Cost-effectiveness of introducing infant vaccination against pneumococcal disease in Poland – comparison of non-typeable Haemophilus influenzae protein D (PHiD-CV) and 13-valent (PCV-13) pneumococcal conjugate vaccines


Authors

Name Affiliation
Jan Olbrecht
GSK, Wavre, Belgium Profile ORCID
Benedetto Simone
GSK, Uxbridge, UK
Katarzyna Wepsięć
GSK, Warsaw, Poland Profile ORCID
Iwona Kuter
GSK, Warsaw, Poland Profile ORCID
Magdalena Mrożek-Gąsiorowska
Pracownia HTA, Krakow, Poland
Andrzej Radzikowski
Medical University of Warsaw, Warsaw, Poland Profile ORCID
Alicja Książek
GSK, Warsaw, Poland
Rafał Rdzany
GSK, Warsaw, Poland Profile ORCID
contributed: 2021-12-09
final review: 2022-03-06
published: 2022-05-16
Abstract

Background: Streptococcus pneumoniae can cause invasive pneumococcal diseases (IPD), pneumonia and acute otitis media (AOM), a common childhood infection that may require antibiotics. There were 3,236 IPD cases detected in Poland between 2006-2016, with incidence peaks among infants and the elderly. The case-fatality rate in 2016 was 6.7% among infants and 49.3% among the elderly. Since 2009, two infant pneumococcal conjugate vaccines are available in Poland (the pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine [PHiD-CV], and the 13-valent pneumococcal conjugate vaccine [PCV-13]). The objective of this study was to assess the cost-effectiveness of routine PHiD-CV versus no vaccination and versus PCV-13.

Methods: A previously published Markov cohort model was adapted for Poland to compare PHiD-CV to no vaccination and PCV-13 from the public payer perspective, regarding lifetime direct costs and quality-adjusted life years (QALYs) associated with morbidity and mortality due to IPD, pneumonia and AOM. PHiD-CV and PCV-13 were assumed to have the same efficacy for their ten common vaccine serotypes, and PHiD-CV was assumed to have conservative cross-protection effectiveness against serotypes 6A and 19A, and to be more protective against AOM due to its effectiveness against non-typeable Haemophilus influenzae. Scenario analyses assessed outcomes when vaccine price parity was assumed, when the effectiveness of PHiD-CV against serotype 19A IPD was omitted or increased, and, when the effectiveness of PCV-13 against serotype 3 IPD was varied.

Results: PHiD-CV was a cost-effective option versus no vaccination, with a cost per QALY gained of Polish złoty (PLN) 94,933 (below the threshold for cost-effectiveness of PLN 134,514). Both vaccines had comparable health outcomes regarding IPD and pneumonia, while PHiD-CV achieved better health outcomes against AOM. PHiD-CV was the dominant strategy for Poland versus PCV-13 (resulting in a gain of 170 QALYs at a direct cost-saving of PLN 61.1 million). In scenario and sensitivity analyses, PHiD-CV remained the dominant strategy versus PCV-13.

Conclusions: The introduction of PHiD-CV in the Polish national immunization programme is likely to reduce the disease burden due to IPD, pneumonia and AOM. It is a cost-effective strategy (versus no vaccination) and a cost-saving strategy (versus PCV-13) for the healthcare payer.



Keywords: cost-effectiveness, Poland, pneumococcal conjugate vaccine, PCV-13, PHiD-CV

1.    Introduction

Pneumococcal disease is an infection caused by the Streptococcus pneumoniae (S. pneumoniae) bacterium. There are currently over 90 serotypes (STs) recognized worldwide, 15 of which cause the majority of disease [1]. The burden of disease is important, as infection is a leading cause of life-threatening invasive pneumococcal disease (IPD) which mainly includes meningitis and bacteraemia, as well as non-invasive illness such as pneumonia and acute otitis media (AOM) [2]. In Poland, between 2010 and 2016, the National Reference Center for Diagnosis of Central Nervous System Infections (KOROUN) detected 3,447 IPD cases. There were significant differences between provinces and between the analyzed periods in the same provinces. Data reported suggested underreporting and the differences among provinces most likely reflect inconsistence medical practices i.e., low number of blood cultures and serotyping test performed. In 2016, the highest incidence rates of 4.76 and 5.43 per 100,000 people in Poland were observed in those aged over 65 years and under two years, respectively. The IPD case fatality rate was 49.3% (over 65-year-olds), 38.4% (45-64-year-olds), 33.3% (25-44 and 5-9-year-olds), and 6.7% in children under two years [3]. AOM is a very common childhood disease typically treated with antibiotics, with 60-70% of clinical cases caused by bacteria [4]. A meta-analysis reports that on average 35.9% of AOM episodes are caused by S. pneumoniae and 32.3% by non-typeable Haemophilus influenzae (NTHi) [5].

Vaccination in infants is an effective means of preventing diseases, not only in vaccinated but even in unvaccinated infants and in older age groups due to herd immunity [6-10]. Moreover, it plays an important role given increased antimicrobial resistance among some pneumococci [11-13]. A recent Polish study found antibiotic resistance in children with AOM was an important cause of treatment failure [14]. Pneumococcal conjugate vaccines are recommended by the World Health Organization (WHO) [15] for routine immunisation of infants and in many countries introduced in their National Immunization Programme (NIP). There are two licensed conjugate vaccines available in Poland: the pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV; Synflorix, GSK), and the 13-valent pneumococcal conjugate vaccine (PCV-13; Prevenar13, Pfizer). Since 2017, PHiD-CV is administered as part of the NIP for all healthy infants, in a 2+1 schedule given at two, four and 13 months of age. The vaccine is intended to protect against all spectrum of pneumococcal disease i.e., IPD, pneumonia and AOM. Both vaccines can be used for risk groups in a 3+1 schedule [16]. While the vaccine STs contained in the two vaccines differ to some extent i.e., number of STs, carrier protein, there is evidence of protection exerted from PHiD-CV against cross-related STs. Recently, WHO’s global systematic review [10,17] on the impact of PHiD-CV and PCV-13, and 2 other industry-independent studies, concluded that at this stage, there is no evidence of difference on the net impact on pneumococcal diseases despite the difference of composition between the two vaccines [18,19]. Regardless of the vaccine used and of local epidemiology, countries which have implemented a childhood pneumococcal immunization program with a high coverage, observed a significant reduction in the burden of IPD in children [20].

The objective of this study was to assess the cost-effectiveness of introducing a routine infant vaccination programme against pneumococcal disease in Poland. Two analyses were performed: comparing PHiD-CV to no vaccination, and, comparing PHiD-CV to PCV-13.

2.    Materials and Methods

2.1.   Model and population

A previously published Markov cohort model [21] was adapted for Poland to assess the cost-effectiveness of introducing routine infant vaccination against pneumococcal disease, from the public payer perspective. Vaccination with PHiD-CV was compared to no vaccination and to vaccination with PCV-13.

The model is an age-compartmental, deterministic, static cohort model that assesses the health and economic impact of IPD caused by S. pneumoniae (i.e., meningitis and bacteraemia), all-cause pneumonia, and AOM caused by S. pneumoniae and NTHi, in a birth cohort over lifetime, using monthly cycles. Fig. 1 shows the flow diagram of the model. [22]

Fig. 1 Model flow diagram

Circle boxes represent mutually-exclusive health states. Dashed rectangles (sequelae and deaths) and natural deaths in susceptible individuals show the populations removed from the model. Age-specific incidence was applied monthly to the susceptible population. Costs and benefits were calculated monthly and aggregated over the cohort’s lifetime. Non-consulting AOM were included in the quality of life impact calculation. Redrawn from Delgleize et al.[22]. AOM: acute otitis media; Sp: Streptococcus pneumoniae; TPP: tympanostomy tube placement.

 A Polish birth cohort of 373,527 babies [23] was modelled; during each model cycle, the probability of an individual entering a specific health state was governed by age-specific incidence rates and applicable vaccine efficacy (VE) levels. Infants received, in the vaccine arms, two primary doses of one of the vaccines, at two and four months old, with a booster dose at 13 months old [4,24]. Age-specific overall monthly mortality rates for the general population were obtained from Polish life expectancy tables [25]. Age-specific disease incidence and disease progression were represented by health states (i.e., disease with or without general practitioner (GP) visits, hospitalisation, complications, long-term sequelae or death), linked to resource utilisation (e.g., hospitalisation, GP visits, and specific interventions such as myringotomies for AOM), resulting in direct costs and quality-adjusted life years (QALYs) over lifetime.

In the model, lifetime direct costs and QALYs associated with morbidity and mortality due to IPD, pneumonia and AOM were compared for PHiD-CV versus no vaccination and PHiD-CV versus PCV-13. The incremental cost per QALY gained or incremental cost-effectiveness ratio (ICER), expressed as Polish złoty (PLN)/QALY, was calculated for both comparisons.

 

Table 1. Vaccine effectiveness: model inputs and assumptions

 

VE % (95%CI)

Source

PHiD-CV

PCV-13

IPD

Ten common STs for PHiD-CV and PCV-13a

94.7 (87.0; 99.9)

94.7 (87.0; 99.9)

[30]

ST 3

0.0

26.0 (-69.0; 68.0)b

[32,34]

ST 6A

76.0 (39.0; 90.0)

94.7 (87.0; 99.9)

[30,36]

ST 19A

62.0 (20.0; 85.0)c

94.7 (87.0; 99.9)

[30,39]

Pneumonia

% reduction in hospitalisations

21.8 (7.7; 33.7)

21.8 (7.7; 33.7)

[43]

% reduction in GP visits

8.7 (3.8; 13.4)

8.7 (3.8; 13.4)

[43]

Outpatient AOM

 

 

 

Ten common STs for PHiD-CV and PCV-13a

69.9 (29.8; 87.1)

69.9 (29.8; 87.1)

[43]

NVTs

-33.0 (-80.0; 1.0)

-33.0 (-80.0; 1.0)

[44]

ST 6A

63.7 (-13.9; 88.4)

69.9 (29.8; 87.1)

[43,45]

ST 6C

0.0

63.7 (-13.9; 88.4)

PCV-13 same as 6A for PHiD-CV [49]

ST 19A

45.8d (model calculation)

69.9 (29.8; 87.1)

[43]

NTHi

21.5 (-43.4; 57.0)

-11.0 (-34.0; 8.0)

[43,44]

Inpatient AOM

% reduction in TTP (AOM hospitalisation)e

21.2 (model calculation)

12.7 (model calculation)

[48,50]

AOM: Acute otitis media; GP: General Practitioner; IPD: Invasive pneumococcal disease; NVTs: non-vaccine serotypes; PCV-7: 7-valent pneumococcal conjugate vaccine; PCV-13: 13-valent pneumococcal conjugate vaccine; PHiD-CV: Pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine; NTHi: Non-typeable Haemophilus influenzae; ST: Serotype; TTP: Tympanostomy tube placement; VE: Vaccine effectiveness.

a PHiD-CV and PCV-13 assumed to have the same ST efficacy for the ten common STs as the average VE of PCV-7 vaccine STs (94.7% for IPD and 69.9% for AOM).

b For ST 3, 26% VE was used for PCV-13 in the base case based on Andrews et al. (26%, 95% CI: -69; 68, not significant) [32] and 0% [34] and 79.5% [35] in scenario analyses.

c For ST 19A, 62% VE was used for PHiD-CV [39] in the base case and 0% (assume no protection) [37] and 82.2% (95%CI: 10.7; 96.4) [38] in scenario analyses

d PHiD-CV efficacy was estimated by taking the ratio of the vaccines’ efficacy against IPD ST 19A;

e Extrapolated VE estimates were well in agreement with findings of the FinIP study [29]

 

2.2.   Comparators and vaccine effectiveness assumptions

The model compared vaccination with PHiD-CV versus no vaccination and versus vaccination with PCV-13. A 2+1 regimen as previously described was used for both vaccines.

The vaccines have never been compared directly in trials. As they contain different STs, vaccine effectiveness against IPD, pneumonia and AOM were based on ST-specific efficacy from clinical trials (Table 1). Both vaccines directly protect against disease caused by 10 common STs 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. In addition, PCV-13 directly protects against STs 6A, 19A and 3 [4,24], while PHiD-CV, which includes STs 6B and 19F, has shown evidence of cross-protection against 19A [8] and a decrease of 6A in real-world evaluations after its introduction [26]. Cross-protection occurs when a vaccine demonstrates effectiveness against STs not included in the vaccine.  and 19A [8]. Cross-protection occurs when a vaccine demonstrates effectiveness against STs not included in the vaccine.

Eight of ten STs of PHiD-CV are conjugated to a protein D from NTHi, eliciting robust immune responses [27]. Higher serum antibody levels to protein D have been found to be associated with reduced risk of future AOM [28]. Efficacy against NTHi caused IPD was omitted in this analysis for both vaccines.  Vaccine efficacy was assumed to increase with the number of doses (i.e., 50% efficacy with dose one, 90% with dose two and 100% with dose three) [29,30], and to wane exponentially from three until ten years of age.

The model assumed 97% coverage for both vaccines, as they will be co-administered with other vaccines in the NIP that have reported coverage no less than 97% (data from 2012-2013) [31].

2.3.   Effectiveness against IPD

PHiD-CV and PCV-13 were assumed to have the same VE (94.7%, [95% confidence interval (CI): 87.0; 99.9]) for the ten common STs, calculated as the average efficacy of STs contained in the predecessor of PCV-13, i.e. the 7- valent pneumococcal conjugate vaccine (PCV-7) [30]. PHiD-CV was assumed to have no efficacy against ST3, while PCV-13 was assumed to have 26% VE (95%CI: -69; 68) [32]. Even not being significant, this assumption was made as this value was previously used in health technology assessment and tender discussions with the government. Many post-marketing surveillance studies [32-34] have shown no consistent impact of PCV-13 on ST 3 IPD, with most studies showing no impact or lack of effectiveness against ST 3 IPD [8]. As diverse vaccine effectiveness can be found in literature, the impact of 0% and 79.5% (95%CI: 30.3; 94.8) VE against ST 3 IPD (i.e., the highest published [35]) was tested in scenario analyses.

Since PHiD-CV was shown to elicit a similar antibody response to PCV-7 against ST 6A, a cross-protection effectiveness of 76% (95%CI: 39.0; 90.0) was assumed in the model [36]. PHiD-CV was shown to elicit a stronger response against ST 19A than PCV-7 [36-39]. Recent large effectiveness studies observed a clear cross-protective effect against ST 19A ranging from 62% (95%CI: 20; 85) to 82% (95%CI: 10.7; 96.4) [37-39]. This prompted many countries to update the Summary of Product Characteristics (SmPC) to include protection against 19A [37-40]. Therefore, the base case analysis assumed a conservative cross-protection effectiveness against ST 19A (62%) [39] which was left out (0%) and increased to 82% in the scenario analyses [38].

VE against STs 6A and 19A IPD was assumed to equal the other STs in PCV-13 (94.7%, 95%CI: 87.0; 99.9).

Indirect or herd protection resulting from continual vaccination of sequential birth cohorts was taken into account for IPD only (we conservatively assumed no herd protection for pneumonia and AOM). Serotype replacement offsets the incremental effect of indirect protection resulting in a net indirect effect. In the model, indirect protection adjusted for the opposing impact of serotype replacement was applied as a fixed effect to the residual disease incidence. This net indirect effect was estimated at 30%, removing the necessity to account separately for the effect of serotype replacement [41,42]. All efficacy estimates and the net indirect effect applied in the model are in line with Tregnaghi et al. [43] and were validated by a panel of experts (GSK PHiD-CV Health Economics Advisory Board. Leuven, Belgium, September, 2013) [22].

2.4.   Effectiveness against pneumonia

Both vaccines were assumed to have the same effectiveness in reducing GP visits (by 8.7%) and hospitalisation (by 21.8%) due to S. pneumoniae [43].

2.5.   Effectiveness against AOM

Efficacy against AOM was modelled against S. pneumoniae vaccine STs (VT) and against non-vaccine STs (NVTs), as efficacy data by ST or by dose were not available. Vaccine effectiveness against the ten common pneumococcal vaccine STs was assumed to be the same for both vaccines, based on the COMPAS study for PHiD-CV; i.e., 69.9% (95%CI: 29.8; 87.1) [43]. As STs 6A and 19A are included in PCV-13, VE of PCV-13 against STs 6A and 19A AOM were also assumed to be 69.9%, based on the COMPAS study findings for vaccine types included in PHiD-CV.  Effectiveness against NVTs was also assumed to be the same for both vaccines, based on PCV-7 data (FinOM study); i.e., -33% (95%CI: -80.0; 1.0) [44]. Negative numbers indicate ST or pathogen replacement, despite no replacement being observed for PHiD-CV in the COMPAS study [43]. Effectiveness of PHiD-CV was 63.7% (95%CI: -13.9; 88.4) [45] against ST 6A, 0% against ST 6C, and, 45.8% against ST 19A (estimated by taking the ratio of the vaccines’ efficacy against ST 19A IPD). Effectiveness of PCV-13 against ST 6C was assumed to be 63.7% (based on same effectiveness used for PHiD-CV against ST 6A).

Efficacy was also modelled against NTHi. Conservatively, PHiD-CV was assumed to have an efficacy against NTHi caused AOM of 21.5% (95%CI: -43.5; 57.0) [43,46] versus -11.0% (95%CI: -34.0; 8.0) for PCV-13, based on FinOM study for PCV-7 [43,44].  NTHi efficacy was included in the overall reduction of AOM-related GP visits and myringotomy procedures. The latest was used as proxy for inpatient AOM estimated to be 21.2% with PHiD-CV and 12.7% with PCV-13. With PCV-7, Black and colleagues (2000) [47] observed a reduction in ventilatory tube placement (tympanostomy tube placement, TTP) of 20.1% (95%CI: 1.5; 35.2%) and a reduction in AOM episodes of 7.0% (95%CI: 4.1; 9.7%). The VE of PCV-7 against TTP was found, based on the FinOM [44] and Kaiser Permanente [48] studies, to depend on the incidence of TTP, assuming an inverted exponential relationship. According to the Polish incidence of TTP, VE for PCV-7 was estimated using this exponential relationship, and extrapolated to PHiD-CV a ratio of the modelled overall VE against AOM of PHiD-CV (23.8%) over PCV-13 (14.3%), i.e 1.7. The FinIP [29] and POET [45] study estimates are in line with this extrapolation.

2.6.   Health outcomes, resources, costs and utilities

Health and economic benefits that could be achieved through vaccination with either PHiD-CV or PCV-13 were a reduction in cases, sequelae, resource use, healthcare costs, and, a gain in QALYs.

The age-specific population data, incidence and deaths related to IPD, pneumonia and AOM, as well as disease management (e.g. rates of GP visits and hospitalisations) were specific to Poland from available evidence and expert opinion (Table 2) [3,51-56]. (See Online Resource 1 for epidemiology inputs). The ST distribution in IPD in Poland from 2006 to 2016 was estimated from recent national laboratory surveillance reports [3,51,52,55]. (See Online Resource 2).

Data from the National Health Fund [57] and expert opinion were used to estimate the average cost of an acute episode of meningitis, bacteraemia, pneumonia and AOM, and annual costs for the management of sequelae (e.g., hearing loss or neurological) for the reference year 2016. The base case analyses used the published vaccine prices [49,58] of PHiD-CV (PLN 100) and PCV-13 (PLN 150), while in a scenario analysis, price parity between the vaccines was assumed (i.e., PLN 125: average of PHiD-CV and PCV-13 published prices). The cost-effectiveness threshold of PLN 134,514/QALY was defined as 3x Gross Domestic Product (GDP)/capita according to the Polish Agency for Health Technology Assessment and Tariff System [59] (based on PLN 44,838 per capita for 2013–2015 [60] ).

Table 2. Resource use, costs and utilities: inputs and assumptions

 

Value

Source and assumptions

Pneumococcal meningitis

Annual hospitalisation rate

100%

Assumption

Pneumococcal bacteraemia

Annual hospitalisation rate

100%

Assumption

Annual GP visit rate

0%

Assumption

All-cause pneumonia

Annual hospitalisation rate per 100,000

0-4y

1,364.2

Based on [53,56]

5-74y

81.5

75-90+y

846.4

Annual GP visit rate per 100,000

<1y

675.7

[53], expert opinion

1-4y

4,092.5

5-74y

244.6

75+y

2,539.3

AOM

Annual GP visit rate per 100,000

<1y

16,701.6

[54], expert opinion

1-4y

25,789.4

5-9y

10,509.0

10-14y

5,610.5

15-19y

1,686.5

20+y

1,090.1

TTP procedures per 100,000

<1y

8,748.4

[54], expert opinion

1-4y

4,640.6

5-9y

1,891.0

10-14y

1,009.6

15-19y

303.5

20+y

196.1

Costs (PLN, 2016)

Vaccine cost per dose

100 (PHiD-CV)

150 (PCV-13)

Public vaccine prices [49,58]

Cost per acute episode

<16y

>=16y

 

Meningitis - first year

4,841.12

5,402.66

National health fund [57], expert opinion

Bacteraemia - hospitalised

5,961.41

3,669.14

Pneumonia - hospitalised

3,244.65

3,244.65

Pneumonia - outpatient

82.59

82.59

AOM hospitalised myringotomy

1,242.33

1,242.33

AOM GP consultations

51.96

51.96

Annual cost long-term sequelae

Meningitisa

690.69

National health fund [57], expert opinion

Bacteraemia

690.69

Utilities – normative population values

<24y

0.941

[61]

25-34y

0.939

35-44y

0.929

45-54y

0.900

55-64y

0.894

65y

0.798

Disutilities (95%CI)

Short-term disutilities per episode

Inpatient meningitis

0,0232 (0,0099; 0,0419)

[62]

Inpatient/outpatient bacteraemia

0,0079 (0,0030; 0,0150)

[62]

Inpatient pneumonia

0,0080 (0,0031; 0,0151)

Assumed same as inpatient bacteraemia

Outpatient pneumonia

0,0060 (0,0015; 0,0134)

[62]

Outpatient AOM

0.005 (0.004;0.006)

[63]

Inpatient TTP/myringotomy

0.005 (0.004;0.006)

Assumed same as AOM

Long term disutilities per year

Neurologic sequelae (meningitis)

0,4000 (0,3200; 0,4800)

[64]

Hearing loss (meningitis)

0,2000 (0,1800; 0,2200)

[64,65] assumes cochlear implant

Hearing loss (AOM)

0,0900 (0,0720; 0,1080)

[66] assumes no cochlear implant

AOM: Acute otitis media; CI: confidence interval; GP: general practitioner; PLN: Polish złoty; TTP: Tympanostomy tube placement; y: year

a Estimate cost as weighted average from hearing loss (690.69 PLN) and neurological sequelae (690.69 PLN) according prevalence of both sequelae due to Sp. Meningitis.

 

Normative population utilities by age group were based on data from Poland [61]. Disease specific disutility data from Poland were not available. Therefore, values from the United Kingdom (UK) were used and applied for an inpatient or outpatient episode of meningitis, bacteraemia, pneumonia or AOM, and, for their long-term sequelae assumed to persist over the individual's remaining lifetime.

2.7.   Currency, price date, and discounting

All costs are in PLN and were updated to 2016 values. Costs and QALYs were discounted at 5.0% and 3.5% per annum, respectively, as per Polish health technology assessment (HTA) guidelines [67] .

2.8.   Sensitivity and scenario analyses

2.8.1. One-way sensitivity analyses

The impact of any important model input on the outcome was evaluated in a one-way sensitivity analysis, whereby key model inputs (e.g., epidemiology, resource use, costs and disutility inputs) were varied one by one, using the lower and upper limits of their 95% confidence interval or in some cases, a range based on plus or minus 20%. A tornado diagram presents the most important impacts on the ICER.

2.8.2. Probabilistic sensitivity analysis

A probabilistic sensitivity analysis (PSA) was conducted to assess the robustness of the ICER when uncertainty in key model inputs was considered simultaneously. In each PSA simulation, the model randomly draws from a probability distribution describing each parameter, thus varying each input simultaneously with every PSA run. The result from 2,000 simulations is presented in a cost-effectiveness plane and cost-effectiveness acceptability curve.

2.8.3. Scenario analyses

Several scenario analyses were also conducted. The first scenario analysis compared PHiD-CV to PCV-13, assuming price parity; with both vaccines costing PLN 125, the average of their published prices. The next scenario analysis (of PHiD-CV versus PCV-13) assessed the impact of parametrising vaccine effectiveness of PHiD-CV against ST19A IPD from the conservative base case value of 62% to a no protection (0%) or to a more optimistic 82.2%, based on recent studies [38] . A final scenario analysis assessed the impact of changing vaccine effectiveness of PCV-13 against ST3 IPD from the base case value of 26% to both 0% and 79.5%, based on post-marketing studies [32-35].

3.    Results

3.1.   Base case results for PHiD-CV versus no vaccination

Based on the model, the introduction of PHiD-CV vaccination versus no vaccination reduced the number of undiscounted IPD cases from 269 to 164 (by 39.2%), pneumonia cases from 261,609 to 252,468 (by 3.5%) and AOM cases from 1,213,534 to 1,113,705 (by 8.2%). This resulted in an increase of 978 QALYs (undiscounted) and a decrease in healthcare costs of PLN 39.6 million(M) (undiscounted), with vaccination costs of PLN 108.5M (undiscounted). The overall incremental cost of the vaccination programme was PLN 71.4M (5% discounted) with 752 QALYs gained (3.5% discounted), resulting in a cost per QALY gained of PLN 94,933 for PHiD-CV versus no vaccination. Therefore, under these assumptions, PHiD-CV was a cost-effective option versus no vaccination, with the cost per QALY gained well below the threshold for cost-effectiveness of PLN 134,514 (Tables 3&4).

Table 3. Undiscounted health and costs outcomes (PLN) (per birth cohort)

Undiscounted outcomes and costs

No vaccination

PHiD-CV

PCV-13

Meningitis

 

 

 

Cases

102

59

58

Long-term sequelae

3

2

2

Deaths

20

13

13

QALYs lost

78

34

33

Direct costs (meningitis) (PLN)

532,374

312,245

307,874

Direct costs (meningitis sequelae) (PLN)

183,220

79,820

76,185

Bacteraemia

 

 

 

Cases

167

105

104

Long-term sequelae

3

2

1

Deaths

77

53

53

QALYs lost

69

29

27

Direct costs (bacteraemia) (PLN)

686,381

407,303

402,014

Direct costs (bacteraemia sequelae) (PLN)

163,230

67,315

63,802

Pneumonia (in/outpatient)

 

 

 

Cases

261,609

252,468

252,468

Deaths

6,240

6,233

6,233

QALYs lost

1,707

1,643

1,643

Direct costs (PLN)

238,477,576

223,503,460

223,503,508

AOM (in/outpatient)

 

 

 

Cases

1,213,534

1,113,705

1,152,167

QALYs lost

6,068

5,569

5,761

Direct costs (PLN)

304,939,441

280,985,886

290,490,383

Total QALYs  

26,065,183

26,066,806

26,066,623

Vaccine costs (PLN)

0

108,463,366

162,695,052

Total direct costs* (PLN)

544,982,222

613,819,394

677,538,819

AOM: Acute otitis media; PLN: Polish złoty; QALY: quality-adjusted life-years

* Inclusive vaccine and vaccination costs

Table 4. Base case incremental health and cost outcomes and cost-effectiveness (5% discount on costs and 3.5% discount on effects) 

 


3.2.   Base case results for PHiD-CV versus PCV-13

When comparing the two vaccines, PHiD-CV had comparable outcomes to PCV-13 regarding IPD and pneumonia health outcomes. PHiD-CV, however, achieved better health outcomes against AOM with fewer inpatient and outpatient cases (38,462), and lower discounted direct costs (PLN 8.3M). Overall, PHiD-CV was associated with a gain in 170 QALYs (discounted at 3.5%) and a reduction in direct disease management costs (- PLN 61.1M, discounted at 5%) compared with PCV-13. Thus, PHiD-CV was the dominant strategy for Poland (Tables 3&4).

Fig. 2 One-way sensitivity analysis results (PHiD-CV versus no vaccination)

The 12 model inputs that had the biggest impact on the ICER (comparing PHiD-CV to no vaccination) when varied in the one-way sensitivity analysis. The central line indicates the base case cost per QALY. Blue: using a lower input, Red: using a higher input for the variable at the left side. AOM: acute otitis media; CAP: community acquired pneumonia; H. influenza: Haemophilus influenzae; NTHi: non-typeable H. influenza; nVT: non-vaccine type; QALY: quality-adjusted life-years; Sp: Streptococcus pneumoniae; VT: vaccine type.

3.3.   One-way sensitivity analyses

Using the one-way sensitivity analysis, the tornado diagrams in Fig. 2 and Fig. 3 show the 12 most impactful model inputs on the ICER when comparing PHiD-CV to no vaccination (Fig. 2) and to PCV-13 (Fig. 3). 

Fig. 3 One-way sensitivity analysis results (PHiD-CV versus PCV-13) The 12 model inputs that had the biggest impact on the ICER (comparing PHiD-CV to PCV-13) when varied in the one-way sensitivity analysis. The central line indicates the base case cost per QALY. Blue: using a lower input, Red: using a higher input for the variable at the left side. AOM: Acute otitis media; IPD: Invasive pneumococcal disease; GP: General Practitioner; H. influenza: Haemophilus influenzae; PCV-13: 13-valent pneumococcal conjugate vaccine; PHiD-CV: Pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine; NTHi: Non-typeable Haemophilus influenzae; Sp VT: Streptococcus pneumoniae vaccine type.


When comparing PHiD-CV to no vaccination, the most influential factors were variations in the percent reduction in tube placement, hospitalisations for community-acquired pneumonia (CAP) and percent reduction in CAP hospitalisation. Only a very unrealistic 10% increase in tube placement after vaccination would result in an ICER above the threshold (i.e., PLN 142,939). In all analyses, PHiD-CV resulted in a gain in QALYs versus no vaccination and remains below the threshold of PLN 134,514. Therefore PHiD-CV remained cost-effective (Fig. 2).

When comparing PHiD-CV to PCV-13, assumptions around AOM were the most influential factors, as present in 10 of the top 12 variables. Variations in the value for ‘GP visits for AOM’ had the largest impact on the ICER; with the cost per QALY ranging from -PLN 512,565 to -PLN267,675 per QALY gained. In all analyses, PHiD-CV resulted in a gain in QALYs versus PCV-13 and was cost-saving. Therefore, despite variations in the ICER, PHiD-CV remained the dominant choice over PCV-13 in all cases (Fig. 3).

3.4.   Probabilistic sensitivity analysis

The PSA results showed that the model outcomes are robust to simultaneous probabilistic variation of key model inputs. When comparing PHiD-CV to no vaccination, PHiD-CV was cost-effective in 79.6% of simulations (Fig. 4). When comparing PHiD-CV to PCV-13, PHiD-CV was the dominant strategy in 94.1% of the simulations (Fig. 5).


Fig. 4 Cost-effectiveness plane (A) and acceptability curve (B) for PHiD-CV vs no vaccination. Panel A: Cost-effectiveness plane. Each PSA run is represented by a dot in terms of difference in direct costs against difference in QALYs gained for PHiD-CV compared to no vaccination. Results below the cost-effectiveness threshold (3xGDP/capita = PLN 134,514/QALY) are considered cost-effective. The red box represents the base case result. Panel B: The cost-effectiveness acceptability curve shows the probability (i.e., proportion of PSA runs) that PHiD-CV is cost-effective compared to no vaccination for increasing cost-effectiveness threshold values. The red circle highlights the proportion of PSA runs when the cost per QALY gained remains below the threshold value (3xGDP/capita = PLN 134,514/QALY). GDP: Gross Domestic Product; cap: capita; QALY: quality-adjusted life-year.

3.5.   Results of scenario analyses

Results of all scenarios are summarised in Table 5.

Table 5. Incremental health and cost outcomes as well as cost-effectiveness (5% discount on costs and 3.5% discount on effects) for different scenarios

PHiD-CV versus no vaccination

PHiD-CV

No vaccination

Difference

QALYs gained

9,235,407

9,234,655

752

Direct costs* (PLN)

366,302,875

294,936,703

71,366,172

ICER (cost per QALY gained)

94,933 (below cost-effectiveness threshold**)

PHiD-CV versus PCV-13

PHiD-CV

PCV-13

Difference

QALYs gained

9,235,407

9,235,237

170

Direct costs* (PLN)

366,302,875

427,411,268

-61,108,392

ICER (cost per QALY gained)

PHiD-CV dominant over PCV-13

PLN: Polish złoty; QALY: quality-adjusted life-years.

* Inclusive vaccine and vaccination costs

**Cost-effectiveness threshold of PLN 134,514 (=3x GDP)

Scenario1: vaccine price parity (PLN 125)

PHiD-CV

PCV-13

Difference

QALYs gained

9,235,407

9,235,237

170

Direct costs* (PLN)

392,735,159

400,978,983

-8,243,824

ICER (cost per QALY gained)

 PHiD-CV was dominant over PCV-13

Scenario: PHiD-CV effectiveness against ST 19A IPD: 0%

PHiD-CV

PCV-13

Difference

QALYs gained

9,235,384

9,235,237

147

Direct costs* (PLN)

367,254,011

427,411,268

-60,157,257

ICER (cost per QALY gained)

PHiD-CV was dominant over PCV-13

Scenario: PHiD-CV effectiveness against ST 19A IPD: 82.2%

PHiD-CV

PCV-13

Difference

QALYs gained

9,235,414

9,235,237

178

Direct costs* (PLN)

365,992,989

427,411,268

-61,418,279

ICER (cost per QALY gained)

PHiD-CV was dominant over PCV-13

Scenario: PCV-13 effectiveness against ST 3 IPD: 0%

PHiD-CV

PCV-13

Difference

QALYs gained

9,235,407

9,235,236

171

Direct costs* (PLN)

366,302,875

427,414,558

-61,111,683

ICER (cost per QALY gained)

PHiD-CV was dominant over PCV-13

Scenario: PCV-13 effectiveness against ST 3 IPD: 79.5%

PHiD-CV

PCV-13

Difference

QALYs gained

9,235,407

9,235,238

169

Direct costs* (PLN)

366,302,875

427,406,662

-61,103,787

ICER (cost per QALY gained)

PHiD-CV was dominant over PCV-13

ICER: incremental cost-effectiveness ratio; PLN: Polish złoty; PCV-13: 13-valent pneumococcal conjugate vaccine; PHiD-CV: Pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine; QALY: quality-adjusted life-years.

* Inclusive vaccine and vaccination costs

 

3.5.1. Scenario analysis: PHiD-CV versus PCV-13, assuming vaccine price parity (PLN 125)

As in the base case, PHiD-CV resulted in more QALYs gained versus PCV-13, and when assuming price parity between the vaccines, PHiD-CV costs remained lower (by PLN 8.2M) than in the PCV-13 arm, making PHiD-CV the dominant strategy over PCV-13. 

3.5.2. Scenario analysis: PHiD-CV versus PCV-13, assuming 0% and 82.2% VE for PHiD-CV against ST 19A IPD

Omitting any cross protection from PHiD-CV against 19A reduced the incremental QALYs gained from 170 to 147, and the total cost saving from PLN 61.1M to 60.0M, however PHiD-CV will still be dominant in this scenario.

Increasing the VE of PHiD-CV against ST 19A IPD from the base case value of 62% to 82.2% resulted in a further gain of QALYs versus PCV-13 (from 170 to 178 QALYs) as well as an extra cost savings of PLN 310,000 versus base case, due to better health outcomes achieved. As a result, PHiD-CV remained the dominant strategy versus PCV-13 in both scenarios.