conjugate vaccine. NV: No Vaccination. ICER: incremental cost-effectiveness ratio. DALYs: disability-adjusted life-years. QALYs: quality-adjusted life-years.

Table 4. Characteristics of interventions and economic evaluations.

Author (Year)	Ref	Regions	Country	Intervention	Comparator	No. of Doses	Vaccine Coverage %	Incremental cost	Incremental effect	ICER	Unit of ICER	Conclusion of EE study
Igarashi A et al, 2021	[56]	HICs	Japan	PCV13	NV	1	_	Payer: JPY8,631.55	0.0076	Payer: JPY1,139,437.94	/QALYs	more cost-effective
								Societal: JPY10,273.72		Societal: JPY1,356,218.11
Gouveia M et al, 2019	[57]	HICs	Portugal	PCV13	NV	1	100%	€ 46.65	0.003	€ 17,746	/QALYs	cost-effective
Biagini L et al, 2018	[58]	HICs	Chile	PCV13	PPV23	1	90%	$42,195.00	6820		/QALYs	cost-effective
Chen C et al, 2018	[59]	HICs	Australia	PCV13	NV	1	_	$4,526,000	64	$71,000	/QALYs	cost-effective
Marbaix S et al, 2018	[60]	HICs	Belgium	PCV13	NV	1	58%	€ 16,810,000	982	€ 17,126	/QALYs	cost-effective
Boccalini S et al, 2017	[61]	HICs	Italy	PCV13	NV	1	60%	EUR216,705,270	14,061	Euro15,412	/QALYs	cost-effective
Heo JY et al, 2017	[62]	HICs	South Korea	PCV13	NV	1	60% OR 80%	$4.48	0.00099	$4,529	/QALYs	more cost-effective
Dirmesropian S et al, 2017	[63]	HICs	Australia	PCV13	NV	1	60%	$9,061,539	102.84	$88,100	/QALYs	unlikely to be cost-effective
Rodríguez González-Moro JM et al, 2016	[64]	HICs	Spain	PCV13	PPV23	1	59.50%	€ 4	0.0024	€ 1,844	/QALYs	highly cost-effective
Mangen MJJ et al, 2015	[15]	HICs	Netherlands	PCV13	NV	1	63.9%-81.5%	€ 42,100,000	4850	€ 8,650	/QALYs	highly cost-effective
Smith KJ et al, 2012	[65]	HICs	United States	PCV13	NV	1	_	$33	0.00116	$28,900	/QALYs	cost-effective

HICs: high-income countries. PCV13: 13-valent pneumococcal conjugate vaccine. PCV10: 10-valent pneumococcal conjugate vaccine. PPV23: 23-valent Pneumococcal Polysaccharide Vaccine. PHiD-CV: pneumococcal non-typeable Haemophilus influenzae protein-D conjugate vaccine. NV: No Vaccination. ICER: incremental cost-effectiveness ratio. DALYs: disability-adjusted life-years. QALYs: quality-adjusted life-years.

3.2. Sensitivity analysis

Sensitivity analysis was an important step to verify the reliability of economic evaluation conclusions. By controlling the changes of several major variables within a certain range, the influence of the changes of variables on the results was tested. Among the 44 included studies, 43 studies performed a sensitivity analysis. One way sensitivity analyses and probabilistic sensitivity analyses (PSA) were the most common. The results of the sensitivity analysis of most studies showed that the most sensitive parameter was the price of the vaccine, followed by the incidence of PDs and vaccine effectiveness (Table 1 and Table 2).

3.3. Cost-effectiveness results

Among the 44 included studies, incremental cost-effectiveness ratio (ICER) was reported in 36 studies, and incremental cost and incremental effect were reported in all studies. The specific ICER is shown in Table 3 and Table 4. Thirty-four studies used quality-adjusted life-years (QALYs), and 10 studies used disability-adjusted life-years (DALYs) [34,35,39,41–44,48,54,55].

3.3.1. Children’s studies

3.3.1.1. HICs

Seven studies were identified [29,38,41,49–52], 5 studies concluded that the PCV13 vaccine was cost-effective [29,38,49–51], 1 studies concluded that the PCV13 vaccine was unlikely to be cost-effective [41] and only 1 studies concluded that it was not to be cost-effective [52].

3.3.1.2. UMCs

Nineteen studies were identified [14,16–18,27,28,30,32–34,37,40,42,43,45–47,53,54], 1 studies concluded that the PCV13 vaccine was highly cost-effective [28], 2 studies concluded that it was more cost-effective [45,53], 11 studies concluded that it was cost-effective [14,30,32–34,37,40,42,43,46,54] and 5 studies concluded that it was not to be cost-effective [16–18,27,47].

3.3.1.3. LMCs

Five studies were identified [31,35,39,44,48], 3 studies concluded that the PCV13 vaccine was highly cost-effective [35,39,48] and 2 studies concluded that it was cost-effective [31,44].

3.3.1.4. LICs

Two studies were identified [36,55]. These 2 studies concluded that the PCV13 vaccine was cost-effective.

3.3.2. Adults’ studies

Eleven studies were identified [15,56–65], where 11 studies were all HICs. Of the included studies, 2 studies concluded that the PCV13 vaccine was highly cost-effective [15,64], 2 studies concluded that it was more cost-effective [56,62], and 6 studies concluded that it was cost-effective [57–61,65]. The remaining 1 study concluded that the PCV13 vaccine was unlikely to be cost-effective [63].

3.4. Risk of bias assessment

The risk of bias assessment scores of the included studies were shown in Table 5. The studies had an average score of 21.5 (ranged 19–23), with quality scores ranging from 75% to 100%. All studies were evaluated as good quality. None of the studies met the excellent standard, and no studies were rated as fair or poor quality. The main quality problems included no characterizing heterogeneity, no measurement and valuation of preferences, no model assumptions or no source of funding.

Table 5. Risk of bias assessment among the studies reviewed.

Author (Year)	Ref	I1	I2	I3	I4	I5	I6	I7	I8	I9	I10	I11	I12	I13	I14	I15	I16	I17	I18	I19		I20	I21	I22	I23	I24	Total
Li Y et al, 2021	[14]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	1	1	1		1	1	1	1	1	1	23
Bakir M et al, 2012	[16]	1	1	1	1	1	1	1	0	1	1	1	0	1	1	1	1	1	1		1	1	0	1	0	1	20
Mo X et al, 2016	[17]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	1	1	1		1	1	0	1	0	0	20
Zhou H et al, 2018	[18]	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1		1	1	0	1	1	1	23
Kim HY et al, 2021	[29]	1	1	1	1	1	0	1	1	1	1	1	0	1	1	1	1	1	1		1	1	0	1	1	1	21
Perdrizet J et al, 2021	[30]	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	0	1	1		1	0	0	1	0	1	20
Perdrizet J et al, 2021	[31]	1	1	1	1	1	1	1	1	1	1	1	0	1	0	1	1	1	1		1	1	0	1	1	1	21
Wang CX et al, 2021	[32]	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	0	1	1		1	1	0	1	1	1	22
Lin L, 2020	[28]	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1		1	1	1	1	0	0	22
Dilokthornsakul P et al, 2019	[33]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	0	1	1		1	1	1	1	0	0	20
Ezoji K et al, 2019	[34]	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1		1	1	0	1	1	1	23
Krishnamoorthy Y et al, 2019	[35]	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1		1	1	0	1	1	1	23
Dorji K et al, 2018	[36]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	1	1	1		1	1	0	1	1	1	22
Shen KL et al, 2018	[37]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	0	1	1		1	1	1	1	1	1	22
Kuhlmann A et al, 2017	[38]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	1	1	1		1	1	0	1	0	0	20
Sundaram N et al, 2017	[39]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	0	1	1		1	1	1	1	0	1	21
Ning GJ, 2017	[27]	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1		1	1	1	1	0	0	22
Maurer KA et al, 2016	[40]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	0	1	1		1	1	0	1	0	1	20
Vucina VV et al, 2015	[41]	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1		1	1	0	1	0	1	22
Mezones-Holguin E et al, 2015	[42]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	0	1	1		1	1	0	1	0	1	20
Kieninger MP et al, 2015	[43]	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	0	1	1		1	1	1	1	0	1	22
Sibak M et al, 2015	[44]	1	0	1	1	1	1	1	1	1	1	1	0	1	1	1	1	1	1		1	1	0	1	1	1	21
Mezones-Holguin E et al, 2014	[45]	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	0	1	1		1	1	0	1	1	1	22
Gomez JA et al, 2013	[46]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	1	1	1		1	1	1	1	1	1	23
Kulpeng W et al, 2013	[47]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	0	1	1		1	1	0	1	1	0	20
Ayieko P et al, 2013	[48]	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1		1	1	0	1	1	1	23
Hoshi SL et al, 2013	[49]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	0	1	1		1	1	1	1	1	1	22
Earnshaw SR et al, 2012	[50]	1	1	1	1	1	1	1	0	1	1	1	1	1	1	1	0	1	1		1	1	0	1	1	1	21
Díez-Domingo J et al, 2011	[51]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	0	1	1		1	1	0	1	1	1	21
Robberstad B et al, 2011	[52]	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	0	1	1		1	1	1	1	0	1	22
Mucino-Ortega E et al, 2011	[53]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	1	1	1		1	1	0	1	1	0	21
Uruena A et al, 2011	[54]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	0	1	1		1	0	0	1	0	1	19
Kim SY et al, 2010	[55]	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1		1	1	1	1	0	1	23
Igarashi A et al, 2021	[56]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	1	1	1		1	1	1	1	1	1	23
Gouveia M et al, 2019	[57]	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	0	1	1		1	1	0	1	1	1	22
Biagini L et al, 2018 [58]	[58]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	0	1	1		1	1	1	1	1	1	22
Chen C et al, 2018	[59]	1	1	1	1	1	0	1	1	1	1	1	0	1	1	1	0	1	1		1	0	0	1	1	1	19
Marbaix S et al, 2018	[60]	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1		1	1	0	1	1	1	23
Boccalini S et al, 2017	[61]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	0	1	1		1	1	0	1	0	1	20
Heo JY et al, 2017	[62]	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	0	1	1		1	1	0	1	1	1	22
Dirmesropian S et al, 2017	[63]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	1	1	1		1	1	1	1	0	1	22
Rodríguez González-Moro JM et al, 2016	[64]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	0	1	1		1	1	0	1	1	1	21
Mangen MJJ et al, 2015	[15]	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1		1	1	0	1	1	1	23
Smith KJ et al, 2012	[65]	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	0	1	1		1	1	1	1	1	1	22

4. Expert opinion

Our findings suggest the economically advantages profile of the PCV13 vaccination in children and adults. Vaccination with PCV13 was found to significantly reduce the mortality and morbidity of pneumococcal diseases. However, countries are reevaluating the impact and economic evaluations of PCV13 vaccination programs, because of the pressure of constrained health budgets [66].

This study is the first to systematically summarize English and Chinese studies on the economic evaluation of PCV13. We found the evidence that PCV13 was cost-effective compared to no vaccine or several other pneumococcal vaccines (e.g. PCV10, PPV23). Among the 44 included studies, most studies on PCV13 concluded that PCV13 inoculation was cost-effective, and six studies reported that PCV13 inoculation was not cost-effective. All the six studies showing that PCV13 was not cost-effective targeted at children [16–18,27,47,52]. Only one study found that PCV13 inoculation was unlikely to be cost-effective among adults. These studies are all from HICs and UMCs. This may be related to three possible reasons. First of all, PCV13 is more often used in children, and there are fewer studies comparing PCV13 inoculation with other inoculation strategies in adults. Secondly, the adults selected in most studies are the elderly, who are susceptible to SPn due to the lack and decrease of circulating IgM memory B cells [67]. A number of clinical trials have found that PCV13 has better immunogenicity than PPV23 in the elderly population, and can largely prevent SPn infection in the elderly population [68,69]. Thirdly, the introduction of vaccination programs in HICs and UMCs were not limited by financial barriers [19].

4.1. Choice of study perspectives

WHO Guide for Standardization of Economic Evaluations of Immunization Programmes and the Consolidated Health Economic Evaluation Reporting Standards statement requires that a full economic evaluation study should clearly demonstrate the study perspective [23]. Different countries, social systems and cultural backgrounds can lead to different study perspectives. Given the perspective impacts the costs and outcomes of the evaluation, it is important to specify the study perspective in order to determine the costs that should be considered in economic evaluations [70]. The societal perspective is most broadly used in economic evaluation studies [23]. The societal perspective refers to the total social costs that should be considered in health economic evaluations, including all costs incurred by society [67]. In the present review, the societal perspective is the most frequently used perspective, followed by the payer perspective (n = 8) and health care perspective (n = 5). Previous research suggests that the societal perspective should be selected in order to gain a scientific result if there is no other specific purpose to be considered in the economic evaluations of PCV13 [23,70].

4.2. Choice of modeling methods and parameters

Cost-effectiveness analyses are useful for predicting potential costs and benefits, and can assist stakeholders in making informed decisions about the value of proposed interventions. The majority of the economic evaluation studies of PCV13 adopted static models, mainly Markov model and decision tree model. The static models have advantages of simplicity and ability of handling both costs and outcomes [71]. One limitation of the cohort Markov model and decision tree model is that these models do not allow state transition probabilities to vary with the time in that state or previous states because it assumes that the probability of disease state is constant over time [72]. In contrast, dynamic models account for interactions among entities, and allow modeling the change of a state to be dependent on the previous states (i.e. feedback) [72,73]. Previous studies have documented that static model in economic evaluations of PCV13 often underestimates the health benefit of PCV13, and further underestimates the cost-effectiveness of PCV13 in NIP. In recent years, an emerging number of studies have applied dynamic or hybrid models in economic evaluations [74,75]. The dynamic model and hybrid model had higher requirements for the model parameters, and are more complex than static models like cohort Markov models and decision tree models. However, the incidence and prevalence trend of PDs in the future can be more accurately predicted using a dynamic or hybrid model [70]. Future research is needed to expand economic evaluations of PCV13 combined with dynamic model to enhance methodologic rigor and prediction accuracy.

Using high quality parameters in economic evaluations of vaccines is crucial in order to provide accurate simulations of the benefits of PCV13 inoculation. However, in some circumstances, ideal parameters for the effectiveness are difficult to be obtained, and researchers have to use proxy measures or parameters from other regions or countries. In this systematic review, we found that some studies used the epidemiological parameters selected from other regions or countries [18,34,35,43,44,52,53,76]. In order to better simulate the real-world PCV effectiveness in each country, and obtain more accurate and robust economic evaluation results, more epidemiological studies like surveillance of pneumococcal disease risk in general populations are required to evaluate the immune effect of PCV13.

We found that cost-effectiveness modeling methods on PCV13 varied with different countries. Studies in HICs tend to use more advanced modeling methods such as Markov model versus a simple decision tree model than studies in LMCs and LICs. Compared with HICs, studies in India, Egypt and other LMCs (i.e. Filipino, Iran) were more likely to use decision tree model in the economic evaluations of PCV13, characterizing as insufficient modeling methods (e.g. single decision tree model), and insufficient reported outcomes (e.g. no ICER report), or low parameters quality [30,31,34,44].

4.3. Reporting of the economic evaluations of PCV vaccines

The findings of this systematic review suggest that the reporting of economic evaluations of PCV13 needs to be further improved. We observed that major quality problems of some individual studies included a lack of clarification of the outcomes such as the immune effects of PCV13 and the valuation of preference for utility measure, a lack of description of model assumptions or source of funding. Future studies should illustrate clearly the measurement and valuation of preference for the vaccine effect, model assumptions, methods of improving the quality of model parameters, characteristics of heterogeneity, and the source of funding. To improve the quality of reporting, researchers should follow the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement [77] in conducting and reporting economic evaluations of PCV.

4.4. Strengths and limitation of this systematic review

This study has several strengths. We conducted a comprehensive literature research for economic evaluation studies on PCV13 both children and adults populations. This study included economic evaluations of PCV13 reported in English and Chinese languages, and conducted in a variety of countries. In addition, reporting of the systematic review followed the PRISMA statement. A limitation of this study is that due to significant differences across countries in the economic levels and the epidemic intensity of PDs, studies have substantial heterogeneities with respect to the perspective, parameters used for the costs and effectiveness, modeling and time horizon, thus the comparability of the results of the included studies between countries is limited.

5. Conclusions

This systematic review suggests that the PCV13 vaccine may be cost-effective in children and adults from the perspective of health care providers, society and payers. However, the cost-effectiveness results may vary due to differences in health systems, the perspective, parameters for the effectiveness, modeling methods and cost-effectiveness thresholds within or across the countries. Future research is needed to evaluate the cost-effectiveness of PCV13 using dynamic transmission models to better capture and more accurately assess the effect of previous risk of PDs on future health state and vaccine costs.

Article highlights

• Pneumococcal diseases (PDs) have become a serious public health problem around the world and the Streptococcus Pneumoniae (SPn) or pneumococcus is acknowledged as the main cause of PDs.

• Pneumococcal vaccination is the most cost-effective measure to prevent SPn infection. However, the evidence-based cost-effectiveness of PCV13 is unclear.

• The current body of situation is limited largely to a few systematic reviews of the cost-effectiveness of PCVs in children or adults separately in some regions, with no systematic reviews have summarized the cost-effectiveness results of PCV13 among populations of both children and adults in all countries.

• We conducted a comprehensive literature research for economic evaluation studies on PCV13 both children and adults populations. This systematic review suggests that the PCV13 vaccine may be cost-effective in children and adults.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or mending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

CPW, ZWW and XYW conceived the study, performed the study selection, data extraction and analysis, and revised the draft manuscript. YZD, HWS, YFX, MY and JWC performed the literature search, study selection, data extraction and analysis. YZD and JJL wrote the original draft manuscript. XYW, YW, YYW and TZ reviewed and revised the draft manuscript. All authors wrote the manuscript, read and approved the submitted version.

Additional information

Funding

This study was supported by Bill & Melinda Gates Foundation Donation Project (OPP1216666), Natural Science Foundation of Shandong Province (ZR202111230174) and Science and Technology Development Plan of Weifang (2022RKX075).