Health and economic burden of invasive pneumococcal disease associated with 15-valent pneumococcal conjugate vaccine serotypes in children across eight European countries

Abstract

Aims

V114, a 15-valent pneumococcal conjugate vaccine (PCV15) currently approved in adults in the US, contains the 13 S. pneumoniae serotypes in PCV13 and two additional serotypes, 22 F and 33 F, which are important contributors to residual PD. This study quantified the health and economic burden of pediatric invasive pneumococcal disease (IPD) associated with V114 serotypes in eight countries in Europe.

Materials and methods

A Markov model estimated V114-type IPD cases and costs in hypothetical unvaccinated birth cohorts from Denmark, France, Germany, Italy, Norway, Spain, Switzerland, and the UK over 20 years. Inputs were obtained from published literature. IPD cases and costs were calculated for three time periods using time-specific epidemiological data: (a) pre-PCV7; (b) pre-PCV13; and (c) post-PCV13. Costs were estimated from a societal perspective (2018 Euros) and discounted at 3%.

Results

The model estimated that 4,649 IPD cases in the pre-PCV7 period, 3,248 cases in the pre-PCV13 period, and 958 cases in the post-PCV13 period were attributable to V114 serotypes. Total discounted costs associated with V114 serotypes were €109.1 million (pre-PCV7 period), €65.7 million (pre-PCV13 period), and €18.7 million (post-PCV13 period).

Limitations

Post-meningitis sequelae, acute otitis media, and non-bacteremic pneumonia were not considered. Direct non-medical costs were not included. Conclusions on effectiveness of V114 or added value over existing infant vaccination programs cannot be drawn.

Conclusions

IPD cases and costs were estimated in hypothetical birth cohorts in eight European countries followed for 20 years during three time periods. Serotypes included in V114 were associated with significant morbidity and costs in pre-PCV7, pre-PCV13, and post-PCV13 periods. Future pediatric pneumococcal vaccines should maintain protection against serotypes in licensed vaccines while extending coverage to additional serotypes to ensure reductions in IPD burden are maintained.

Keywords:

• Invasive pneumococcal disease
• pneumococcal conjugate vaccine
• Markov model
• health burden
• economic burden

JEL Classification Codes:

• I10
• I1
• I
• I19

This article is related to:

Comprehensive value assessments for new pediatric pneumococcal conjugate vaccines

Introduction

Streptococcus pneumoniae (pneumococcus) is a gram-positive bacterium that causes invasive pneumococcal disease (IPD)^1,2. In Europe, IPD is associated with substantial disease burden^1,3,4, with an incidence of approximately 14.5 cases per 100,000 infants aged <1 year of age and five cases per 100,000 children aged 1–5 years of age in 2017⁴. Bacteremia and bacteremic pneumococcal pneumonia are common manifestations of IPD. While meningitis is less common, case fatality rates (CFRs) can be as high as 12.9%^5,6. Meningitis also has an associated risk of developing sequelae such as deafness or developmental delay in children^7,8. IPD is associated with high direct medical costs as well as considerable indirect costs related to lost productivity among parents of children with pneumococcal diseases and among children due to premature death^9,10.

To address the disease and economic burden of pneumococcal disease, a pneumococcal conjugate vaccine (PCV) containing seven S. pneumoniae serotypes (PCV7) was introduced in infant immunization schedules in many European countries in the early 2000s³ (Table 1). Despite a substantial reduction in the number of IPD cases in Europe following the introduction of PCV7, a subsequent increase in the incidence of disease caused by non-vaccine serotypes was observed; this necessitated the development of new vaccines containing additional serotypes²³. A 10-valent PCV (PCV10; SYNFLORIXⁱ) and a 13-valent PCV (PCV13, PREVNAR13ⁱⁱ) were introduced in Europe in 2009, and resulted in further reductions in IPD²³. However, since then, the incidence of disease attributable to non-vaccine serotypes has risen, with some serotypes, such as serotypes 3 and 19 A persisting^4,23,24. Consequently, a number of next-generation PCVs are now in late-stage clinical development for pediatric use, including a 15-valent PCV (PCV15; V114; VAXNEUVANCEⁱⁱⁱ) and a 20-valent PCV (PREVNAR20)²⁵, both recently approved for use in adults in the US^26,27.

Table 1. Year of PCV introduction in European countries.

Country	PCV7	PCV13
UK^11^,^12	2006	2010
France^13	2003	2010
Germany^14^,^15	2006	2009
Italy^16^,^17	2005	2010
Spain^18	2001	2010
Denmark^19^,^20	2007	2010
Norway^21	2006	2011
Switzerland^22	2006	2011

Abbreviation. PCV, pneumococcal conjugate vaccine.

V114 contains all PCV13 serotypes (serotypes 1, 3, 4, 5, 6 A, 6 B, 7 F, 9 V, 14, 18 C, 19 A, 19 F, and 23 F) and two additional serotypes, 22 F and 33 F^28,29. Serotypes 22 F and 33 F are two of the most common non-PCV13 serotypes that cause IPD in European children^{11,14,30–34}. In addition, 33 F has a high invasive disease potential compared with other non-PCV13 serotypes³⁵. To support V114 recommendation decisions, evidence of the potential health and economic value of a V114 pediatric vaccination program is needed. This study aimed to quantify the health and economic burden of IPD attributable to the 15 serotypes in V114 in hypothetical unvaccinated birth cohorts from eight European countries (Denmark, France, Germany, Italy, Norway, Spain, Switzerland, and the UK) that introduced PCV7 into routine infant vaccination schedules followed later by the introduction of PCV13. This study aimed to estimate the number of IPD cases and costs attributable to the 15 serotypes in V114 across three time periods, pre-PCV7, pre-PCV13, and post-PCV13, using time-specific epidemiological data, in order to emphasize the need to maintain the reduction in and address the current IPD burden.

Methods

IPD cases and costs attributable to V114 serotypes were calculated prior to PCV7 introduction. In order to account for the impact of PCVs on disease burden and serotype distribution, IPD cases and costs after introduction of PCV7 but prior to PCV13 introduction (for the six additional serotypes in PCV13), and after introduction of PCV13 (for serotypes 22 F and 33 F), were also calculated.

Analytical approach

This analysis was conducted using a Markov state transition model, which simulated clinical events and societal costs associated with V114 serotypes over a 20-year time horizon. Because IPD is an infectious disease, a dynamic transmission model would have been the preferred analytical approach, although static Markov models are also acceptable^36,37.

Model structure

The structure of the model was similar to that used in a previously published health economic evaluation of PCV13³⁸.

Three health states were included in the model: no pneumococcal disease, IPD (pneumococcal meningitis or bacteremia, including bacteremic pneumococcal pneumonia), and death (Figure 1). The model was run on an unvaccinated birth cohort at risk of developing IPD. Over the time horizon of the model, the likelihood of an infant developing IPD differs by age. The model tracked the birth cohorts up to 20 years of age or until death, whichever occurred earlier, with a cycle length of 1 year. The model assumed that IPD events were mutually exclusive; hence, infants could experience only one IPD event during each model cycle. However, over the course of the time horizon, each infant could experience more than one IPD event. Following IPD episodes, infants could recover and return to the no pneumococcal disease health state. Infants with IPD also faced a risk of death (depending on the specific manifestation of IPD and age).

Figure 1. Markov pathway. Abbreviation: IPD, invasive pneumococcal disease.

The analysis was based on the societal perspective, and, hence, included direct medical costs and indirect costs from productivity losses in children linked to premature death, and in caregivers of children with IPD. Because a Markov model was used, this study did not take into account transmission dynamics of pneumococcal infections from person-to-person, and did not include post-meningitis sequelae or non-IPD manifestations (such as acute otitis media and non-bacteremic pneumococcal pneumonia).

Model inputs

Target population

The target population of the analysis included cohorts of unvaccinated newborns from eight European countries that introduced PCV7 followed by PCV13 into routine infant vaccination schedules (Denmark, France, Germany, Italy, Norway, Spain, Switzerland, and the UK). Cohort sizes were estimated based on publicly available national statistics for 2018. The total cohort consisted of 3.2 million newborns (657,076 from the UK³⁹, 758,590 from France⁴⁰, 787,523 from Germany⁴¹, 439,747 from Italy⁴², 369,302 from Spain⁴³, 61,476 from Denmark⁴⁴, 55,120 from Norway⁴⁵, and 87,851 from Switzerland⁴⁶).

Epidemiologic inputs

Time-specific epidemiological data from the pre-PCV7 period, pre-PCV13 period, and post-PCV13 period (specific years depending on the history of PCV introduction for each country, as shown in Table 1) were retrieved from published literature and surveillance reports. Age-specific IPD incidence^{11,19,21,30,32,33,47–51}, distribution^{11,12,14,19–21,30–34,52–57}, and proportions of IPD that were meningitis and bacteremia (including bacterial pneumonia)^{6,12,30,33,47,48,50,51,54,58–61} were based on published literature and publicly available reports, with the exception of IPD incidence and serotype distribution for Switzerland, which was obtained from the Swiss Ministry of Health (personal communication) (Table 2). CFRs for meningitis and bacteremia were also taken from published literature^{3,5,6,13,32,62–65}. These were the most recent CFRs available and were applied across all periods to reflect current access to medical care and treatment options.

Table 2. Epidemiological inputs.^a

Country	Age group (years)	IPD serotype-specific incidence rates by age group (per 100,000 person-years)									Case fatality rate meningitis/ bacteremia (%)
		Pre-PCV7			Pre-PCV13			Post-PCV13
		PCV7 Serotypes	PCV13 not PCV7 serotypes	V114 not PCV13 serotypes	PCV7 Serotypes	PCV13 not PCV7 serotypes	V114 not PCV13 serotypes	PCV7 Serotypes	PCV13 not PCV7 serotypes	V114 not PCV13 serotypes
UK^6^,^11^,^12	<2	37.0	8.1	1.0	1.9	13.6	2.1	0.2	1.9	1.6	9.6/4.1
	2–4	11.6	2.5	0.3	0.7	4.9	0.7	0.1	0.6	0.5
	5–20	2.1	1.4	0.2	0.3	1.1	0.2	0.0	0.1	0.1
France^6^,^34^,^51^,^55^,^56^,^13	<2	20.5	7.6	0.6	1.1	18.4	0.7	0.8	1.6	1.0	11.0/4.1
	2–4	5.3	2.0	0.2	0.5	7.8	0.3	0.0	0.5	0.3
	5–20	1.1	0.4	0.0	0.1	2.5	0.1	0.4	0.4	0.3
Germany^14^,^47^,^62	<2	13.5	4.0	0.2	2.6	6.1	0.5	0.4	1.9	1.2	7.5/2.0
	2–4	3.6	0.9	0.1	1.8	2.9	0.2	0.1	0.2	0.1
	5–20	0.4	0.5	0.0	0.4	1.1	0.1	0.0	0.3	0.1
Italy^5^,^33^,^48^,^49^,^53^,^54	<1	12.1	5.3	0.5	2.3	6.3	0.4	0.6	0.3	0.2	4.8–12.9/ 0.0–2.90^b
	1–4	9.4	4.1	0.4	1.0	2.8	0.2	0.2	0.1	0.1
	5–9	2.3	1.0	0.1	0.3	0.7	0.0	0.0	0.0	0.0
	10–20	2.3	1.0	0.1	0.1	0.3	0.0	0.0	0.0	0.0
Spain^3^,^30^,^50^,^52	<2	45.3	12.7	1.2	13.2	30.0	0.1	6.5	10.4	0.7	5.6/2.0
	2–4	20.2	5.7	0.5	4.2	27.4	0.0	2.1	7.0	0.2
	5–20	6.3	1.7	0.2	1.7	5.6	0.1	0.9	2.3	0.2
Denmark^31^,^32^,^19^,^20^,^57^,^58^,^63	< 2	34.2	14.6	0.6	2.4	18.8	1.2	0.0	1.2	1.2	8.0/1.0
	2–4	5.2	2.2	0.1	1.0	7.6	0.5	0.0	0.6	0.3
	5–20	0.8	1.0	0.1	0.2	1.4	0.1	0.0	1.4	0.3
Norway^32^,^21^,^59^,^63	< 2	48.4	11.2	0.6	0.6	11.7	2.2	0.0	1.7	1.7	8.0/1.0
	2–4	12.6	2.9	0.2	0.8	2.3	0.9	0.5	0.9	1.4
	5–20	1.9	0.8	0.2	0.1	0.4	0.2	0.3	1.4	2.1
Switzerland^60^,^61^,^64^,^65 ^c	< 2	25.8	2.3	0.0	1.9	12.3	0.0	1.0	0.0	2.0	9.0/1.0
	2–4	4.7	5.2	0.0	2.6	5.9	0.5	0.5	2.5	0.0
	5–20	1.8	1.2	0.0	0.9	1.7	0.2	0.2	0.2	0.0

^aThe IPD serotype-specific incidence rate was calculated by multiplying incidence with serotype distribution data in the reference in pre-PCV7, pre-PCV13, and post-PCV periods.

^bCase fatality rates varied by age in Italy.

^cData on IPD incidence from private communication with the Swiss Ministry of Health.

PCV7 serotypes are 4, 6 B, 9 V, 14, 18 C, 19 F, and 23 F; PCV13 not PCV7 serotypes are 1, 3, 5, 6 A, 7 F, and 19 A; V114 not PCV13 serotypes are 22 F and 33 F.

Abbreviations. IPD, invasive pneumococcal disease; PCV, pneumococcal conjugate vaccine.

Cost inputs

The total costs per episode of IPD comprised direct medical costs and indirect costs (Table 3), including productivity losses due to premature death among children, and productivity losses among adult caregivers of children with IPD, expressed in 2018 Euros and discounted at 3%. Direct costs were obtained from the published literature^{5,61–63,66–68} and inflated to 2018 Euros using consumer price indices for healthcare^81–88. The human capital approach was utilized to determine indirect costs⁸⁹. Age-specific life expectancy values taken from life tables and age-specific average income per year were used to determine lost life-time income associated with premature death. In turn, the number of work days missed multiplied by daily wage rates and labor force participation rates in 2018 were applied to measure work loss in parents caring for children with pneumococcal disease^{62,66,69–74,76–80}. Numbers of work days missed was calculated based on the length of hospital stay associated with bacteremia and meningitis episodes from published literature^59,62,66.

Table 3. Cost inputs (2018 Euros).^a

Country	Manifestation	Direct medical cost (per episode)	Indirect cost (per episode)^b
UK^66	Meningitis	€9,780	€1,262
	Bacteremia	€8,194	€742
France^66–68^,^69^,^70	Meningitis	€6,089	€954
	Bacteremia	€2,422	€561
Germany^62	Meningitis	€7,162	€459
	Bacteremia	€6,897	€459
Italy^5^,^66^,^71^,^72	Meningitis	€8,228	€971
	Bacteremia	€3,239	€571
Spain^66^,^73–75^c	Meningitis	€10,874–€11,789	€687
	Bacteremia	€3,786–€4,039	€404
Denmark^59^,^63^,^76^,^77	Meningitis	€12,245	€606
	Bacteremia	€8,258	€493
Norway^59^,^78^,^77	Meningitis	€19,862	€834
	Bacteremia	€18,054	€679
Switzerland^59^,^61^,^79^,^80	Meningitis	€10,675	€1,014
	Bacteremia	€4,887	€592

^aCosts were inflated to 2018 Euros using consumer price indices for healthcare^81–88; exchange rates were obtained from the Federal Reserve Bank of St Louis (https://www.federalreserve.gov/releases/g5a/current/).

^bIndirect costs were calculated by multiplying the episode length from the source reference for each country with the daily lost wage (calculated using earnings and labor force participation data for each country from the references indicated).

^cDirect medical costs in Spain varied by age.

Model verification and validation

The validity of the model was confirmed by comparing its structure with that of previously published models during collaboration with experts. In addition, a number of tests were used in the model to ensure internal validity and verify the results⁹⁰. Tests were used to check for all three major types of model errors – logic, mechanical, and omission. As an example for verifying the model logic, the total number of persons in each health state at each cycle for each age was ensured to be equal to the size of the population at that age. Mechanical tests were also included to ensure that the right inputs were used in all calculations. Omission tests were used to ensure that the theoretical model structure and its components were all adequately represented in the calculations.

Model outputs

Estimated outcomes included number of IPD cases and deaths and overall total, direct, and indirect costs attributable to vaccine-type serotypes in the pre-PCV7, pre-PCV13, and post-PCV13 periods.

Sensitivity analysis

A one-way sensitivity analysis was conducted to assess the impact of uncertainties of key model parameters and assumptions on model results in the pre-PCV7 period. IPD incidence, CFR, and cost data were varied by ±20%, and the discount rate was varied from 0–5%. Given the key parameters used, the sensitivity analyses focused on the results for the pre-PCV7 period only. This is because the qualitative results (i.e. the positive/negative impact of the key parameters on the outcomes) were similar across the time periods.

Results

Clinical events

IPD cases by serotype

The model estimated that 4,649 IPD cases in the pre-PCV7 period, 3,248 cases in the pre-PCV13 period, and 958 IPD cases in the post-PCV13 period were attributable to V114 serotypes. The majority of IPD cases in the pre-PCV7 period were attributable to PCV7 serotypes (3,374 cases; 73%) (Table 4).

Table 4. IPD cases attributable to V114 serotypes in the pre-PCV7, pre-PCV13, and post-PCV13 periods.

Cases, N (%)	Pre-PCV7 period	Pre-PCV13 period	Post-PCV13 period
PCV7 serotypes	3,374 (73)	566 (17)	228 (24)
ST18C	376 (8)	76 (2)	15 (2)
ST4	239 (5)	49 (2)	12 (1)
ST6B	612 (13)	65 (2)	18 (2)
ST9V	242 (5)	60 (2)	14 (1)
ST14	1,065 (23)	179 (6)	61 (6)
ST19F	480 (10)	99 (3)	102 (11)
ST23F	360 (8)	39 (1)	7 (1)
PCV13, but not PCV7 serotypes	1,170 (25)	2,544 (78)	546 (57)
ST3	115 (2)	232 (7)	185 (19)
ST19A	250 (5)	625 (19)	94 (10)
ST6A	182 (4)	84 (3)	43 (4)
ST1	337 (7)	882 (27)	136 (14)
ST5	76 (2)	87 (3)	13 (1)
ST7F	210 (5)	633 (19)	76 (8)
ST22F and 33 F (V114, but not PCV13 serotypes)	106 (2)	137 (4)	184 (19)
Total V114 serotypes	4,649	3,248	958

Abbreviations. IPD, invasive pneumococcal disease; PCV, pneumococcal conjugate vaccine; ST, serotype.

The six additional serotypes in PCV13, but not in PCV7, increased from 1,170 cases in the pre-PCV7 period, to 2,544 cases in the pre-PCV13 period. The increase was primarily due to increases in serotype 1 (from 337 cases [7%] to 882 cases [27%]), serotype 3 (from 115 cases [2%] to 232 cases [7%]), serotype 7 F (from 210 cases [5%] to 633 cases [19%]), and serotype 19 A (from 250 cases [5%] to 625 cases [19%]). The number of cases attributable to serotype 6 A decreased in the pre-PCV13 period compared with the pre-PCV7 period, while the number attributable to serotype 5 remained relatively constant.

The number of cases associated with serotypes 22 F and 33 F combined was 106 (2%) in the pre-PCV7 period, 137 (4%) in the pre-PCV13 period, and 184 (19%) in the post-PCV13 period.

The numbers of cases in each country are shown in Supplementary Table S1.

Mortality due to IPD

The number of estimated IPD deaths associated with V114 serotypes was 178 in the pre-PCV7 period, 121 in the pre-PCV13 period, and 34 in the post-PCV13 period (Table 5). Most of these deaths were attributable to PCV7 serotypes (129 deaths; 72%) in the pre-PCV7 period. The number of IPD deaths associated with the six additional serotypes in PCV13 increased from 45 (25%) in the pre-PCV7 period to 97 (80%) in the pre-PCV13 period. The number of IPD deaths associated with serotypes 22 F and 33 F combined was four (2%) in the pre-PCV7 period, six (5%) in the pre-PCV13 period and eight (23%) in the post-PCV13 period. IPD deaths in each country are shown in Supplementary Table S2.

Table 5. IPD deaths attributable to V114 serotypes in the pre-PCV7, pre-PCV13, and post-PCV13 periods.

Deaths, n (%)	Pre-PCV7 period			Pre-PCV13 period			Post-PCV13 period
	Bacteremia	Meningitis	Total	Bacteremia	Meningitis	Total	Bacteremia	Meningitis	Total
PCV7 serotypes	80 (73)	49 (72)	129 (72)	11 (15)	7 (17)	19 (15)	5 (24)	3 (24)	8 (24)
PCV13, but not PCV7 serotypes	27 (25)	17 (26)	45 (25)	63 (80)	34 (79)	97 (80)	11 (55)	7 (49)	18 (53)
ST3	3 (3)	2 (3)	5 (3)	5 (7)	3 (8)	9 (7)	4 (21)	3 (24)	8 (23)
ST19A	6 (6)	4 (6)	10 (6)	16 (21)	9 (20)	25 (20)	2 (10)	1 (10)	3 (10)
ST6A	4 (4)	2 (4)	7 (4)	2 (2)	1 (2)	3 (2)	1 (4)	0 (2)	1 (3)
ST1	8 (8)	5 (7)	13 (7)	21 (27)	10 (24)	32 (26)	3 (13)	1 (7)	4 (10)
ST5	1 (1)	1 (1)	2 (1)	2 (2)	1 (2)	3 (2)	0 (1)	0 (1)	0 (1)
ST7F	4 (4)	3 (5)	8 (4)	17 (21)	9 (22)	26 (21)	1 (7)	1 (5)	2 (6)
ST22F and 33 F (V114, but not PCV13 serotypes)	3 (2)	1 (2)	4 (2)	4 (5)	2 (4)	6 (5)	4 (20)	4 (27)	8 (23)
Total V114 serotypes	110 (100)	67 (100)	178 (100)	78 (100)	43 (100)	121 (100)	20 (100)	14 (100)	34 (100)

PCV7 serotypes are 4, 6 B, 9 V, 14, 18 C, 19 F, and 23 F.

Abbreviations. IPD, invasive pneumococcal disease; PCV, pneumococcal conjugate vaccine; ST, serotype.

Economic impact by serotype

Total discounted costs (medical costs and indirect costs) due to V114 serotypes were estimated to be €109.1 million in the pre-PCV7 period, €65.7 million in the pre-PCV13 period, and €18.7 million in the post-PCV13 period (Table 6). Of these costs, €84.1 million (77%) in the pre-PCV7 period, €50.7 million (77%) in the pre-PCV13 period, and €14.1 million (76%) in the post-PCV13 period were attributable to indirect costs, of which the majority was comprised of productivity losses due to premature death.

Table 6. Discounted direct medical costs and indirect costs (including productivity losses due to premature death) attributed to IPD in the pre-PCV7, pre-PCV13, and post-PCV13 periods (2018 Euros).

€ millions (%)	Pre-PCV7 period				Pre-PCV13 period				Post-PCV13 period
	Direct medical costs	All indirect costs	Prod. loss due to premature death^a	Total costs	Direct medical costs	All indirect costs	Prod. loss due to premature death^a	Total costs	Direct medical costs	All indirect costs	Prod. loss due to premature death^a	Total costs
PCV7 serotypes	18.5 (74)	61.0 (73)	59.1 (73)	79.4 (73)	2.8 (18)	8.1 (16)	7.8 (16)	10.8 (16)	0.9 (20)	3.1 (22)	3.0 (22)	4.0 (21)
PCV13 but not PCV7 serotypes	6.0 (24)	21.2 (25)	20.6 (25)	27.3 (25)	11.4 (76)	39.7 (78)	38.4 (78)	51.1 (78)	2.5 (56)	7.3 (52)	7.1 (52)	9.8 (53)
ST3	0.7 (3)	2.5 (3)	2.4 (3)	3.2 (3)	1.1 (7)	4.0 (8)	3.9 (8)	5.1 (8)	0.9 (19)	3.3 (23)	3.2 (23)	4.1 (22)
ST19A	1.2 (5)	4.5 (5)	4.3 (5)	5.6 (5)	2.9 (19)	10.0 (20)	9.6 (20)	12.8 (20)	0.5 (11)	1.5 (11)	1.5 (11)	2.0 (11)
ST6A	1.0 (4)	3.0 (4)	2.9 (4)	4.0 (4)	0.5 (3)	1.2 (2)	1.2 (2)	1.7 (3)	0.2 (5)	0.4 (3)	0.4 (3)	0.6 (3)
ST1	1.8 (7)	6.6 (8)	6.4 (8)	8.4 (8)	3.6 (24)	12.5 (25)	12.1 (25)	16.1 (25)	0.5 (12)	1.3 (9)	1.2 (9)	1.8 (10)
ST5	0.3 (1)	0.8 (1)	0.8 (1)	1.1 (1)	0.4 (2)	1.0 (2)	1.0 (2)	1.4 (2)	0.1 (1)	0.1 (1)	0.1 (1)	0.2 (1)
ST7F	1.2 (5)	3.9 (5)	3.8 (5)	5.1 (5)	3.0 (20)	11.0 (22)	10.6 (22)	14.0 (21)	0.4 (8)	0.8 (6)	0.8 (6)	1.2 (6)
ST22F and 33 F (V114, but not PCV13 serotypes)	0.6 (2)	1.9 (2)	1.8 (2)	2.5 (2)	0.8 (6)	2.9 (6)	2.9 (6)	3.8 (6)	1.1 (25)	3.7 (26)	3.6 (26)	4.8 (26)
Total V114 serotypes	25.1 (100)	84.1 (100)	81.6 (100)	109.1 (100)	15.0 (100)	50.7 (100)	49.1 (100)	65.7 (100)	4.5 (100)	14.1 (100)	13.7 (100)	18.7 (100)

PCV7 serotypes are 4, 6 B, 9 V, 14, 18 C, 19 F, and 23 F.

^aProductivity losses due to premature death are included in all indirect costs.

Abbreviations. IPD, invasive pneumococcal disease; PCV, pneumococcal conjugate vaccine; prod., productivity; ST, serotype.

IPD associated with PCV7 serotypes accounted for the largest proportion of costs (€79.4 million; 73% of the total costs) in the pre-PCV7 period. The cost of the six additional serotypes in PCV13 but not in PCV7 increased from €27.3 million (25%) in the pre-PCV7 period to €51.5 million (78%) in the pre-PCV13 period. This was primarily due to increases in costs attributable to serotype 1 from €8.4 million (8%) to €16.1 million (25%), serotype 3 from €3.2 million (3%) to €5.1 million (8%), serotype 7 F from €5.1 million (5%) to €14.0 million (21%), and serotype 19 A from €5.6 million (5%) to €12.8 million (20%). Costs attributable to serotype 6 A decreased in the pre-PCV13 period compared with the pre-PCV7 period, and costs due to serotype 5 were similar in both periods.

Total costs associated with serotypes 22 F and 33 F together were €2.5 million (2%) in the pre-PCV7 period, €3.8 million (6%) in the pre-PCV13 period, and €4.8 million (26%) in the post-PCV13 period.

Costs by country are shown in Supplementary Table S3.

Sensitivity analysis

The discounted total cost was sensitive to uncertainties around all key parameters, as demonstrated by the one-way sensitivity analysis, but most affected by the discount rate. Total costs associated with IPD increased by 231–238% for 0% discount rates and decreased by 42–43% for 5% discount rates (Table 7). A 20% increase and decrease in total costs was observed when varying IPD incidence by 20%. Varying the CFR for meningitis and bacteremia by 20% led to a 15% increase and decrease in the total cost. When the direct medical cost of an IPD episode varied by 20%, total costs increased by 4–5% and decreased by 5%. Sensitivity analyses for each country are shown in Supplementary Table S4.

Table 7. One-way sensitivity analyses results (2018 Euros).

€millions (% change from base cost)	PCV7 serotypes		PCV13 but not PCV7 serotypes		V114 but not PCV13 serotypes
	Discounted indirect costs due to premature death	Discounted total costs	Discounted indirect costs due to premature death	Discounted total costs	Discounted indirect costs due to premature death	Discounted total costs
Base case	59.1	79.4	20.6	27.3	1.8	2.4
Incidence −20%	47.3 (−20)	63.5 (−20)	16.5 (−20)	21.8 (−20)	1.5 (−20)	2.0 (−20)
Incidence +20%	71.0 (20)	95.3 (20)	24.7 (20)	32.7 (20)	2.2 (20)	2.9 (20)
CFR −20%	47.3 (−20)	67.6 (−15)	16.5 (−20)	23.1 (−15)	1.5 (−20)	2.1 (−15)
CFR +20%	71.0 (20)	91.3 (15)	24.7 (20)	31.4 (15)	2.2 (20)	2.8 (15)
Cost −20%	59.1 (0)	75.4 (−5)	20.6 (0)	25.9 (−5)	1.8 (0)	2.3 (−5)
Cost +20%	59.1 (0)	83.1 (5)	20.6 (0)	28.5 (4)	1.8 (0)	2.6 (4)
Discount factor 0%	239.9 (306)	262.8 (231)	83.4 (305)	91.2 (235)	7.6 (311)	8.3 (238)
Discount factor 5%	26.9 (−54)	46.0 (−42)	9.4 (−54)	15.5 (−43)	0.8 (−55)	1.4 (−43)

PCV7 serotypes are 4, 6 B, 9 V, 14, 18 C, 19 F, and 23 F; PCV13 not PCV7 serotypes are 1, 3, 5, 6 A, 7 F, and 19 A; V114 not PCV13 serotypes are 22 F and 33 F.

Abbreviations. CFR, case fatality rate, OWSA, one-way sensitivity analysis; PCV, pneumococcal conjugate vaccine.

Discussion

This modeling analysis, that used a hypothetical unvaccinated birth cohort from eight European countries over 20 years, demonstrated that a substantial number of IPD cases and deaths were attributable to the 15 pneumococcal serotypes included in V114 during the pre-PCV7, pre-PCV13, and post-PCV13 periods. Across all three time periods, high total discounted costs were observed for V114 serotypes. The overall number of IPD cases and costs decreased over time, yet an increase in the proportion associated with the six additional serotypes in PCV13 was observed in the pre-PCV13 period compared with the pre-PCV7 period, driven by serotypes 1, 3, 7 F, and 19 A. Compared with the pre-PCV7 period, in the pre- and post-PCV13 periods, there was an increase in the proportion of cases and costs linked to 22 F and 33 F, the two unique serotypes in V114.

The findings of our analysis are consistent with the literature. Prior to the introduction of PCV7, 67–92% of all IPD cases were caused by the seven vaccine serotypes in children aged < 5 years in the eight European countries included in this analysis^{12,14,20,21,52,53,55}. Following the introduction of PCV7, there was a significant increase in IPD incidence associated with several non-PCV7 serotypes due to serotype replacement, in particular serotypes 1, 3, 7 F, and 19 A^24,91,92. Similarly, due to serotype replacement following PCV13 introduction, disease caused by non-PCV13 serotypes now accounts for 72% of IPD in European children^23,24. Several studies have also highlighted the persistence of select vaccine serotypes after PCV13 introduction, particularly serotype 3^14,93.

The next generation of pediatric pneumococcal vaccines must therefore continue to protect against serotypes that were highly prevalent and invasive prior to the introduction of PCV7 and PCV13, as well as extending coverage to non-vaccine serotypes that have since emerged as important causes of disease following successive PCV7 and PCV13 introductions in children. The importance of this strategy is confirmed by this modeling analysis, which estimated cases and deaths attributable to vaccine-type and non-vaccine-type serotypes (22 F and 33 F) in hypothetical birth cohorts in eight European countries in the pre-PCV7, pre-PCV13, and post-PCV13 periods. The impact of next generation PCVs on nasopharyngeal carriage and transmission of pneumococcal infections, while important, was not evaluated in the modeling analysis.

In the pre-PCV7 period, 3,374 PCV7-type IPD cases were estimated to occur in the eight birth cohorts, leading to over €100 million in direct and indirect costs. The disease burden associated with the six additional serotypes in PCV13 increased from 1,170 cases in the pre-PCV7 period to 2,544 cases in the pre-PCV13 period, at a total cost of €51.1 million. Substantial clinical and economic burden continues to be prevented by serotypes targeted by PCVs, particularly those included in PCV7. Excluding these serotypes from next-generation pediatric pneumococcal vaccines could have significant public health implications for both pediatric and adult populations^94,95.

There is also evidence that certain vaccine-type serotypes continue to persist in European countries that have introduced PCV13 into their routine immunization schedules for infants^15,96. Serotype 3 has been associated with vaccine failures^97,98, suggesting a need for vaccines with greater effectiveness against this serotype. In this simulation, serotype 3 caused 185 IPD cases and €4.1 million in direct and indirect costs in the post-PCV13 period. Furthermore, despite substantial disease reduction following the introduction of PCVs, disease caused by non-vaccine serotypes has emerged. In Europe, non-vaccine serotypes accounted for 72% of IPD in children in the post-PCV13 period^23,24, with serotypes 22 F and 33 F causing a large proportion^{11,14,30–34}. In this simulation, serotypes 22 F and 33 F were associated with 184 IPD cases and €4.8 million in direct and indirect costs in the post-PCV13 period.

This analysis has several limitations. First, post-meningitis sequelae, prevention of non-bacteremic pneumococcal pneumonia, and prevention of acute otitis media were not considered. Additionally, indirect costs associated with productivity loss for caregivers were estimated using conservative values for earnings, and the analysis did not include direct non-medical costs borne by families or caregivers, such as transportation and accommodation. As the model used was a Markov model that did not account for transmission dynamics, it ignored the impact of PCVs on nasopharyngeal carriage, the transmission of pneumococcal infections from person to person, and the indirect protective effect of PCVs on unvaccinated groups. Finally, pneumococcal disease in adults was not considered in this analysis since the time horizon of the model was only 20 years. Inclusion of any of these factors in the model would likely have affected overall disease and economic burden estimates.

V114 is currently in clinical development; thus, the effectiveness of this vaccine against the 15 serotypes included, and therefore the extent to which it may address the health and economic burden described here, cannot be determined based on this analysis. Additionally, the potential impact of V114 on emergence of new non-vaccine serotypes, and the subsequent increase in health and economic burden, is also unknown. It should also be noted that this analysis was not designed to evaluate the added value of V114 over existing infant vaccination programs.

Conclusions

The present analysis simulated IPD cases, deaths, and direct and indirect costs attributable to V114 serotypes across eight European countries. Three time periods were considered: pre-PCV7, pre-PCV13, and post-PCV13. Results suggested that in these countries, in the pre-PCV7 period, the majority of IPD-related morbidity, mortality, and associated costs in children were attributable to PCV7 serotypes. Four of the six additional serotypes included in PCV13 but not in PCV7 (1, 3, 7 F, and 19 A) were associated with substantially greater morbidity, mortality, and costs after the introduction of PCV7 and prior to the introduction of PCV13. The unique V114 serotypes 22 F and 33 F were associated with additional morbidity and costs of a magnitude comparable to that of serotype 3 in all three periods. The full value of next-generation pediatric pneumococcal vaccines should account for serotypes in the previously licensed vaccines, as well as the additional non-vaccine type serotypes.

Transparency

Declaration of funding

This analysis was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Declaration of financial/other interests

All authors are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, who may own stock and/or hold stock options in Merck & Co., Inc., Kenilworth, NJ.

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

Author contributions

TP, TH, TW, and KOE designed the study; TP, GB, and TH analyzed the study data; and TP, GB, TH, and TW interpreted the study data. All authors critically reviewed the manuscript and approved the final version for submission.

Previous presentations

These data were presented as a poster at the 38^th Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID), May 6–11, 2019, Ljubljana, Slovenia.

Acknowledgements

Medical writing assistance and editorial support, under the direction of the authors, was provided by Rachel Wright, PhD, and Gauri Saal, MA Economics, of Scion (London, UK) funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, according to Good Publication Practice guidelines (https://www.acpjournals.org/doi/10.7326/M15-0288).

Notes

i   SYNFLORIX is a trademark of GlaxoSmithKline Biologicals, s.a., Rixensart, Belgium.

ii  PREVNAR13 is a trademark of Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer, Inc., Philadelphia, PA, USA.

iii VAXNEUVANCE is a trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.