A cost-effectiveness analysis of revaccination and catch-up strategies with the 23-valent pneumococcal polysaccharide vaccine (PPV23) in older adults in Japan

Figures & data

Table 1. Strategies compared in the model.

	2014 vac cohort		2019 vac cohort		2019 catch-up cohort^b
	65–100 yrs, interval of 5 years of age in 2014^a		65 years		70–100 years, interval of 5 years of age in 2019^a
	Primary vac	Revac	Primary vac	Revac	Primary vac	Revac
Strategy 1 (no revac & no catch-up)	✓		✓
Strategy 2 (revac & no catch-up)	✓	✓	✓	✓
Strategy 3 (catch-up & no revac)	✓		✓		✓
Strategy 4 (catch-up & revac for cohorts vaccinated in 2014 and 65 yrs cohort in 2019)	✓	✓	✓	✓	✓
Strategy 5 (catch-up & revac)	✓	✓	✓	✓	✓	✓

revac, revaccination; vac, vaccination; yrs, years.

^a Interval of 5 years of age refers to population who were 65, 70, 75, 80, 85, 90, or 95 years old in Japanese fiscal year 2014 or 70, 75, 80, 85, 90, 95, 100 years old in Japanese fiscal year 2019.

^b 2019 catch-up cohort refers to population who were 65, 70, 75, 80, 85, 90, or 95 years old in Japanese fiscal year 2014 and did not receive primary vaccination in 2014.

Duration between primary vaccine and revaccination is assumed to be 5 years in base analyses.

QALYs and costs were calculated from the year 2019 onwards.

Figure 1. Model structure. Figure reprinted with permission of publisher from: ‘Cost?effectiveness of vaccinating adults with the 23-valent pneumococcal polysaccharide vaccine (PPV23) in Germany’ by Yiling Jiang, Aline Gauthier, Lieven Annemans, Mark van der Linden, Laurence Nicolas-Spony & Xavier Bresse, in Expert Review of Pharmacoeconomics & Outcomes Research, January 9th 2014, Taylor & Francis Ltd.

Table 2. Clinical parameters related to IPD and NBPP.

Parameter	Base case value	SA value	Reference
IPD
IPD incidence per 100,000 person- years:	2.98	DSA: 0.8–1.2 times of the base case value	Ohkusa et al.^8
65+ years		PSA: beta distribution, alpha = 2,766, beta = 92,816,026
Proportion of IPD caused by PPV23 serotypes	67.2%	DSA: 60.0–82.2% PSA: Dirichlet distribution, count of PPV23: 332, count of non-PPV23: 162	Fukuzumi et al.^30
Case-fatality rate  65+ years	8.71%	DSA: 0.8–1.2 times of the base case value PSA: beta distribution, alpha = 241, beta = 2,526	Ohkusa et al.^8
IPD manifestation
Meningitis	17.6%	DSA: only tested by varying associated costs	Fukuzumi et al.^30
Bacteremic pneumonia	58.7%	PSA: Dirichlet distribution, count of each of the four: 87, 290, 80, 37
Bacteremia without focus	16.2%
Others	7.5%
Proportion of meningitis survivors who will  develop sequelae	31.7%	DSA: only tested by varying associated costs	Jit^31
		PSA: beta distribution, alpha = 127, beta = 274
NBPP
Incidence per 100,000 person-years		DSA: 0.8–1.2 times of the base case value	Morimoto et al.^9
65–74 years	479.4	PSA: lognormal distribution, for each of the three groups:
75–84 years	1024.6	Mean/SE of the underlying normal distribution = 6.1680/0.0948; 6.9289/0.0794; 7.3052/0.0944
85+ years	1494.6
Case fatality rate		DSA: 0.8–1.2 times of the base case value
65–74 years	3.3%	PSA: beta distribution, for each of the three groups: alpha/beta =24/719; 24/551; 23/243
75–84 years	4.2%
85+ years	8.6%
Hospitalization rate		DSA: Only tested by varying associated costs
65–74 years	68.7%	PSA: beta distribution, for each of the three groups: alpha/beta =7.1380/3.2521; 3.6800/0.8078; 0.2740/0.0141
75–84 years	82.0%
85+ years	95.1%

Abbreviations. DSA, Deterministic sensitivity analysis; IPD, Invasive pneumococcal disease; NBPP, Non-bacteremic pneumococcal pneumonia; PPV23, 23-valent pneumococcal polysaccharide vaccine; PSA, Probabilistic sensitivity analysis; SA, Sensitivity analysis; SE, Standard error.

Table 3. Vaccine effectiveness.

Parameter	Base case value (range used in DSA)				PSA assumptions	Reference
Vaccine efficacy
Vaccine efficacy of PPV23 against IPD	74.0% at year 0 (55.0–86.0%)				Lognormal distribution, Mean/SE of the underlying normal distribution: –0.3068/0.1066	Moberley et al.^32
Vaccine efficacy of PPV23 against NBPP	37.7% at year 0 (4.8–59.2%)				Lognormal distribution, Mean/SE of the underlying normal distribution: –1.0390/0.3565	Suzuki et al.^13
Waning function
		Base case	6 years	15 years
Waning function	Year 0	100.0%	100.0%	100.0%	Triangular distribution Lower and upper bound: ±10% of the mean; bounded between 0 and 1; monotonic decreasing by time	Suzuki et al.^13
	Year 1	97.7%	97.7%	97.7%
	Year 2	95.5%	95.5%	95.5%
	Year 3	91.6%	89.4%	91.9%
	Year 4	89.2%	80.5%	90.3%
	Year 5	83.4%	69.0%	86.7%
	Year 6	77.6%	0.0%	83.2%
	Year 7	66.2%	0.0%	79.6%
	Year 8	55.2%	0.0%	76.1%
	Year 9	27.6%	0.0%	72.5%
	Year 10	0.0%	0.0%	69.0%
	Year 11			55.2%
	Year 12			41.4%
	Year 13			27.6%
	Year 14			13.8%
	Year 15			0.0%

Abbreviations. DSA, Deterministic sensitivity analysis; IPD, Invasive pneumococcal disease; NBPP, Non-bacteremic pneumococcal pneumonia; PPV23, 23-valent pneumococcal polysaccharide vaccine; PSA, Probabilistic sensitivity analysis; SE, Standard error.

Table 4. Utility.

Utility	Base case value (range used in DSA)	PSA assumptions (triangular distribution (lower and upper bound)	References and notes
Baseline utility values
65–69 years	0.868	0.844/0.892	Fujikawa et al.^34, in which utility values were elicited by EQ-5D, based on the Japanese instrument
70–79 years	0.780	0.745/0.815
80+ years	0.684	0.632/0.736
IPD (as a utility value)	0.20 for 34 days (±20%)	Triangular distribution, lower and upper bound: 0.15/0.25 for 34 days	Sisk et al.^35, which cited the assumption used in the Healthy People 2000 survey in the US^42
NBPP (as a utility decrement)	0.00 (0.01)	Triangular distribution, lower and upper bound: 0.00/0.01	Assumption
PMS (as a utility value)	0.68	Triangular distribution, lower and upper bound: 0.51/0.86	De Wals et al.^36, which assumed a 0.80 utility multiplier for hearing loss, and 0.60 for other neurological sequelae based on Torrance^43; des Portes^37, which reported that 22% of subjects had hearing loss, while 30% had other neurological sequelae

Abbreviations. DSA, Deterministic sensitivity analysis; IPD, Invasive pneumococcal disease; NBPP, Non-bacteremic pneumococcal pneumonia; PMS, Post-meningitis sequelae; PSA, Probabilistic sensitivity analysis.

Table 5. Costs.

Parameter	Base case value	SA value	Reference and notes
Vaccine costs
Unit price of Pneumovax23^®	¥4,666	Not tested	MHLW^44, the National Health Insurance fee list price of the vaccine, per unit
Cost of vaccine administration	¥3,020	Not tested	MHLW^45, the National Health Insurance reimbursed price for vaccine administration
Cost per IPD episode
Bacteremic Pneumonia	¥869,242	DSA: 0.8–1.2 times of the base case value PSA: gamma distribution, assuming SE is 20% of the mean, for each of the three groups: alpha/beta: 25.00/34,769.68; 25.00/20,705.28; 25.00/36,252.28	MHLW (2016)^46 MHLW (2015)^47 For meningitis and bacteremia without focus, the costs were calculated using the Japanese national Diagnosis Procedure Combination data (i.e. Japanese Diagnosis-related Group [DRG]) Mikoshiba et al.^48 MHLW (2016)^49 For bacteremic pneumonia, the costs were based on the total costs estimated from a single center, inflated to 2017, using the National Health Insurance fee vision data
Meningitis	¥517,632
Bacteremia without focus	¥906,307
Cost of managing post-meningitis sequelae (annual cost)	¥974,125	DSA: 0.8–1.2 times of the base case value PSA: gamma distribution, assuming SE is 20% of the mean: alpha/beta: 25.00/38,965.00	Watanabe et al.^50 Japan Pension Service (2014)^51 The annual cost was assumed to be the annual amount of disability pension, following the same approach used in the Watanabe study
Cost per NBPP episode
Inpatient	¥869,242 (the same as bacteremic pneumonia)	DSA: 0.8–1.2 times of the base case value PSA: gamma distribution, assuming SE is 20% of the mean, for each of the three groups: alpha/beta: 25.00/34,769.68; 25.00/20,705.28; 25.00/36,252.28	Mikoshiba and Shimizu^48 MHLW (2016)^49 Assumed to be the same as bacteremic pneumonia
Outpatient	¥21,264	DSA: 0.8–1.2 times of the base case value PSA: gamma distribution, assuming SE is 20% of the mean: alpha/beta: 25.00/850.56	MIAC (2014)^52 The costs were based on the average costs of an episode of outpatient pneumonia, as reported in the 2016 Social Care Intervention Survey

Abbreviations. DSA, Deterministic sensitivity analysis; IPD, Invasive pneumococcal disease; MHLW, Ministry of Health, Labour and Welfare; MIAC, Ministry of Internal Affairs and Communications; NBPP, Non-bacteremic pneumococcal pneumonia; PSA, Probabilistic sensitivity analysis; SA, Sensitivity analysis; SE, Standard error.

Table 6. Base case results: summary effectiveness and costs (in thousands for costs, QALYs and life years).

	Strategy 1	Strategy 2	Strategy 3	Strategy 4	Strategy 5
Number of IPD cases	3,160	2,999	2,800	2,639	2,495
Number of NBPP cases	1,185,410	1,157,209	1,122,414	1,094,212	1,063,976
Number of deaths due to IPD	345	331	314	300	287
Number of deaths due to NBPP	128,349	126,310	123,531	121,492	118,696
Total life years (undiscounted)	103,912	103,943	103,981	104,013	104,045
Total QALYs (discounted)	64,894	64,896	64,898	64,900	64,900
Vaccine and administration costs (discounted)	¥4,521,582	¥26,181,555	¥33,090,363	¥54,750,337	¥75,122,407
Costs due to IPD (discounted)	¥2,001,606	¥1,892,361	¥1,744,289	¥1,635,044	¥1,543,726
Costs due to NBPP (discounted)	¥741,392,631	¥722,737,622	¥697,420,661	¥678,765,652	¥659,461,540
Total costs (discounted)	¥749,523,541	¥752,347,217	¥733,694,843	¥736,518,520	¥737,448,887

Abbreviations. IPD, Invasive pneumococcal disease; NBPP, Non-bacteremic pneumococcal pneumonia; QALY, Quality adjusted life year.

Costs and QALYs are discounted.

Table 7. Base case results: summary of incremental costs and effectiveness (in thousands for costs and QALYs; all discounted).^a

	Total		vs Strategy 1			vs previous non-dominated strategy
	Discounted costs	QALYs	Incremental costs	QALYs	ICER	Incremental costs	QALYs	ICER
Strategy 1	¥749,523,541	64,894	—	—	—	—	—	—
Strategy 2	¥752,347,217	64,896	¥2,823,676	1.74	¥1,622,153	—	—	Extendedly dominated
Strategy 3	¥733,694,843	64,898	–¥15,828,698	3.61	Dominating	–¥15,828,698	3.61	Dominating
Strategy 4	¥736,518,520	64,900	–¥13,005,022	5.35	Dominating	¥2,823,676	1.74	¥1,622,153
Strategy 5	¥737,448,887	64,900	–¥12,074,655	6.01	Dominating	¥930,367	0.66	¥1,410,138

^a When comparing the cost-effectiveness of a strategy relative to the previous non-dominated strategy on the efficacy frontier, strategy 5 is the most cost-effective strategy under the pre-defined willingness-to-pay threshold.

Abbreviations. ICER, Incremental cost-effectiveness analysis;QALY, Quality adjusted life year; vs, versus.

Figure 2. Tornado diagram for DSA results (Strategy 2 vs Strategy 1). Abbreviations. Excl., excluding; ICER, incremental cost-effectiveness ratio; IPD, invasive pneumococcal disease; NBPP, non-bacteremic pneumococcal pneumonia; PPV23, 23-valent pneumococcal polysaccharide vaccine; QALY, Quality adjusted life years.

Table 8. DSA results.

Parameter	ICER: strategy 2 vs strategy 1	ICER: strategy 3 vs strategy 1	ICER: strategy 4 vs strategy 1	ICER: strategy 5 vs strategy 1
Base case analysis	¥1,622,153	Dominating	Dominating	Dominating
Vaccine efficacy, PPV23: lower	¥75,265,684	¥42,368,784	¥52,960,838	¥67,318,772
Vaccine efficacy, PPV23: higher	Dominating	Dominating	Dominating	Dominating
Vaccine efficacy, PPV23: 0% against NBPP	¥402,071,140	¥229,579,396	¥281,863,336	¥356,956,899
Protection duration, PPV23: 15 years	¥2,827,195	Dominating	Dominating	Dominating
Protection duration, PPV23: 6 years	¥1,609,833	Dominating	¥54,511	Dominating
Time to revaccination =7 years	Dominating	Dominating	Dominating	Dominating
Time to revaccination =10 years	Dominating	Dominating	Dominating	Dominating
Costs (excl. vaccines): –20%	¥3,786,377	Dominating	Dominating	¥741,657
Costs (excl. vaccines): +20%	Dominating	Dominating	Dominating	Dominating
Utility, IPD:−20%	¥1,621,657	Dominating	Dominating	Dominating
Utility, IPD: +20%	¥1,622,649	Dominating	Dominating	Dominating
Utility, outpatient NBPP: with a 0.01 decrement	¥1,418,115	Dominating	Dominating	Dominating
Incidence, IPD: –20%	¥1,652,798	Dominating	Dominating	Dominating
Incidence, IPD: +20%	¥1,591,881	Dominating	Dominating	Dominating
Incidence, NBPP: –20%	¥4,629,064	Dominating	Dominating	¥845,865
Incidence, NBPP: +20%	Dominating	Dominating	Dominating	Dominating
Case fatality rate: –20%	¥3,408,726	Dominating	Dominating	Dominating
Case fatality rate: +20%	¥998,235	Dominating	Dominating	Dominating
Discount rate: both 0%	¥371,827	Dominating	Dominating	Dominating
Discount rate: both 4%	¥3,325,312	Dominating	Dominating	Dominating
Serotype distribution: 2013 (IASR): 69.6%	¥1,193,777	Dominating	Dominating	Dominating
Serotype distribution: assumption (PPV23 60%)	¥3,118,120	Dominating	Dominating	Dominating
Primary vaccination uptake (50%)	¥1,622,153	Dominating	Dominating	Dominating
Primary vaccination uptake (80%)	¥1,622,153	Dominating	¥159,582	¥212,847
Revaccination uptake (40%)	¥1,622,153	Dominating	Dominating	Dominating

Abbreviations. ICER, Incremental cost-effectiveness ratio; IPD, Invasive pneumococcal disease; NBPP, Non-bacteremic pneumococcal pneumonia.

Figure 3. Probabilistic sensitivity analysis: cost-effectiveness plane. Abbreviation. QALY, Quality adjusted life years.

Figure 4. Probabilistic sensitivity analysis: cost-effectiveness acceptability curves. Abbreviation. QALY, Quality adjusted life years.

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Data availability statement

The data that support the findings of this study are available from the corresponding author, XY, upon reasonable request.