
==== Front
Hum Vaccin Immunother
Hum Vaccin Immunother
Human Vaccines & Immunotherapeutics
2164-5515
2164-554X
Taylor & Francis

39279284
10.1080/21645515.2024.2400751
2400751
Version of Record
Research Article
Licensed Vaccines
An economic evaluation of pneumococcal conjugate vaccines, PCV20 versus PCV15, for the prevention of pneumococcal disease in the Swedish pediatric population
A.-C. FRIDH ET AL.
HUMAN VACCINES & IMMUNOTHERAPEUTICS
Fridh Ann-Charlotte a *
Palmborg Andreas b *
Ta An c
Freigofaite Donata d
Warren Sophie e
https://orcid.org/0000-0002-4260-7607
Perdrizet Johnna f
a Access and Value, Pfizer AB , Stockholm, Sweden
b Medical and Scientific Affairs, Pfizer AB , Stockholm, Sweden
c Evidence Value and Access, Cytel , London, UK
d Evidence Value and Access, Cytel , Rotterdam, Netherlands
e Global Value and Evidence, Vaccines, Pfizer Inc , New York, NY, USA
f Global Value and Evidence, Pfizer Canada , Kirkland, Canada
CONTACT Johnna Perdrizet Johnna.Perdrizet@pfizer.com Pfizer Canada, Kirkland H9J 2M5, Canada.
* Contributed equally

15 9 2024
2024
15 9 2024
20 1 2400751Integra14 9 2024
Integra14 9 2024
29 5 2024
31 7 2024
31 8 2024
© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.
2024
The Author(s)
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

ABSTRACT

In September 2023, 10-valent pneumococcal conjugate vaccine (PCV) was replaced by 15-valent PCV (PCV15) in Sweden’s pediatric national immunization program. Following European approval of 20-valent PCV (PCV20) in March 2024, we assessed the cost-effectiveness of PCV20 versus PCV15, both under 2 + 1 schedule, among Sweden’s pediatric population. A Markov state-transition model evaluated the economic and health benefits of PCV20 versus PCV15 among all ages over a 10-year time horizon. The base case adopted a Swedish payer perspective with an annual cycle length and 3.0% discount rate for costs and outcomes. Country-specific data informed population size, epidemiology, costs, and quality of life estimates. PCV15/PCV20 effect estimates were informed by PCV13 clinical effectiveness and impact studies plus PCV7 efficacy studies. Sensitivity analyses evaluated model robustness, including PCV20 under a 3 + 1 schedule. PCV20 was associated with higher quality-adjusted life year gains versus PCV15, averting an estimated 3,116 invasive pneumococcal disease cases 21,109 inpatient pneumonia cases, 6,618 outpatient pneumonia cases, and 36,209 otitis media cases, plus 3,281 pneumococcal disease-related deaths. PCV20 yielded substantial cost savings exceeding 5.4 billion SEK over a 10-year time horizon, primarily attributed to reduced direct medical costs due to improved health outcomes compared with PCV15. The findings confirmed the dominance of PCV20 in the base case, which remained robust across deterministic and probabilistic sensitivity analyses as well as scenario assessments. PCV20 was the dominant strategy versus PCV15 over 10 years. The broader serotype coverage of PCV20 suggests superior clinical and economic advantages over PCV15, warranting inclusion in Sweden’s pediatric immunization program.

KEYWORDS

Pneumococcal disease
cost-effectiveness
pneumococcal conjugate vaccination
pediatric
pneumonia
invasive pneumococcal disease
otitis media
Pfizer Inc This study was funded by Pfizer Inc.
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pmcIntroduction

Streptococcus pneumoniae is a genetically diverse, gram-positive bacterial pathogen that causes pneumococcal disease including severe invasive pneumococcal diseases (IPD), such as bacteremia and meningitis, as well as less severe mucosal diseases, such as non-bacteremic pneumonia and otitis media (OM).1 Among young children, those with underlying risk conditions, and the elderly, pneumococcal diseases are a major contributor to global mortality and morbidity.2 In Sweden, pneumococcal disease represents a significant public health burden. According to the 2023 statistical data from the Swedish Public Health Agency, the annual incidence of IPD is 13.86 per 100,000 inhabitants.3 Additionally, the number of all-cause pneumonia episodes was shown to increase between 2005 and 2015, reaching over 30,000 cases per 100,000 person-years in 2015.4 Acute OM (AOM) has been reported to occur in ~200,000 Swedish children aged 0–4 years each year.5

Pneumococcal conjugate vaccines (PCVs) have been shown to induce immune responses among all age groups that are both strong and persistent. The implementation of PCVs into pediatric immunization programs (NIPs) has yielded a significant reduction in the incidence of pneumococcal disease among vaccinated children as well as in unvaccinated populations as a result of indirect effects.6–8 In 2001, the 7-valent PCV (PCV7, Prevnar®) was approved in Europe. Sweden introduced PCV7 for regional usage in 2007 and implemented pediatric vaccination nationally in 2009. A year after being nationally implemented, PCV7 was replaced by higher-valent vaccines: either 10-valent PCV (PCV10, Synflorix™) or 13-valent PCV (PCV13; Prevnar 13®), depending on regional preference. In September 2019, PCV10 became the only recommended vaccine in the pediatric NIP following national procurement.4,9 Children are offered vaccination with PCV within the program at 3, 5, and 12 months of age, with a 97% vaccine completion rate for the full three dose (2 + 1) vaccination series.9,10

In early 2022, two new higher-valent conjugate vaccines, 15-valent PCV (PCV15, Vaxneuvance®) and 20-valent PCV (PCV20, Apexxnar®) were approved for adult use. PCV15 includes the same serotypes as PCV10 (1, 4, 5, 6B, 7F, 9 V, 14, 18C, 19F, and 23F) as well as serotypes 3, 6A, 19A, 22F, and 33F. PCV20 contains the same serotypes as PCV15 as well as serotypes 8, 10A, 11A, 12F, and 15B. PCV15 was approved for an expanded indication to include children 6 weeks through 17 years of age in October 2022 and replaced PCV10 in the pediatric NIP in September 2023.11 In March 2024, PCV20 (Prevnar 20®, previously Apexxnar®) was licensed for infants, children, and adolescents from 6 weeks to less than 18 years of age.12

Considering the broader serotype coverage of PCV20 versus PCV15, the objective of this study was to determine the cost-effectiveness of PCV20 in Sweden’s pediatric population compared with PCV15 over 10 years.

Materials and methods

Modeling approach

Model structure

A decision-analytic Markov cohort model (state-transition model) was developed in Microsoft Excel® to assess the costs and health outcomes of PCV20 and PCV15 use in the pediatric population in Sweden. Markov models are commonly used in assessing costs and benefits of vaccines, like PCVs, and is widely accepted in Sweden and globally.13–16

The model tracks pneumococcal disease-related events through either vaccinated or unvaccinated states with death as an absorbing health state. The model structure is depicted in Figure 1. Figure 1. Model structure.

Abbreviations: IPD, invasive pneumococcal disease; OM, otitis media; yrs, years.

The transition probabilities pertaining to individual health states varied annually, taking into consideration both age and vaccination status. Within each 1-year cycle, individuals could transition to (i) IPD that would lead to either meningitis or bacteremia, (ii) all-cause nonbacteremic pneumonia (non-hospitalized or hospitalized), (iii) OM, which could either be simple or complex, or (iv) no pneumococcal disease. Subjects were allowed to transition into one or multiple clinical events or remain in a non-disease state during each one-year cycle. The risk of death was also accounted for in the model and was based on both general mortality and case fatality, as patients were assumed to have fatal consequences from meningitis, bacteremia, or hospitalized pneumonia. Sequelae following disease states were not considered in this analysis. Consistent with epidemiological data and most other cost-effectiveness analyses of pediatric PCVs, the model assumed non-hospitalized pneumonia and OM did not result in fatalities.

Costs and quality-adjusted life year (QALY) decrements associated with all relevant events were modeled to reflect the non-mutually exclusive nature of pneumococcal disease events. To simulate temporal dynamics, the model employed multi-cohorts; at the start of each annual cycle, a new birth cohort received vaccination.

Model population

The model population included both vaccinated and non-vaccinated cohorts, of which only children under the age of 2 years are directly vaccinated, while other age groups benefit from indirect effects. The population was split into age groups to capture age-specific epidemiology, disease probabilities, vaccine effectiveness, costs, and utilities. Children under the age of 5 years were stratified into 1-year age groups (<12 months, 12–23 months, 24–35 months, 36–47 months, and 48–59 months), whereas wider intervals were used to group individuals aged ≥5 years (5–17 years, 18–34 years, 35–49 years, 50–64 years, and 65+ years). Population size and the sizes of yearly birth cohorts (Table S1 and Table S2 Supplementary materials) were informed by Statistics Sweden (SCB) data.17,18

Time horizon, perspective, and discounting

The base-case analysis was conducted from a Swedish payer perspective (i.e., healthcare-sector perspective) following the change in guidelines by the Swedish Dental and Pharmaceutical Benefits Agency (Tandvårds- och läkemedelsförmånsverket; TLV), which no longer considers productivity gains from extended life years (i.e., societal perspective) in the base case due to concerns about fairness to individuals outside of the workforce.19 However, the societal perspective was tested in a scenario analysis. The study used a 10-year time horizon, which is considered a sufficient time period to capture the costs and effects of the PCV vaccination program, in line with observational data showing that direct and indirect effects of PCV7 and PCV13 achieved a steady state 5–10 years after implementation.20,21 An annual discount rate of 3% was applied to both costs and outcomes, as per the Swedish TLV guidelines.22

Disease incidence

Due to the recent inclusion of PCV15 in the Swedish pediatric NIP, there is a lack of suitable data to reflect its impacts on epidemiology, as vaccine effects typically take time to manifest. The background data used in the model were derived from studies conducted between 2015 and 2022, reflecting the prevailing use of PCV10 and PCV13 in Sweden. The model assumed that the previous standard of care reflected the current incidence, given its long-term presence in the market and the stable herd effect it had achieved. These epidemiological inputs were used to estimate the potential impact of higher-valent PCVs (PCV15 and PCV20) under the status quo situation.

Disease incidence rates per 100,000 persons stratified by age group were taken from surveillance data and published literature sources. IPD incidence and serotype distribution was informed by surveillance data from the European Centre for Disease Prevention and Control (ECDC) (Table S3).23 Hospitalized pneumonia incidence was informed by Naucler et al. 4 Lacking robust data regarding non-hospitalized pneumonia incidence, the ratio between hospitalized cases and non-hospitalized cases from Theilacker et al. was used to extrapolate non-hospitalized pneumonia incidence from the data in Naucler et al. 4,24 The values for AOM and chronic OM per 1,000 person-years from Johansson Kostenniemi et al. informed the incidence of the simple and complex OM disease states in the model, respectively.5 The model assumed IPD cases to consist of either meningitis or bacteremia. Based on Swedish data, 8% of IPD cases were assumed to be meningitis, with the remaining 92% being bacteremia.2

Serotype coverage

The serotype-specific coverage of each PCV was stratified by the same age groups used for other inputs in the model. Swedish-specific surveillance data from ECDC were applied to define the coverage for PCV7 serotypes and each additional serotype found within higher valent PCVs (Table S4).23

Mortality

General mortality was informed by the World Health Organization (WHO) life table, Swedish statistical database, and population data from 2022 population Statistics Sweden.25,26 Age-specific case fatality rates (CFRs) were applied to meningitis, bacteremia, and all-cause hospitalized pneumonia (Table S5), while no mortality was assumed for non-hospitalized pneumonia and OM.27–29

Costs

The model included vaccination costs and direct medical costs. Vaccine costs consisted of both vaccine price per dose and administration cost per dose, primarily derived from the Apoteket AB and Västra Götalands Regionen price lists, respectively (Table 1).37,38 Vaccination costs were incurred in annual cycles and depended on vaccine schedules. The analysis did not consider vaccine wastage as both PCV15 and PCV20 are available in pre-filled syringes, which minimizes wastage. Direct medical costs for each acute episode per health state were embedded within all pertinent age groups in the model. All costs were assessed in Swedish Krona (SEK) using the most recent estimates from 2023 for both resource use and vaccine costs. The detailed cost input data for medical costs per episode are summarized in Table S7.Table 1. Key model inputs.

Indirect effect – ramp-up,* %6,30	
 	Year 1	Year 2	Year 3	Year 4	Year 5+	
PCV15/PCV20	37.5	52.8	67.7	82.7	100.0	
Indirect effect – maximum reduction, %	
 	IPD6,30	Hospitalized pneumonia5,7,31,32	Non-hospitalized pneumonia31,33	Complex OM5,32	Simple OM5,32	
Age group, years	<5	83.0	43.8	32.3	24.9	24.9	
5–17	83.0	35.6	26.2	24.9	24.9	
18–49	88.0	22.5	0.0	–	–	
50–64	77.0	25.2	0.0	–	–	
≥65	73.0	26.9	0.0	–	–	
Direct effects – maximum reduction, # %	
 	IPD7	Hospitalized pneumonia34	Non-hospitalized pneumonia35	Complex OM36	Simple OM36	
 	88.7	25.5	6.0	12.3	6.4	
Medical cost (per episode),* SEK37,38	
 	Meningitis	Bacteremia	Hospitalized pneumonia	Non-hospitalized pneumonia	Complex OM	Simple OM	
Age group, years	<18	114,500	123,154	171,667	3,634	117,000	62,000	
 	≥18	114,500	94,830	171,667	3,634	–	–	
Vaccination cost,* SEK37,38	
Cost per dose	PCV15	PCV20	Administration	
653.00	648.69	372.00	
QALY decrements	
 	Meningitis	Bacteremia	Hospitalized pneumonia	Non-hospitalized pneumonia	Complex OM	Simple OM	
Age group, years	≤1939	0.023	0.008	0.006	0.004	0.005	0.005	
>1940	0.130	0.130	0.130	0.045	 	 	
*Price per vaccine dose was based on list price derived from Apoteket AB, a state-owned pharmaceuticals retailer in Sweden, and VGR, the second largest healthcare region in Sweden. VGR publicly provides a price list for DRG, which was used to derive healthcare costs in the model.

Abbreviations: DRG, diagnosis-related groups; IPD, invasive pneumococcal disease; OM, otitis media; PCV15, 15-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine; PCV, pneumococcal conjugate vaccine; QALY, quality-adjusted life year; SEK, Swedish krona, VGR, Västra Götalands Regionen.

Utility

Baseline utility values were sourced from Swedish studies that described EuroQol-5D (EQ5D) for the general population. Age- and sex-specific utilities were informed by Klok et al. for individuals aged 0-19 years, and by Burström et al. for adults aged 20–84 years.39,40 No utility data were available for people aged 85+; therefore, utility values for those aged 80–84 years were applied for this age group (Table S8). Publications on the cost-effectiveness of PCV informed the age-specific QALY decrements for IPD (meningitis and bacteremia), non-hospitalized and hospitalized pneumonia, and AOM (Table S9).41–45

Clinical data and key assumptions

The direct vaccine effects against IPD were defined as the anticipated decrease in vaccine serotype IPD incidence within the vaccinated population (children <2 years of age). As there are no clinical efficacy or effectiveness data for PCV15 or PCV20, the direct vaccine effects were modeled after PCV7 efficacy data and PCV13 effectiveness data. As such, the direct vaccine effectiveness against IPD for PCV15 and PCV20 was assumed to be 88.7% based on PCV13 vaccine-type vaccine effectiveness data after complete vaccination from Savulescu et al.7 For the direct effect against all-cause non-invasive disease, the model used all-cause efficacy data from PCV7 trials and assumed PCV15 and PCV20 would be 25.5%, 6.0%, 6.4%, and 12.3% effective against hospitalized pneumonia, non-hospitalized pneumonia, simple OM, and complex OM, respectively, which were then adjusted based on PCV7 circulating serotypes at the time of the clinical trial (80.6%) (Table S10).34–36 The direct effects were assumed to wane over time. In line with real-world effectiveness data from Savulescu et al., who reported stable PCV13 vaccine effectiveness for up to 4 years after the booster dose,7 the full direct effect for each vaccine was maintained for 5 years after the final dose then conservatively assumed to reduce by 10% annually after year 6.

Indirect effects (also known as herd effects) were considered in the total population (i.e., both the unvaccinated population and children whose vaccination protection was not 100%) for all disease states in the model. These indirect effects were considered alongside the direct effects and adjusted to avoid any duplication in the <5 year age group. High uptake of PCV15 and PCV20 was assumed to yield reductions in future rates of invasive and noninvasive disease (i.e., due to the additional serotypes versus PCV10) among unvaccinated children and adults based on real-world impact studies of PCV13. The model incorporated the indirect effects by progressively diminishing the expected age-specific disease incidence over time until a steady state was attained. A detailed description of methods employed to estimate indirect effects is set forth in Appendix A (Supplementary materials), which followed the same approach as another study on the PCV20 pediatric vaccine.46 Herd effects were incorporated for all age groups for IPD and hospitalized pneumonia, and for those aged <17 years for non-hospitalized pneumonia and OM (Tables S11 and S12).

Sensitivity analyses

Deterministic sensitivity analysis (DSA), probabilistic sensitivity analysis (PSA), and scenario analyses were performed to assess the uncertainty in the model. In the DSA, parameters were varied individually with a default 20% variance to estimate the upper and lower bound of the inputs. The analyses were conducted for disease incidence, CFRs, proportion of IPD (meningitis and bacteremia), serotype distribution, vaccine waning, vaccination effectiveness, vaccine coverage, baseline utilities, and disutilities.

A PSA was conducted to account for the joint uncertainty of the underlying parameter estimates. Different probability distributions, as described in Briggs et al.,47 were used; for example, the beta distribution confined by the interval 0–1 for continuous random parameters (such as proportion, rate, probability, and utilities), and the gamma distribution ranging between 0 and infinity for costs. A standard error (SE) of 20% was used in the PSA, and the probabilistic analysis was performed with 1,000 iterations at a willingness to pay a threshold of 300,000 SEK per QALY gained.

Table 2 describes the scenarios that were conducted to assess structural uncertainties and test alternative input options/data sources and assumptions. We tested different data sources and inputs for epidemiology, including disease incidence for non-hospitalized pneumonia (scenario 1a: Guest and Morris, 1997, reported hospitalized cases representing 32% of all pneumonia cases) and OM (scenario 1b: Gissellsson-Solen, 2017), percentage of meningitis among IPD cases (scenario 2: Miller et al.,), and CFR (scenario 3a, 3b, and 3c).48–53 These scenarios aimed to explore how different epidemiology input sources impact the results of the analysis. In addition, we tested several assumptions around both vaccine direct and indirect effects. Scenario 4a used an “efficacy-based approach” to estimate direct effect against IPD, in which we used PCV7 original clinical trial efficacy data and assumed vaccine effectiveness was the same for PCV15 and PCV20, as opposed to the base case using PCV13 real-world data. Scenario 4b allowed for cross-protection for two additional serotypes against IPD: serotype 6C (i.e., maximum reduction of IPD incidence: 93.7%) and serotype 15C (i.e., maximum reduction of IPD incidence: 88.7%). A series of scenarios (5a–5c) explored the impact of different assumptions on indirect effects, as these were identified as key drivers of costs and QALY. We first excluded 40% of adults aged ≥65 years who were assumed to receive pneumococcal vaccines, such as PCV13 and the 23-valent pneumococcal polysaccharide vaccine (PPSV23), from indirect effects (scenario 5a). In addition, other scenarios tested results assuming that the estimated indirect effect against all diseases was reduced by half (scenario 5b) and extending the accrual time to fully realize indirect effect from 4 years in the base case to 6 years (i.e., assuming that no indirect effects were observed in the first 2 years of the vaccination roll-out). The last three scenarios explored different settings, such as a societal perspective. In scenario 6, productivity loss was included in total costs. Scenario 7a explored PCV20 administered under a 3 + 1 schedule (i.e., using a different direct effect against IPD for the 2 + 1 and 3 + 1 schedules and considering additional vaccination cost from the extra dose). In scenario 7b, the same vaccine effect was assumed for PCV20 3 + 1 and PCV15 2 + 1, and the effect was only adjusted within the first year of life, which also considered the cost of the extra dose. Scenario 8 was an undiscounted analysis (i.e., assuming a 0% annual discount rate for both cost and benefit). The data used in these scenarios are reported in Appendix B in Supplementary materials.Table 2. Scenario analysis list.

 	Parameter	Base-case value	Scenario analysis	
1a	Epidemiology:
Disease incidence for non-hospitalized pneumonia	Ratios between hospitalized and nonhospitalized from Theilacker24	An assumption that hospitalized cases represent 32% of all CAP cases: Guest and Morris48	
1b	Epidemiology:
Disease incidence for OM	Source: Johansson Kostenniemi et al.5	Source: Gissellsson-Solen49	
2	Epidemiology:
Breakdown IPD cases	Source: Bergman et al.2	Source: Miller et al.50	
3a	Epidemiology:
CFR for meningitis and bacteremia	Source: ECDC23	Source: Block et al.51	
3b	Epidemiology:
CFR for hospitalized pneumonia	Data for children from Kuhlmann et al. and data for adults from Deb et al., with age adjustments28,29	Source: Miller et al.48	
3c	Source: Data for individuals aged <18 years from de Miguel-Díez et al., and data for adults from the CMBD (Hospital Discharge National Database from the Ministry of Health)52,53	
4a	Direct effect approach35,36	“Effectiveness-based approach” for IPD: 88.7%, “efficacy-based approach” for noninvasive disease: 25.5% (hospitalized pneumonia), 6% (nonhospitalized pneumonia), and 7.8% (AOM)	“Efficacy-based approach” for IPD: 93.9%	
4b	Cross-protection assumed for two additional serotypes against IPD: serotype 6C (93.7%) and serotype 15C (88.7%)	
5a	Indirect effects5–6-30–33-54–55	Applied to all population

Applied to all age groups for IPD and hospitalized pneumonia

Applied to ages 0–17 years for non-hospitalized pneumonia and AOM

Ramp-up over 5 years and reached steady state by year 6

	Exclude indirect effects on 40% of adults aged ≥65 years who were assumed to receive pneumococcal vaccines, such as PCV13 and the 23-valent pneumococcal polysaccharide vaccine	
5b	Reduce indirect effects by half	
5c	Extend time to realized indirect effects (i.e., accrual data in the first two years at 0%)	
6	Model perspective	Payer perspective	Societal perspective Burden from children population: Productivity loss data from Li et al.56

Burden from adult population: Productivity loss days calculated from Socialstyrelsen, SoS (The National Board of Health and Welfare)57

Salary data from Statistics Sweden (SCB) 2022, VAT on employment, Skatteverket (The Swedish Tax Agency) 202258,59

	
7	Vaccine schedule	Both PCV20 and PCV15 under 2 + 1 schedule	7a. PCV20 3 + 1 and PCV15 2 + 1a, using different direct effect against IPD	
7b. PCV20 3 + 1 and PCV15 2 + 1a, using the same direct effect against IPD	
8	Discount rate	3% for both cost and benefit	No discount (0%)	
aMinor adjustments were made for PCV comparisons under different schedules, where the direct effect of PCVs against IPD for a complete vaccine schedule was assumed to be equivalent to the adjusted PCV13 effectiveness against PCV13-type IPD, of which 78.2% (95% CI: 56.0, 89.0) was applied for PCV15 in a 2 + 1 schedule while 89.7% (95% CI: 82.0, 94.0) was used for PCV20 in 3 + 1 schedule, with a < 12-month modifier of 67% for 2 + 1 and 75.6% for 3 + 1 to account for potential reduced effectiveness in the first year of life.7 Additionally, the cost of an extra dose and administration visit were accounted for in the 3 + 1 schedule.

Abbreviations: AOM, acute otitis media; CI, confidence interval; CAP, community-acquired pneumonia; CFR, case fatality rate; ECDC, European Centre for Disease Prevention and Control; IPD, invasive pneumococcal disease; OM, otitis media; PCV, pneumococcal conjugate vaccine; PCV13, 13-valent pneumococcal conjugate vaccine; PCV15, 15-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine.

Results

Base case

Discounted results from the base-case analysis are summarized in Table 3. In the base case, PCV20 was estimated to produce clinically meaningful benefits for all ages, resulting in 33,349 additional life years and 48,736 additional QALYs over a 10-year time horizon compared to PCV15. PCV20 was the dominant strategy with a total saving of 5,466,151,199 SEK, the majority of which was contributed by significantly lower direct medical cost from PCV20 compared to PCV15.Table 3. Cost-effectiveness results and incremental difference of PCV20 versus PCV15 (discounted).

Outcome	PCV15	PCV20	Incremental	
Cases of IPD	14,159	11,043	−3,116	
Meningitis cases	1,133	883	−249	
Bacteremia cases	13,026	10,160	−2,867	
Cases of hospitalized pneumonia	370,608	349,499	−21,109	
Cases of non-hospitalized pneumonia	718,694	712,076	−6,618	
Cases of complex AOM	46,296	43,658	−2,638	
Cases of simple AOM	710,181	676,609	−33,572	
Number of deaths due to disease	55,560	52,279	−3,281	
Total costs, SEK	105,390,627,022	99,924,475,823	−5,466,151,199	
Cost of doses, SEK	2,806,450,285	2,794,651,310	−11,798,976	
Medical costs, SEK	102,584,176,736	97,129,824,513	−5,454,352,223	
Direct costs of IPD, SEK	1,219,584,632	955,356,442	−264,228,190	
Direct costs of hospitalized pneumonia, SEK	55,553,462,111	52,446,846,099	−3,106,616,012	
Direct costs of non-hospitalized pneumonia, SEK	2,286,936,242	2,266,184,972	−20,751,270	
Direct costs of complex OM, SEK	4,769,027,290	4,502,549,272	−266,478,018	
Direct costs of simple OM, SEK	38,755,166,461	36,958,887,728	−1,796,278,733	
Total QALYs	218,784,148	218,832,885	48,736	
Total LYs	269,980,173	270,013,522	33,349	
ICER cost per QALY	PCV20 is dominant	
Abbreviations: AOM, acute otitis media; ICER, incremental cost-effectiveness ratio; IPD, invasive pneumococcal disease; LY, life year; PCV15, 15-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine; QALY, quality-adjusted life year; SEK, Swedish Krona.

The model estimated greater health benefits related to PCV20, which were captured by a significant number of cases averted for IPD (3,116 cases), hospitalized and non-hospitalized pneumonia (21,109 and 6,618 cases, respectively), and OM (2,638 complex OM cases and 33,572 simple OM cases) compared with PCV15. PCV20 was associated with a greater reduction in direct medical costs (5,454,352,223 SEK) as a result of broader serotype coverage.

Sensitivity and scenario analyses

The DSA results outlined the key parameters and their impacts on costs and QALYs when comparing PCV15 and PCV20, which are depicted in tornado diagrams (Figure 2 for costs and Figure 3 for QALYs). The factors with the greatest impact on both costs and QALYs were serotype distribution by age and the maximum indirect effect of PCV20 against hospitalized pneumonia. Other key drivers of costs were related to indirect effects (e.g., maximum indirect effects against simple OM and indirect effect accrual from PCV20, maximum indirect effects against hospitalized pneumonia from PCV15, and against OM from PCV15), medical cost, disease incidence of hospitalized pneumonia, and simple OM. Figure 2. DSA results in costs for PCV20 versus PCV15.

Abbreviations: DSA, deterministic sensitivity analysis; Inc, incremental; PCV15, 15-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine; SEK, Swedish Krona.

Figure 3. DSA results in QALYs for PCV20 versus PCV15.

Abbreviations: DSA, deterministic sensitivity analysis; Inc, incremental; IPD, invasive pneumococcal disease; PCV15, 15-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine; QALY, quality-adjusted life year.

QALYs were predominantly driven by baseline utilities, indirect effects (i.e., accrual for PCV20 and PCV15, and maximum incidence reduction of hospitalized pneumonia from both vaccines), incidence and CFR related to hospitalized pneumonia, and IPD. Overall, despite variation in the key drivers of the results, PCV20 remained a cost-saving strategy and resulted in marked QALY gains compared to PCV15, which aligned with the base case.

Results of the PSA were also aligned with the base-case results (Figure 4). With a mean incremental QALY of 48,225 and a mean incremental cost of −5,363,762,629.85 SEK, PCV20 was dominant over PCV15 in 100% of the iterations. Figure 4. PSA cost-effectiveness plane.

Abbreviations: PCV20, 20-valent pneumococcal conjugate vaccine; PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life year; SEK, Swedish Krona

PCV20 was the dominant strategy versus PCV15 in all tested scenarios, which aligned with the base-case results. Testing different assumptions and data sources for epidemiological aspects such as disease incidence rate, breakdown of IPD cases, and CFR did not change the outcome of dominance. Changes in the assumptions for the direct and indirect effects of the vaccine impacted the results; however, PCV20 persisted as the dominant strategy over its comparator. When considering undiscounted results, both total cost and QALY increased for PCV15 and PCV20 but PCV20 remained dominant. Two scenarios in which PCV20 was administered under 3 + 1 schedule compared to PCV15 2 + 1 confirmed that PCV20 3 + 1 would provide both greater health benefit and cost saving (i.e., dominance) versus the lower-valent alternative (Table S13). A summary of the results from all explored scenario analyses is reported in Table 4.Table 4. Scenario analyses – PCV20 versus PCV15.

Scenario description	SoC with PCV15	PCV20	Incremental cost, SEK	Incremental QALY	
Total costs, SEK	Total QALYs	Total costs, SEK	Total QALYs	
-	Base case	105,390,627,022	218,784,148	99,924,475,823	218,832,885	−5,466,151,199	48,736	
1a	Incidence of non-hospitalized pneumonia: hospitalized cases represent 32% of all pneumonia cases (Guest 1997)	104,108,483,978	218,764,571	101,400,604,414	218,813,289	−2,707,879,565	48,718	
1b	Disease incidence rate OM: Gissellsson-Solen (2017)	67,624,894,101	218,786,807	66,578,277,267	218,835,418	−1,046,616,834	48,611	
2	Breakdown IPD cases: Miller (2011)	102,626,253,830	218,784,149	99,913,008,735	218,832,885	−2,713,245,094	48,736	
3a	CFR for meningitis and bacteremia: Block et al.	102,642,958,552	218,803,683	99,926,213,833	218,846,283	−2,716,744,719	42,599	
3b	CFR hospitalized pneumonia: Miller (2011)	102,883,229,528	219,164,569	100,143,713,376	219,194,896	−2,739,516,152	30,326	
3c	CFR hospitalized pneumonia: Data for individuals aged <18 years from de Miguel-Díez et al. and data for adults from the CMBD (Hospital Discharge National Database from the Ministry of Health)	102,804,415,493	219,120,725	100,072,197,783	219,150,611	−2,732,217,710	29,887	
4a	Direct effect against IPD: “efficacy approach” of 93.9%	105,390,658,534	218,784,143	99,924,771,532	218,832,860	−5,465,887,002	48,716	
4b	Direct effects: Cross-protection for 6C (93.7%) and 15C (88.7%)	105,379,816,677	218,784,360	98,789,147,641	218,836,666	−6,590,669,036	53,306	
5a	Exclude indirect effects on adults	106,575,462,090	218,765,989	104,100,271,576	218,768,159	−2,475,190,514	2,170	
5b	Reduce indirect effects by half	106,771,789,713	218,774,145	103,836,228,045	218,797,150	−2,935,561,668	23,005	
5c	Extending time to realize indirect effects (i.e., accrual in the first two years = 0%)	106,283,229,425	218,777,899	102,446,117,192	218,810,539	−3,837,112,233	32,640	
6	Societal Perspective (burden from pediatric population)	113,422,859,719	218,784,148	110,295,271,186	218,832,885	−3,127,588,532	48,736	
7a	PCV20 3 + 1 vs PCV15 2 + 1* using different direct effect against IPD	105,347,522,239	218,784,163	100,722,632,326	218,832,881	−4,624,889,913	48,718	
7b	PCV20 3 + 1 and PCV15 2 + 1*, using the same direct effect against IPD	105,390,627,022	218,784,148	100,820,022,921	218,832,892	−4,570,604,101	48,744	
8	No discount rate (i.e., undiscounted results)	120,272,250,642	437,388,273	113,912,655,945	437,469,724	−6,359,594,697	81,451	
*In the scenario testing PCV20 3 + 1 vs PCV15 2 + 1, data used for direct effect against IPD were 89.7% and 78.9%, respectively (as opposed to the pooled data used in the base case, i.e. 88.7%). Indirect effect assumptions and inputs were conservatively kept the same as the base case.

All scenarios resulted in PCV20 being dominant (i.e., cost saving and higher QALY gain versus PCV15). Abbreviations: CFR, case fatality rate; IPD, invasive pneumococcal disease; PCV15, 15-valent pneumococcal conjugate vaccine; PCV20, 20-valent pneumococcal conjugate vaccine; QALY, quality-adjusted life year; SEK, Swedish Krona; SoC, standard of care.

Discussion

This analysis explored the cost-effectiveness of the PCV20 pediatric immunization program in Sweden compared with PCV15, both under a 2 + 1 schedule, over a 10-year time horizon from a payer perspective. The potential benefits of PCV20 versus PCV15 were examined by estimating the total disease cases, deaths, and costs resulting from direct and indirect effects across all ages of vaccination. For the base case and all the explored scenarios, PCV20 was the dominant strategy (i.e., lower costs and higher QALYs) compared to PCV15. Therefore, sensitivity and scenario analyses demonstrated the robustness of the model findings. Besides the expected health benefit of PCV20 versus PCV15, the potential saving in healthcare resource utilization is especially important considering Sweden has one of the lowest number of hospital beds per capita among the Organization for Economic Cooperation and Development (OECD) countries.60

The results are primarily driven by the serotype distribution by age due to the broader serotype coverage of PCV20 compared to PCV15. PCV20 includes five more serotypes than PCV15, including serotypes 8, 10A, 11A, 12F, and 15B.61 Serotype 8 is characterized by high virulence and commonly identified in outbreaks of IPD.62 In the European Union and European Economic Area countries, the frequency of confirmed serotyped cases of IPD caused by serotype 8 in all age groups increased by 120% between 2013 and 2017.27 Also in Sweden, serotype 8 is on the rise with a reported incidence of 3.8 IPD cases per 100,000, accounting for 9% of total IPD cases.9 As such, protection against serotype 8, a serotype covered by PCV20, is important in the Swedish setting.

In Sweden’s pediatric schedule, hexavalent vaccine including diphtheria, tetanus, pertussis, poliomyelitis, Haemophilus influenzae type b (HiB), and hepatitis B is administered at 3, 5, and 12 months of age together with PCV. Also, rotavirus vaccine is given at ages 6 weeks, 3 months, and 5 months.63 As such, there are a total of three scheduled visits for vaccination during the first 5 months after birth with booster vaccination at age 12 months. Consequently, there is an opportunity to provide PCV20 in Sweden’s pediatric national immunization program either in a 3 + 1 or a 2 + 1 schedule, pending recommendations and preference as well as expected health benefits (both direct and indirect effects). In this cost-effectiveness analysis, both schedules, 3 + 1 and 2 + 1, are expected to provide health benefits and cost savings versus PCV15. Although additional direct vaccination cost was expected with the 3 + 1 regimen, PCV20 3 + 1 was assumed to provide minor improvements in direct individual-level protection for infants, leading to similar favorable results for PCV20 using this vaccination schedule, which was also dominant (Table S13). Similar findings have been found in other geographic settings, such as Germany, where it was found that PCV20 under a 3 + 1 schedule provided greater clinical and economic benefits (i.e., was dominant) versus PCV15 and PCV13, both under a 2 + 1 schedule.64

Countries that have historically used PCV10 in their NIPs, such as Sweden, typically observe more disease caused by serotype 19A than countries that have historically used PCV13.65 In Sweden, there has been a notable rise in the proportion of serotype 19A cases from 11% of total IPD cases in 2019 to being the most common serotype in 2022, representing 24% of IPD cases across all ages. Among children under the age of 5 years, 50% of IPD cases (34 out of 68) were due to serotype 19A. Furthermore, 19% (n = 13) of cases in children under 5 years of age were caused serotype 3, which is not covered by PCV10 but included in PCV13.3 Other neighboring PCV10 NIP countries have also experienced elevated rates of IPD caused by serotype 19A, with Finland reporting 35% of IPD cases due to this serotype across all ages in 2022.23 Despite the overall success of PCVs in reducing pneumococcal disease incidence, residual cases of serotype 19A continue to affect children in countries that have historically used PCV10 in their NIPs.65,66 In this context, PCV20 has a substantial advantage compared to lower-valent alternatives, such as PCV10, PCV13, or PCV15, as it offers the most extensive protection against serotypes, including coverage of serotype 19A and other emerging serotypes, such as serotype 8.65,67 Moreover, evidence suggests that switching to higher-valent vaccines reduces transmission of vaccine serotypes, producing indirect herd effects on the newly covered serotype incidence in the unvaccinated population.39,61,68 Thus, switching to PCV20 is a potential pathway to improving protection in both vaccinated and unvaccinated populations, which could lead to significant improvements in Sweden’s overall public health across all ages.3

The results of this analysis are subject to some limitations as they are based on several assumptions and different data sources that may be subject to bias. First, the Markov state-transition model is a simplified representation of disease transmission and pneumococcal disease outcomes. We developed the model to account for heterogeneity between different vaccine alternatives and incorporate aspects such as herd effects. By incorporating indirect effects, the model demonstrates the overall effects of vaccination at the population level comprising these components, making it somewhat compatible with the dynamic modeling approach in capturing the broad-ranging impacts of pneumococcal vaccines. The heterogeneous nature of the Swedish population and healthcare systems by region may not be fully reflected from the model estimations and hence, uncertainty remains. The analyses, however, have been performed with several sensitivity and robustness checks to limit uncertainty and increase the robustness of the results.

Second, at the time of model development, there was no real-world evidence regarding the public health impact of PCV15 and PCV20 following pediatric NIP implementation. Additionally, there are no clinical studies that measure clinical efficacy for these new generation PCVs, as it would be unethical to conduct such studies. Because of this, vaccine direct effect estimates were derived from PCV7 efficacy data (for all-cause noninvasive diseases) and PCV13 effectiveness data (for vaccine-type IPD) with assumptions made to account for the newly covered serotypes of PCV15 and PCV20.7,35,36 This constitutes a pragmatic approach to capture the direct effect of higher-valency PCVs and has been widely used in cost-effectiveness analyses.16 However, future cost-effectiveness analyses of PCV20 and PCV15 would benefit significantly from demonstrated effectiveness in the real world.

Furthermore, estimating indirect effects presented similar challenges due to unavailable data for higher-valent PCVs, as these are observed after long-term implementation of pediatric immunization programs. Because of this, the potential indirect effects against the newly covered serotypes were assumed to be the same as observed following PCV13 pediatric program implementation. In addition, since PCV10/PCV13 impact data from Sweden was only available for simple and complex OM, a hybrid approach was taken to estimate the indirect effect for IPD and pneumonia, in which the model used high-quality data that measured the impact of PCV13 in unvaccinated populations from France and the United Kingdom. The observed maximum reduction in disease incidence and accrual after the implementation of PCV13 in those countries was applied to the additional serotypes covered by PCV15 and PCV20. Extensive sensitivity analyses were conducted to test the vaccine effectiveness assumptions. Besides the typical PSA and DSA, several scenarios testing the choices of inputs and different assumptions regarding vaccine effectiveness were also performed. The results from these analyses did not vary significantly from the base-case analysis and the conclusion remained the same.

Lastly, the model is also limited by the lack of serotype distribution data for noninvasive diseases, as well as gaps in epidemiology data, such as disease incidence and sequelae following pneumococcal diseases. As done in previous cost-effectiveness analyses of PCVs, the model assumed the same serotype distribution observed for IPD as for noninvasive diseases for each vaccine.30,46,69 Where epidemiological inputs from Sweden were unavailable, data from European countries with similar epidemiology were preferred over other sources. For instance, the model did not consider sequelae following severe diseases, such as IPD meningitis and bacteremia or complex OM, as there was not sufficient data to support these inputs for Sweden.

Conclusion

The results of this cost-effectiveness analysis suggest that PCV20 would result in cost savings and fewer disease cases (i.e., more effective) compared with PCV15 from a Swedish payer perspective over 10 years, making it the dominant strategy. In addition, the sensitivity analyses show that this conclusion is robust to plausible changes in the assumptions upon which the analysis was based. As such, PCV20 could be regarded as a cost-saving strategy in Sweden. Policymakers should consider moving toward higher-valent vaccines, as they provide the population with improved coverage against pneumococcal serotypes, reducing the burden of pneumococcal disease on the healthcare system through cost savings and decreased resource use.

Supplementary Material

Pfizer PCV20_Sweden_manuscript_suppl_Revision_clean_submitted.docx

CHEERS Checklist.docx

Acknowledgments

The original model was developed by Des Dillon-Murphy, PhD, and Ruth Chapman, PhD, of Evidera and funded by Pfizer Inc. Writing support for this manuscript was funded by Pfizer and provided by Colleen Dumont and Sally Neath of Cytel Inc, Waltham, MA, US, who were employed by Cytel Inc, Waltham, MA, US at the time of the manuscript development.

Johnna Perdrizet is a distinguished epidemiologist and health economist at Pfizer Inc., bringing over a decade of experience to the field of public health research. Specializing in pneumococcal disease, she excels in the comprehensive public health, economic, and clinical evaluation of pneumococcal conjugate vaccines. Through her extensive research and publications, Johnna contributes novel insights into population health strategies and passionately advocates for global health policies designed to alleviate the burden of pneumococcal diseases.

Disclosure statement

Ann-Charlotte Fridh, Andreas Palmborg, Sophie Warren, and Johnna Perdrizet were employees of Pfizer at the time of this study. An Ta and Donnata Freigofaite were employees of Cytel Inc at the time of this study, of which recieved funding to conduct this study.

Author contributions statement

Funding acquisition: Johnna Perdrizet

Conceptualization: Johnna Perdrizet, Ann-Charlotte Fridh, Andreas Palmborg, and Sophie Warren

Formal analysis: An Ta and Donata Freigofaite

acquisition: Johnna Perdrizet

Investigation: Johnna Perdrizet, Ann-Charlotte Fridh, Andreas Palmborg, and Sophie Warren

Methodology: Johnna Perdrizet, Ann-Charlotte Fridh, Andreas Palmborg, and Sophie Warren

Project administration: An Ta

Supervision: Johnna Perdrizet, Ann-Charlotte Fridh, Andreas Palmborg

Validation: Johnna Perdrizet, Ann-Charlotte Fridh, Andreas Palmborg

Visualization: N/A

Roles/Writing – original draft: Johnna Perdrizet, Ann-Charlotte Fridh, Andreas Palmborg, Sophie Warren, An Ta, and Donata Freigofaite

Writing – review & editing: Johnna Perdrizet, Ann-Charlotte Fridh, Andreas Palmborg, Sophie Warren, An Ta, and Donata Freigofaite

Data availability statement

All data generated or analyzed during this study are included in this published article/as supplementary information files.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2400751
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