Abstract
Objective: In Japan, the National Immunization Program (NIP) includes PPV23 as the primary vaccination for adults and catch-up cohorts. The Japanese Association for Infectious Diseases recommends revaccination for older adults who received primary vaccination ≥5 years earlier. The cost-effectiveness of adding revaccination and/or continuing catch-up vaccination in the NIP was evaluated from the public payer perspective in Japan.
Methods: The Markov model included five health states: no pneumococcal disease, invasive pneumococcal diseases (IPD), non-bacteremic pneumococcal pneumonia (NBPP), post-meningitis sequelae, and death. Cohorts of adults aged 65–95 were followed until age 100 or death: 2014 cohort (aged 65–95, vaccinated: 2014); 2019 cohort (aged 65: 2019); and 2019 catch-up cohort (aged 70–100: 2019, unvaccinated: 2014). Strategies included: (1) vaccinate 2014 and 2019 cohorts; (2) vaccinate 2014 and 2019 cohorts and revaccinate both; (3) strategy 1 and vaccinate 2019 catch-up cohort; (4) strategy 2 and vaccinate 2019 catch-up cohort; and (5) strategy 4 and revaccinate 2019 catch-up cohort. Parameters were retrieved from global and Japanese sources, costs and QALYs discounted at 2%, and incremental cost-effectiveness ratios (ICERs) estimated.
Results: Strategy 1 had the highest number of IPD and NBPP cases, and strategy 5 the lowest. Strategies 3–5 dominated strategy 1 and strategy 2 was cost-effective compared to strategy 1 (ICER: ¥1,622,153 per QALY gained). At a willingness-to-pay threshold of ¥5 million per QALY gained, strategy 2 was cost-effective and strategies 3–5 were cost-saving compared to strategy 1.
Conclusions: Strategies including revaccination, catch-up, or both were cost-effective or cost-saving in comparison to no revaccination and no catch-up. Results can inform future vaccine policies and programs in Japan.
Introduction
Streptococcus pneumoniae (S. pneumoniae) is a gram-positive bacterium that colonizes the upper respiratory tract, which can lead to acute infectionCitation1. Non-bacteremic pneumococcal pneumonia (NBPP) is the most common non-invasive manifestation in adults, while invasive pneumococcal disease (IPD) manifestations include bacteremia without focus, bacteremic pneumococcal pneumonia, and meningitisCitation1–3. IPD is, therefore, associated with substantial disease burden, including high case fatality and risk of developing post-meningitis sequelae (PMS)Citation2,Citation4. Populations at greatest risk of pneumococcal disease include young children and older adultsCitation2,Citation5.
In Japan, IPD is classified as a Category V infectious Disease by the Prevention of Infectious Diseases and Medical Care for Patients with Infectious Diseases Act (the Infectious Diseases Control Law) and is notifiableCitation6. Between April 2013 and December 2016, a total of 7,546 IPD cases were registered in JapanCitation7. Incidence was reported at 6.33 per 100,000 person-years for children younger than 5 years and 2.98 per 100,000 person-years for adults 65 years and olderCitation8. The incidence and burden of NBPP is understood to be considerably higher than IPD, but NBPP is difficult to diagnose definitelyCitation3,Citation9. Of the estimated 530,000 cases of community-onset pneumonia due to S. pneumoniae in 2012, 6% were bacteremic, and the highest incidence was reported in adults aged 65 years and olderCitation9.
Vaccination is the most effective strategy to reduce the burden of pneumococcal disease. The 23-valent pneumococcal polysaccharide vaccine (PPV23) was approved in Japan for the prevention of pneumococcal disease in adults in 1988Citation10. The 13-valent pneumococcal conjugate vaccine (PCV13) received approval for use in adults in 2014, but has not been included in the national immunization program (NIP).
In 2014, PPV23 was introduced in the NIP in Japan for adults aged 65 years old and adults with certain chronic medical or immunocompromising conditions aged between 60 and 64 years oldCitation11. Adults who turn age 70, 75, 80, 85, 90, 95, and 100 years each fiscal year until March 2019 are also eligible for vaccination, at which point the NIP will be reviewedCitation11. Randomized controlled trials and observational studies have demonstrated the effectiveness of PPV23 against pneumococcal disease across multiple populations, including in JapanCitation12,Citation13. The effectiveness of PPV23 against all-type pneumococcal pneumonia (PP) was reported to be 27.4% (95% confidence interval [CI] = 3.2–45.6%) in hospitalized individuals in Japan, aged 65 years or older, while the effectiveness of PPV23 against vaccine-type pneumococcal pneumonia was reported to be 33.5% (95% CI = 5.6–53.1%), and 2.0% (95% CI = −78.9–46.3%) against non-PPV23 serotypesCitation13. Most studies suggest that immune response after PPV23 vaccination is maintained 5–10 years after primary vaccination in middle-age and elderly populationsCitation13–16. However, the exact period and rate of waning is unknown. Therefore, revaccination may be required to provide continued protection against pneumococcal disease.
The Japanese Association for Infectious Diseases recommends revaccination of adults aged 65 years or older at least 5 years after the initial dose of PPV23Citation17, but this recommendation is not included in the current NIP. The Japanese Ministry of Health, Labor and Welfare (MHLW) plans to update the NIP in 2019 and decided to review the eligible cohorts of the current NIP at the 19th MHLW Immunization Policy Committee on 14 September 2017. Given the relatively low uptake of the current vaccine, there is potential for multiple strategies to be considered in the update, including continuation of the current NIP, vaccinating adults aged 65 years only in 2019 (i.e. removal of the catch-up cohort aged 70, 75, 80, 85, 90, 95, and 100 in 2019), the addition of revaccination of adults aged 65 years only, and addition of revaccination for the catch-up cohortCitation18. In 2016, the German Standing Committee on Vaccination (STIKO) found revaccination with PPV23 to be cost-effective compared to a single dose of PPV23, thus revaccination (at least 6 year after initial dose) was recommended for adults aged 60 years or olderCitation4.
In Japan, cost-effectiveness is a key aspect, in addition to vaccine effectiveness and safety, when MHLW reviews whether to include a vaccine in the pneumococcal NIP or notCitation19. Prior to the current NIP, MHLW conducted health economic analyses for primary vaccination in 2011 and found it cost saving. However, the analysis period is only 5 years from the vaccinationCitation16, rather than a lifetime horizon. To date, a cost-effectiveness analysis has been conducted for the strategy to vaccinate 65, 70, 75, 80, and 85 years of age, but not for other strategiesCitation16.
In the light of the upcoming MHLW review of the current NIP in 2019, economic evidence is required to support decision-making, especially in terms of the cost-effectiveness analysis of alternative vaccination strategies. This study aimed to address the question of whether alternative vaccination programs with PPV23 (with or without catch-up vaccination, and with or without revaccination) of older community-dwelling adults are cost-effective, when compared to the strategy under consideration; that is, vaccinating only 65 years old adults with PPV23.
Methods
Target population and assessed strategies
According to the current schedule of the Japanese NIP with introductory catch-up program, pneumococcal vaccination is available to (1) those aged 65 and catch-up populations consisting of adults who turn aged 70, 75, 80, 85, 90, 95, 100 years and older, and (2) those aged between 60 and 64 years with certain chronic medical or immunocompromising conditions that impede daily activitiesCitation11. The target population considered in the current analysis included community-dwelling individuals aged 65, 70, 75, 80, 85, 90, and 95 who received primary vaccination at clinics or hospitals in 2014 based on the current NIP and could be considered in the model (2014 cohort), individuals who will turn 65 in 2019 (2019 cohort) and the remainder of the 2014 cohort who had not been vaccinated in 2014 (2019 catch-up cohort). The following strategies were compared in the base case, to strategy 1:
Strategy 1 (vaccinate the 2014 and 2019 cohorts) (i.e. no revaccination and no catch-up): vaccinate adults aged 65, 70, 75, 80, 85, 90, and 95 years in 2014 and those who turn 65 years in 2019.
Strategy 2 (vaccinate the 2014 and 2019 cohorts with revaccination of both cohorts): vaccinate adults aged 65, 70, 75, 80, 85, 90, and 95 years in 2014 and revaccinate this group who are aged 70, 75, 80, 85, 90, 95, and 100 in 2019; vaccinate adults who turn 65 years in 2019 and revaccinate this group when they turn 70 years in 2024 (5 years after the first vaccination).
Strategy 3 (strategy 1 and vaccinate the 2019 catch-up cohort): vaccinate adults aged 65, 70, 75, 80, 85, 90, and 95 years in 2014, vaccinate those who turn 65 years in 2019, and those aged 70, 75, 80, 85, 90, 95, and 100 in 2019 who missed the primary vaccination in 2014.
Strategy 4 (strategy 2 and vaccinate the 2019 catch-up cohort): vaccinate adults aged 65, 70, 75, 80, 85, 90, and 95 years in 2014 and revaccinate these adults in 2019; vaccinate adults aged 70, 75, 80, 85, 90, 95, and 100 in 2019 who missed the primary vaccination in 2014; vaccinate those who turn 65 years in 2019 and revaccinate those aged 70 in 2024.
Strategy 5 (strategy 4 and revaccination of the 2019 catch-up cohort): vaccinate adults aged 65, 70, 75, 80, 85, 90, and 95 years in 2014 and revaccinate these adults in 2019; vaccinate adults who turn 65 years in 2019 and revaccinate those aged 70 in 2024, vaccinate those aged 70, 75, 80, 85, 90, 95, and 100 in 2019 who missed the primary vaccination in 2014 and revaccinate these adults when they are 75, 80, 85, 90, 95, and 100 in 2024.
provides an overview of the strategies.
Table 1. Strategies compared in the model.
Model structure
A deterministic cohort Markov model was adapted for Japan from previously published modelsCitation20–24. The model was a cost-effectiveness analysis, in which effectiveness was measured in quality-adjusted life years (QALYs). As illustrated in , the model has five health states: no pneumococcal disease, IPD, NBPP, PMS, and death. The choice of the model structure and health states was based on the natural history of pneumococcal diseasesCitation25–27.
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.
A cohort of eligible individuals enters the model with no pneumococcal disease, and is at risk of developing IPD or NBPP. Following IPD and/or NBPP, patients may recover and return to the no pneumococcal disease health state. A proportion of patients who survive IPD may develop PMS. Patients with IPD or NBPP also face a higher risk of death than individuals without pneumococcal disease. It was assumed that, following PMS, patients would not develop another episode of IPD or NBPP, because such a situation is considered rare. The model tracks eligible cohorts until death or 100 years of age. Costs and QALYs were counted from 2019 onwards.
The model has a cycle length of 1 year and, therefore, the seasonality of pneumococcal disease did not need to be reflected in the model. The public payer perspective in Japan was used in the analysis, as the analysis aims to inform decisions of the MHLW. Therefore, costs from the societal perspective (e.g. productivity loss, caregiver costs) were not included in the analysis. Inclusion of these costs would increase cost offsets and improve the cost-effectiveness profile of vaccination. Nevertheless, the study population was individuals aged 65 years or older, and productivity loss would be limited as these individuals were less likely to be in employment. The impact on cost offsets, therefore, was judged to be limited.
Data sources
Model parameters were retrieved from Japanese sources; where not available, international literature was used.
Demography
Population size and life tables were obtained from the Portal Site of Official Statistics of JapanCitation28,Citation29. The proportion of individuals who receive the vaccine was calculated using the vaccine uptake rate of 38.3% for each age cohort, based on the MHLW uptake record for the vaccines in NIPCitation18. No vaccination was assumed for the rest of the population.
For those who turned 65–95 (by 5 year age-groups) in 2014, 2,775,000 received the vaccination in 2014 (2014 cohort), and 4,470,000 received the vaccination in 2019 (2019 catch-up cohort), depending on the strategy chosen. A total of 588,000 received the vaccination in the 2019 cohort (38.3% of 65 year olds who were 60 years old in 2014). No vaccination was assumed for the rest of the population, rather it was assumed 100% of adults who had received the primary vaccination were revaccinated, if a revaccination strategy was considered.
Epidemiology of invasive pneumococcal disease (IPD)
The epidemiology of IPD was obtained from an MHLW-funded study on pneumococcal and H. influenzae diseases between 2013 and 2015Citation8. provides the clinical parameters related to IPD. Between September 2013 and December 2015, the incidence of IPD was estimated at 2.98 per 100,000 person-years in adults aged 65 years and olderCitation8. The proportion of IPD associated with serotypes covered by PPV23 was 67.0%Citation30. Bacteremic pneumonia, meningitis, and bacteremia without focus comprised 58.7%, 17.6%, and 16.2% of all IPD cases, respectivelyCitation30. The case-fatality rate for IPD was estimated at 8.7% for those aged 65 years and older (between September 2013 and 31 December 2015)Citation8. The probability of developing PMS in survivors of meningitis (31.7%) was obtained from a meta-analysis of international dataCitation31.
Table 2. Clinical parameters related to IPD and NBPP.
Epidemiology, non-bacteremic pneumococcal pneumonia (NBPP)
The proportion of NBPP attributable to serotypes covered by PPV23 was assumed to be the same as for IPD. The incidence of NBPP, case fatality rate, and hospitalization rate for individuals aged between 65 and 74, 75 and 84 years, and aged 85 years or above were derived from Morimoto et al.Citation9 (see ).
Vaccine effectiveness
PPV23 efficacy against IPD (74.0%) was taken from a meta-analysis of randomized controlled trials of PPV23Citation32. Effectiveness against NBPP was taken from a large observational study in Japan and estimated at 33.5% in the first year after vaccination (see )Citation13. The duration of protection was estimated over 10 years using the following time points from the observational study: year 0 = 37.7% (calculated from 1 month to 2 years); year 3.5 = 34.7% (calculated from 2–5 years); year 7.5 = 26% (calculated from 5+ years). illustrates that protection wanes from year 5, and assumes the vaccine renders no protection after 10 years, based on the same observational studyCitation13. The efficacy and durability of PPV23 revaccination is unknown. However, in a systematic review by Grabenstein and ManoffCitation33, revaccination with PPV23 5–10 years after the primary vaccination consistently increased both immunoglobulin G and functional antibody levels. In Japan, a non-randomized, open-label, multi-center study evaluated the immunogenicity and safety of revaccination with PPV23 in the elderly population, and found that immune response following a second dose of PPV23, administered 5 years after the initial dose, was comparable to that achieved after primary vaccinationCitation17. The Japanese Association for Infectious Diseases (JAID) recommendation for revaccination also noted that, since revaccination was estimated to have comparable immunogenicity to primary vaccination with PPV23, it is expected that revaccination has the same level of protection against pneumococcal disease as primary vaccinationCitation17. Therefore, in this analysis, revaccination was assumed to provide the same protection against disease as the initial vaccination.
Table 3. Vaccine effectiveness.
Effectiveness
Effectiveness was measured as the number of IPD and NBPP cases and deaths, as well as QALYs, for each strategy under consideration. The baseline utility weight in the general population was retrieved from a Japanese EQ-5D study (see )Citation34. Assumptions on utility values for health states are in line with previous studies, utilizing data from international literatureCitation35–37. QALYs were discounted at 2% following the Guideline for Preparing Cost-Effectiveness Evaluation to the Central Social Insurance Medical Council (2015)Citation38.
Table 4. Utility.
Costs
Corresponding to the public payer perspective used, only direct medical costs were considered, including the cost of PPV23 vaccine, cost of vaccine administration, cost of treating IPD, NBPP, and managing PMS (see ). Costs were expressed in 2017 Japanese yen and were discounted at 2%Citation38.
Table 5. Costs.
Economic analysis
The base case analysis compared strategies 2–5 to strategy 1 (no revaccination and no catch-up). For the base case analysis, the total number of IPD and NBPP cases and deaths, as well as the total costs and QALYs for each strategy, were estimated from 2019 onwards. The cost-effectiveness of strategies 2–5 vs strategy 1 was evaluated by calculating the incremental cost-effectiveness ratio (ICER) (i.e. the incremental cost per QALY gained). Although there is no formal cost-effectiveness threshold in Japan, ¥5 million per QALY gained is generally used from the payer’s perspective, following a willingness-to-pay studyCitation39.
Deterministic and probabilistic sensitivity analyses (DSA and PSA) were conducted to assess the impact of uncertainties around key parameters and assumptions. The tested parameters and assumptions are presented in . The following assumptions were also explored in the DSA: protection duration of 6 or 15 years; primary vaccination uptake rate (50% or 80%); time to revaccination of 7 or 10 years; discount rate of 0 or 4%, disutility associated with NBPP managed in outpatient settings, and vaccine efficacy. The choice of parametric distributions in the PSA was based on the recommendations by Briggs et al.Citation40. PSA was run for 1,000 iterations.
Results
A total of 8,781,000 individuals who received the vaccination in 2014 or who would receive vaccination in 2019 were modeled until death or 100 years old. presents the effectiveness and costs for each of the five strategies. As shown in , over the time horizon, strategy 1 was associated with the highest number of IPD (3,160) and NBPP (1,185,410) cases. When compared to strategy 1, the number of cases under strategies 2 and 5 ranged between 2,495 and 2,999 cases for IPD and between 1,063,976 and 1,157,209 cases for NBPP. Strategy 5 resulted in the lowest number of IPD and NBPP cases and deaths among these strategies.
Table 6. Base case results: summary effectiveness and costs (in thousands for costs, QALYs and life years).
presents base case analysis results on incremental costs, incremental effectiveness, and ICERs for strategies 2–5 vs strategy 1, respectively. Strategies 3–5 were found to be cost saving compared to strategy 1. Strategies 3–5 dominated strategy 1 (all having lower costs and more QALYs gained vs strategy 1). The ICER for strategy 2 vs strategy 1 was estimated at ¥1,622,153 per QALY gained. At the typically accepted willingness-to-pay threshold of ¥5 million per QALY gained in Japan, strategy 2 was cost-effective and strategies 3–5 were cost-saving compared to strategy 1. When comparing the cost-effectiveness of a strategy relative to the previous non-dominated strategy on the efficiency frontier, strategy 5 is the most cost-effective strategy under the pre-defined willingness-to-pay threshold ().
Table 7. Base case results: summary of incremental costs and effectiveness (in thousands for costs and QALYs; all discounted).Table Footnotea
and present the DSA results of strategy 2 versus strategy 1, and strategies 2-5 versus strategy 1, respectively. The ICER was sensitive to assumptions on the vaccine efficacy of PPV23, protection duration, incidence of NBPP, case fatality, serotype distribution, time to revaccination, and costs, especially at the lower bound. For strategies 3–5 vs strategy 1, the ICER was sensitive to assumptions on vaccine efficacy of PPV23 and protection duration, costs, and incidence of NBPP, whereas, in other scenarios, these strategies remained dominant or cost-effective (see ).
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.
PSA confirmed the results from the base case analysis, as shown in and . As shown in , the probability of being cost-effective at a threshold of ¥5 million per QALY gained was estimated at 4.5% for strategy 1, 0% for strategy 2, 30.4% for strategy 3, 13.3% for strategy 4, and 51.8% for strategy 5.
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.
Discussion
Our findings provide insight into the cost-effectiveness of PPV23 vaccination strategies, including revaccination and catch-up vaccination, in adults aged 65 years or older in Japan. Following a cohort of 8,781,000 adults who are eligible for vaccination in 2014 or 2019, strategies including revaccination and/or catch-up vaccination with PPV23 (strategies 2–5) were associated with the fewest pneumococcal disease cases (IPD and NBPP) when compared to no revaccination and no catch-up (strategy 1). These strategies were also associated with cost savings in the majority of scenarios. From a public health perspective, revaccinating the initial 2014 cohort as well as the 2019 catch-up cohort is the most effective strategy, and is also cost saving (strategy 5). The ICER of ¥1,622,153/QALY for revaccination only compared with no revaccination and no catch-up is well below the typically used willingness-to-pay-threshold of ¥5 million per QALY gained in JapanCitation39, and is, therefore, considered to be a cost-effective strategy. When comparing the cost-effectiveness of a strategy relative to the previous non-dominated strategy on the efficiency frontier, strategy 5 is the most cost-effective strategy under the pre-defined willingness-to-pay threshold. Thus, there is an incremental difference between strategies 2–5 compared to strategy 1, illustrating that strategy 5 is not the only cost-effective option as compared to strategy 1. In most scenarios explored, sensitivity analyses indicated that the results were robust to the different model parameters.
Results are aligned with STIKO’s analysis, which also showed that revaccination with PPV23 was more effective (i.e. more hospitalizations and deaths prevented) and cost-effective compared to no revaccination in GermanyCitation4. This analysis adds to previous studies evaluating adult revaccination in Japan. Kawakami et al.Citation41 previously demonstrated that revaccination with PPV23 was well tolerated and associated with an increase in IgG concentrations and OPA titers in older Japanese adults who had received PPV23 at least 5 years prior.
Strengths and limitations
A key strength of the study is that the model was based on local burden of disease and epidemiological data. It also included a range of sensitivity analyses, allowing for a better understanding of the impact of uncertainty around the assumptions. Furthermore, several potential strategies on revaccination and/or catch-up were compared to the current no revaccination and no catch-up strategy.
There are also limitations which are inherent to the model. The analysis did not account for the indirect effect of infant vaccination programs on unvaccinated older age groups. Dynamic models need information on disease transmission for estimating the indirect effect, which is not yet available in Japan. Furthermore, the impact of revaccination and catch-up strategies from a societal perspective was not considered, which may under-estimate the cost-effectiveness of these strategies.
Another limitation is the model assumed 100% of the vaccinated population was revaccinated in the base case, which may over-estimate the impact revaccination had on the number of cases. This assumption, however, was explored in sensitivity analyses.
A final limitation is that the incidence of IPD may be under-estimated due to under-reporting in Japan. Using the under-reported IPD incidence is a conservative approach that does not capture the full benefit of PPV23, as an increase in the point estimate of incidence used in the model will only lead to an improvement in the ICER (as fewer disease cases would be prevented in the model than in reality).
Conclusion
Vaccination strategies, including revaccination, catch-up vaccination, or both, are cost-effective or cost saving from a public payer perspective in comparison to no revaccination and no catch-up vaccination in Japan. Results can inform future vaccine policies and programs.
Transparency
Declaration of funding
This research was funded by Merck & Co., Inc., Kenilworth, NJ.
Declaration of financial/other relationships
XY and TP are employees of Merck & Co., Inc., Kenilworth, NJ. YJ is an employee of Merck Sharp & Dohme Ltd., Hoddesdon, Hertfordshire, UK. KT and MA are employees of MSD K.K, Tokyo, Japan. Peer reviewers on this manuscript have received an honorarium from JME for their review work. One reviewer discloses employment with Merck, while the remaining reviewers have no relevant financial relationships to disclose.
Acknowledgments
The authors thank Emily Farrington, Claire Spencer, and Yunni Yi, employees of Adelphi Values, for their assistance with manuscript preparation and submission.
Data availability statement
The data that support the findings of this study are available from the corresponding author, XY, upon reasonable request.
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