Recommendations on the use of conjugate pneumococcal vaccine – 15 valent (PNEU-C-15) and 20 valent (PNEU-C-20) in adults: Economic evidence supplementary appendix

An Advisory Committee Statement (ACS)

National Advisory Committee on Immunization (NACI)

Table of Contents

• Preamble
• I. Systematic Review
  • I.1 Description of Included Studies
  • I.2 Results of Age-Based Strategies
  • I.3 Results of Risk-Based Strategies
  • I.4 Results of Combined Age- and Risk-Based Strategies
  • I.5 Generalizability
  • I.6 Influential Parameters and Assumptions
  • I.7 Conclusions
• II. Cost-Utility Analysis
  • II.1 Economic Model Description
  • II.2 Model Parameters
  • II.3 Base Case
  • II.4 Sensitivity Analysis
  • II.5 Scenario Analyses
  • II.6 Study limitations
  • II.7 Conclusions
• III. Multi-Model Comparison
  • III.1 Approach
  • III.2 Multi-Model Comparison Results
  • III.3 Conclusions
• List of Abbreviations
• References

Preamble

The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.

In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.

The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.

This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

A systematic review, de novo model-based economic evaluation, and a multi-model comparison were used as economic evidence to support decision-making for the use of 15-valent (PNEU-C-15) and 20-valent (PNEU-C-20) conjugate vaccines. Each component is described below.

Systematic Review

A systematic review of the cost-effectiveness of PNEU-C-15 and PNEU-C-20 vaccines for preventing pneumococcal disease (PD) was conducted. The review included economic evaluations conducted in adults aged 18 or older, comparing currently used vaccines to prevent pneumococcal disease to PNEU-C-15 or PNEU-C-20. The components of the research question are:

• Population: Adults aged 18 years or older
• Intervention: PNEU-C-15 or PNEU-C-20 (alone or in series with other pneumococcal vaccines)
• Comparator: Current vaccines for pneumococcal disease (PNEU-C-7, PNEU-C-10, PNEU-C-13, PNEU-P-23 (23-valent polysaccharide))
• Outcomes: Measures of cost-effectiveness (incremental cost per quality-adjusted life year, incremental cost per disability-adjusted life year, cost per life year, etc.)

A systematic literature search of Embase, International Pharmaceutical Abstracts, Ovid Medline, EBM Reviews, and Econlit was conducted for January 1, 2018, to September 30, 2021. Language of publication was restricted to English or French. Keywords used included: pneumococcal vaccine, conjugate vaccine, pneumococcal infection, PCV15, PCV20, economic evaluation, economic impact, and financial effect. The search strategy was developed in consultation with and validated by a librarian. A search of grey literature was also conducted, guided by recommendations put forth by the Canadian Agency for Drugs and Technologies in Health (CADTH) in their Grey Matters tool, which is a checklist of grey literature sources including both Canadian and international health technology assessment agencies^{Footnote 1}. Titles and abstracts of retrieved references were screened using DistillerSR systematic literature review software^{Footnote 2} by two reviewers. Inclusion and exclusion criteria were discussed prior to screening to ensure criteria would be applied consistently, and any discrepancies were resolved through discussion. The full texts of references that were eligible for inclusion after title and abstract screening were retrieved and assessed by the same two reviewers to determine final inclusion/exclusion. A standardized data extraction tool was used to record study characteristics, methods, and findings of included studies. ICERs are presented in 2021 US dollars and were inflated using the Health Care component of Personal Consumption Expenditures where necessary^{Footnote 3}. The Joanna Brigs Institute (JBI) Critical Appraisal Checklist for Economic Evaluations^{Footnote 4} was used to assess the overall quality of included studies. The applicability or transferability of included studies was assessed using Heyland's Generalizability Criteria^{Footnote 5}. No studies were excluded on the basis of these appraisals.

I.1 Description of Included Studies

Four model-based cost-utility analyses were identified, all of which were conducted in the United States. Only one study was published in the peer-reviewed literature at the time of the search^{Footnote 6}, with the remaining studies identified in a search of the grey literature. Results for three of the economic evaluations were included in a single report to the Advisory Committee on Immunization Practices (ACIP)^{Footnote 7}. To distinguish between these studies, the three economic evaluations from this single report are referred to by the names of the authors of the individual studies^{Footnote 8 Footnote 9 Footnote 10}. A version of one of the studies included in the ACIP report was also described in greater detail in a separate report^{Footnote 11}. Two of the four included studies were industry sponsored^{Footnote 8 Footnote 9}. Two studies used a health system perspective^{Footnote 6 Footnote 9} and two used a societal perspective^{Footnote 8 Footnote 10}. All studies used a 3% discount rate for costs and outcomes, as recommended in the US. Cost-effectiveness outcomes were reported as ICERs, presented as the incremental cost per QALY gained. All studies used a lifetime time horizon.

Two studies used Markov models that followed a single age cohort over time^{Footnote 6 Footnote 10} and the other two used multi-cohort Markov models that followed a population consisting of multiple age cohorts over time^{Footnote 8 Footnote 9}. Although the model structures varied, all used a similar approach to model the risk of PD, generally conceptualized as invasive pneumococcal disease (IPD) or non-bacteremic pneumococcal pneumonia (NBPP) and the potential for long-term sequelae following IPD. Risk of PD was dependent on age, vaccination status, and for some models, presence of immunocompromising conditions (IC) or chronic medical conditions (CMC). None of the models used were dynamic but some did evaluate indirect effects by assuming a reduction in vaccine-type PD incidence over time due to potential use of PNEU-C-15 or PNEU-C-20 in pediatric populations^{Footnote 9 Footnote 10}.

The model-based evaluations compared outcomes, including costs and QALYs, for vaccination strategies using PNEU-C-15 or PNEU-C-20 to current US recommendations. At the time the studies were conducted, the US pneumococcal vaccination guidance for adults aged 19 years or older included the following age- and risk-based recommendations: PNEU-P-23 plus optional PNEU-C-13 under shared clinical decision-making for adults aged 65 years or older; PNEU-P-23 at diagnosis of chronic medical conditions (CMC) if under age 65 years; and PNEU-C-13 in series with PNEU-P-23 at diagnosis of IC if under age 65 years^{Footnote 12}. Different age-, risk-, or combined age- and risk-based vaccination strategies were evaluated, which are discussed in turn below. Results are presented for both the health system and societal perspectives, with the perspective used noted in the tables.

I.2 Results of Age-Based Strategies

All four model-based economic evaluations examined the cost-effectiveness of age-based strategies, consisting of different approaches for the use of PNEU-C-15 or PNEU-C-20 either alone or in series with PNEU-P-23 in the population aged 50 or 65 years and older (Table 1).

The use of PNEU-C-15 alone in the population aged 65 years was evaluated in a single study and was found to have an ICER ranging from $250,434 to 479,494 per QALY gained compared to the current vaccine recommendations in this age group^{Footnote 6}. The ICER was higher when indirect effects of a potential pediatric vaccination program for reducing adult PD were included. There was variability across the three studies that reported results for use of PNEU-C-15 in series with PNEU-P-23 at age 65 years. One study estimated that use of PNEU-C-15 plus PNEU-P-23 would result in lower costs and improved health outcomes compared to current recommendations (i.e., was the dominant strategy)^{Footnote 10}. The two other studies estimated ICERs ranging from $237,000-611,169 per QALY gained^{Footnote 6 Footnote 8}, suggesting that this strategy was unlikely to be considered cost-effective under commonly used thresholds.

Three studies evaluated the use of PNEU-C-20 alone at age 50 years compared to the current age-based recommendations. One study reported variable estimates of potential value, depending on assumptions, ranging from PNEU-C-20 dominating current recommendations when indirect effects were included, to use of PNEU-C-20 leading to lower costs and reduced health outcomes when indirect effects were ignored^{Footnote 10}. A second study estimated ICERs ranging from $174,000-514,000 per QALY gained^{Footnote 8} and the third study reported an ICER of $18,000 per QALY gained^{Footnote 9}.

Four studies evaluated the use of PNEU-C-20 alone at age 65 years compared to the current age-based recommendations. Two studies reported PNEU-C-20 to be the dominant strategy, resulting in lower costs and improved outcomes compared to current recommendations^{Footnote 9 Footnote 10}. In one study that included four scenario analyses, ICERs ranged from dominant to $39,000 per QALY gained^{Footnote 8}. In another study, the ICER estimates ranged from $187,761-410,900 per QALY gained^{Footnote 6}.

The single study to evaluate PNEU-C-20 in series with PNEU-P-23 at age 65 years showed the strategy was unlikely to be cost-effective, with ICERs ranging from $488,716-704,702 per QALY gained^{Footnote 6}.

I.3 Results of Risk-Based Strategies

Three studies evaluated the cost-effectiveness of risk-based strategies in people aged 19 to 49 or 19-64 years with IC or CMC, population groups for whom different pneumococcal vaccination recommendations apply in the US, where the studies were conducted (Table 2).

The two studies that evaluated risk-based use of PNEU-C-15 in series with PNEU-P-23 in the population aged 19-64 years found this strategy unlikely to be cost-effective under commonly used thresholds, with ICERs ranging from $250,000-656,000 per QALY gained^{Footnote 8 Footnote 10}.

There was variability across the three studies that evaluated the use of PNEU-C-20 alone for the population aged 19-49 years. In scenario analyses, one study reported that the use of PNEU-C-20 would range from dominating current recommendations to an ICER of $25,000 per QALY gained^{Footnote 8}. The other two studies reported a range from $94,000-$483,000 per QALY gained^{Footnote 9 Footnote 10}.

Risk-based use of PNEU-C-20 in the population aged 19-64 years also produced variable results across studies, with one study suggesting that the strategy could be cost-effective or dominate current recommendations^{Footnote 9}, and the other two studies estimating ICERs ranging from $58,999-$292,000 per QALY gained^{Footnote 8 Footnote 10}. Overall, risk-based use of PNEU-C-20 was estimated to result in lower ICERs when the strategy was used in the population aged 19-64 years compared to its use in the population aged 19-49 years.

I.4 Results of Combined Age- and Risk-Based Strategies

Two studies evaluated combined age- and risk-based strategies (Table 3). Overall, evaluations that combined age- and risk-based strategies tended to result in more favourable ICER estimates compared to risk-based only strategies.

PNEU-C-15 use in series with PNEU-P-23 for people with CMC or IC aged 19-64 years and at age 65 years for the general population was not likely to be cost-effective under commonly used thresholds in the single study that evaluated this strategy (ICER of $338,000 per QALY gained)^{Footnote 10}.

The use of PNEU-C-20 alone for people aged 19-49 years with CMC or IC and the general population at age 50 years resulted in estimates ranging from dominant to $11,000 per QALY gained^{Footnote 9 Footnote 10}. The use of PNEU-C-20 alone for people aged 19-64 years with CMC or IC and the general population at age 65 years was estimated to dominate current recommendations in both studies^{Footnote 9 Footnote 10}. This finding was consistent with the age-only and risk-based only comparisons, where the interventions appeared more cost-effective at age 65 years compared to at 50 years.

I.5 Generalizability

Given that all of the studies were conducted in the US, the transferability of the cost-effectiveness estimates was assessed. The clinical generalizability, analysis type, costing method, outcome measure method, and use of a preference-based measure instrument to obtain utility values were aligned with the NACI guidelines for the conduct of economic evaluations in the Canadian setting^{Footnote 13}. The discount rate (3%) was higher than the recommended discount rate of 1.5%.The US vaccination recommendations at the time of the analyses differed from Canadian pneumococcal vaccination recommendations, such that the comparator used in the included analyses may not reflect the Canadian context. For instance, in the US, PNEU-P-23 plus optional PNEU-C-13 under shared clinical decision-making was recommended for adults aged 65 years or older, while in Canada, population-level recommendations were for PNEU-P-23 for this age group.

I.6 Influential Parameters and Assumptions

Model parameters that were reported to influence the estimated cost-effectiveness included: overall effectiveness of the conjugate vaccines; effectiveness of the conjugate vaccines against serotype 3 disease; waning of vaccine effectiveness; incidence of pCAP, and vaccine price. The assumption of declines in vaccine-type disease in the adult population associated with a putative infant vaccination program generally resulted in higher ICERs than scenarios that did not consider these potential indirect effects.

ICER estimates from Smith et al.^{Footnote 6} tended to be higher than in the other models, with results generally less favourable toward to use of PNEU-C-15 or PNEU-C-20 relative to current vaccine recommendations. Although reasons for this difference are uncertain, the Smith et al. study differed from the others by not modelling people with IC. It also used less recent data for vaccine serotype coverage and PD incidence^{Footnote 7}. This model, along with that of Weycker et al.^{Footnote 9} used the health system perspective; the use of a narrower perspective (compared to the societal one) that does not account for the full range of benefits associated with vaccination programs may also have contributed to less favourable cost-effectiveness estimates.

I.7 Conclusions

A review of the peer-reviewed and grey literature identified four cost-utility studies of PNEU-C-15 and PNEU-C-20 compared to current vaccination recommendations. The studies generally found that PNEU-C-20 use in older adults was associated with increased QALYs, with lower ICERs when the vaccine was used in adults aged 65 years and older compared to programs in adults aged 50 years and older. ICER estimates for PNEU-C-15 use in series with PNEU-P-23 at age 65 years showed variability across studies. The estimated impact of adding risk-based programs for younger adults with IC/CMC to an age-based strategy depended on the vaccine product, with more favourable cost-effectiveness estimates for PNEU-C-20 than for PNEU-C-15 in series PNEU-P-23.

Cost-utility Analysis

II.1 Economic Model Description

A cost-utility model was developed to evaluate the cost-effectiveness of PNEU-C-15 and PNEU-C-20 vaccines in the Canadian population. The model compared the health and economic outcomes of different vaccination strategies. Summaries of the methods and results are provided below.

The economic analysis incorporated the following considerations: recommended age at vaccination and whether PNEU-C-15 or PNEU-C-20 should be used alone or in series with PNEU-P-23. Given higher rates of PD in circumpolar regions of Canada, separate analyses were conducted for the Northern Territories (Northwest Territories, Yukon, and Nunavut) and the provinces, referred to as "North" and "Rest of Canada" (ROC), respectively. Due to data limitations, the model only evaluated age-based vaccination strategies and did not separately model risk in population groups known to experience higher risk of PD, including people with immunocompromising conditions and chronic medical conditions.

The model followed a single cohort of people aged 50, 65, or 75 years without a history of previous pneumococcal vaccination over their lifetime. The age at model entry was varied to evaluate different possible age recommendations for vaccination. The current Canadian population-level recommendation of PNEU-P-23 use for older adults was compared to PNEU-C-15 or PNEU-C-20 alone or in series with PNEU-P-23. When used in series, the conjugate vaccine was assumed to be given first, followed by PNEU-P-23 one year later. Vaccine was assumed to be administered on model entry.

People did not have PD on model entry but could develop invasive pneumococcal disease (IPD) or pneumococcal community-acquired pneumonia (pCAP) over their lifetimes (Figure 1). pCAP could be treated outside of the hospital (outpatient) or require hospitalization (inpatient). There was a risk of death associated with PD and mortality from other causes was also modelled^{Footnote 14}. People recovering from IPD (all assumed to require hospitalization) could experience long-term consequences associated with their infection (neurologic or auditory sequelae). Vaccination was assumed to reduce the risk of pneumococcal disease due to serotypes included in the vaccine. The cohort model was static and did not incorporate dynamic feedbacks. It used a lifetime time horizon, a discount rate of 1.5% for costs and outcomes, and assessed cost-effectiveness from the health system and societal perspectives. The model was programmed using R 4.0 and the data.table package and used the approach described by Krijkamp et al. (2020)^{Footnote 15 Footnote 16 Footnote 17}.

Model outcomes included cases of IPD and pCAP, deaths due to PD, life years, quality-adjusted life years (QALYs), and costs. QALYs and costs were used to estimate incremental cost-effectiveness ratios (ICERs). Model estimates were based on 2,000 simulations with parameters drawn from distributions. Conventional probability distributions were used: beta distributions were used for parameters constrained between zero and one, such as probabilities and utilities; Dirichlet distributions were used for multivariate probabilities, such as the proportion of PD cases attributable to serotype groups; gamma and lognormal distributions were used for parameters constrained to positive values, such as costs and rate ratios. Because multiple vaccine products and strategies were evaluated, sequential analyses were conducted, to determine if certain strategies would result in a more efficient use of resources. For a given age group and geographic region, sequential ICERs were calculated by ordering the strategies by lowest to highest cost and comparing the incremental costs and QALYs gained for a given strategy to the next less costly strategy. In the sequential analysis, strategies could be eliminated because there were other strategies that were projected to result in more QALYs gained at lower costs (i.e., the strategy was dominated) or there was a combination of other strategies that would result in more QALYs gained for lower costs, such that the excluded strategy would never be the optimal intervention, regardless of the cost-effectiveness threshold used (i.e., the strategy was subject to extended dominance).

IPD=invasive pneumococcal disease; pCAP=pneumococcal community acquired pneumonia.

Figure 1 - Text description

Figure 1 shows a schematic of the pneumococcal model in which the relationship between different health states is represented with ovals labelled with each health state and arrows representing how people can move between the different health states. There is a two-way relationship between "no pneumococcal disease" and the "invasive pneumococcal disease" and "pneumococcal community-acquired pneumonia" states, indicating that people can develop pneumococcal disease and recover. There is one-way movement between "invasive pneumococcal disease" and "post-meningitis sequelae" state, indicating that some people will develop long-term consequences of infection and not recover. People can move to the "dead" state from any of the other health states and cannot exit this health state once they enter it.

Footnote *

IPD: invasive pneumococcal disease

pCAP: neumococcal community acquired pneumonia

Return to footnote * referrer

II.2 Model Parameters

Model parameters describing PD epidemiology (Table 4), vaccine characteristics (Table 5), costs (Tables 6 and 7), and health utilities (Table 8) were derived from available data and literature, wherever possible, and by assumption otherwise. Canadian data were used preferentially, when available. In the absence of vaccine effectiveness (VE) data for PNEU-C-15 and PNEU-C-20, VE was assumed to be equal to that reported for PNEU-C-13 but extended to cover additional serotypes not included in PNEU-C-13. VE for preventing PD caused by serotype 3 was assumed lower than for other serotypes for the conjugate and polysaccharide vaccines^{Footnote 11 Footnote 18}. Protection was assumed to be more durable for the conjugate vaccines than for PNEU-P-23^{Footnote 10}.

Data on age- and region-specific incidence of IPD were obtained from the International Circumpolar Surveillance program and the Canadian Notifiable Disease Surveillance System^{Footnote 19}. Incidence of community-acquired pneumonia (CAP) was estimated using records of hospitalizations with pneumonia from the Discharge Abstract Database in 2018-2019. Data from the Serious Outcomes Surveillance (SOS) Network was used to estimate the proportion of hospitalized CAP cases due to S. pneumoniae^{Footnote 20}. The incidence of outpatient pCAP cases was estimated from studies reporting the proportion of CAP cases that are hospitalized^{Footnote 21 Footnote 22 Footnote 23 Footnote 24}. The proportion of PD cases attributable to serotypes contained in the vaccines was obtained from Canadian surveillance data^{Footnote 19 Footnote 20}. Estimates of case-fatality^{Footnote 20 Footnote 25} and risk of long-term sequelae^{Footnote 26 Footnote 27 Footnote 28 Footnote 29 Footnote 30 Footnote 31 Footnote 32 Footnote 33 Footnote 34 Footnote 35} were obtained from the literature.

Costs of IPD and hospitalizations with pneumonia were estimated using Resource Intensity Weights obtained from the Discharge Abstract Database (2015-2019)^{Footnote 36 Footnote 37 Footnote 38 Footnote 39} and the cost of a standard hospital stay^{Footnote 40}. Costs of outpatient pneumonia were assumed to comprise either a physician office visit or an emergency department visit. Costs of long-term sequelae were based on costs of auditory or neurologic complications of bacterial meningitis^{Footnote 41}. Vaccination costs included administration costs^{Footnote 42} and vaccine price. The prices of PNEU-P-23 and PNEU-C-13 were based on contract prices communicated in confidence by PHAC Vaccine Supply and Assurance. Prices for PNEU-C-15 and PNEU-C-20 were based on the relative US incremental prices of these vaccines compared to PNEU-C-13^{Footnote 43}. Based on the US data, the incremental price for PNEU-C-20 was higher than that for PNEU-C-15. For the societal perspective, costs included productivity loss due to illness, caregiver costs, and out-of-pocket medical costs. Productivity loss was estimated using the human capital method.

Age-specific utilities for the Canadian general population were based on EQ-5D-5L index scores of residents from Alberta, Canada^{Footnote 44}. Utilities of IPD, pCAP, and long-term sequelae were derived by applying utility multipliers for each condition^{Footnote 45 Footnote 46 Footnote 47 Footnote 48 Footnote 49 Footnote 50} against utility norms for the general population.

II.3 Base Case

Health outcomes, compared to projected outcomes with use of PNEU-P-23 in the population, are displayed graphically in Figure 2 by cohort age and region. For all age cohorts and geographic regions, use of PNEU-C-20, alone or in series with PNEU-P-23 and use of PNEU-C-15 in series with PNEU-P-23, were projected to avert cases of IPD, pCAP, as well as pneumococcal-attributable hospitalizations and deaths, compared to continued use of PNEU-P-23. In the age 50 cohort, use of PNEU-C-15 alone was projected to result in more cases of IPD than use of PNEU-P-23. For all other ages and outcomes, PNEU-C-15 was projected to result in fewer cases of IPD, pCAP, hospitalizations, and deaths compared to PNEU-P-23.

Figure 2 - Text description

Figure two is a multi-panel bar graph that shows averted health outcomes per 100,000 population. The figure is arranged in three rows and each row has four graphs. Each row shows results for a different age cohort. The top row shows results for the age 50 cohort, the middle row for the age 65 cohort and the bottom row for the age 75 cohort. The four graphs for each row are labelled "IPD", "pCAP", "Hospitalization" and "Death". For each graph, the x-axis is labelled "Mean lifetime outcomes averted per 100,000 population (compared to PNEU-P-23). The numeric scale of the x-axis varies across the row for the different outcomes, with maximum values of 30 for IPD, 300 for pCAP, 200 for hospitalization, and 20 for death. The y-axis is labelled with the names of the vaccination strategies: "PNEU-C-15", "PNEU-C-20", "PNEU-C-15 + PNEU-P-23", and "PNEU-C-20 + PNEU-P-23". For each strategy on the y-axis there are two bars, a blue one for Northern Canada and a yellow one for Rest of Canada. For the rows displaying the age 50 and age 65 years cohorts, the bars for the number of health events averted are longer for Northern Canada than Rest of Canada, indicating that more health outcomes are averted in this population group. For the age 75 cohort, except for IPD cases, there are more cases averted for the rest of Canada compared to Northern Canada. All of the values on the graph are positive except for the graph showing IPD cases averted in the age 50 years cohort using PNEU-C-15, which has small negative values, indicating fewer IPD cases occur when using PNEU-P-23. For all age cohorts and geographic regions, the rates of health outcomes averted are lowest for PNEU-C-15 and highest for PNEU-C-20 + PNEU-P-23. There is some variability for PNEU-C-20 and PNEU-C-15+PNEU-P-23 but in general, the rates of averted outcomes are similar.

Health outcomes averted with different vaccination strategies compared to PNEU-P-23 use in the age 50 cohort, in Northern Canada

Outcome	Strategy	Mean lifetime outcomes averted per 100,000 population
IPD	PNEU-C-15	-1.71825
IPD	PNEU-C-20	17.93882
IPD	PNEU-C-15 + PNEU-P-23	21.99199
IPD	PNEU-C-20 + PNEU-P-23	29.06004
pCAP	PNEU-C-15	111.5491
pCAP	PNEU-C-20	260.824
pCAP	PNEU-C-15 + PNEU-P-23	214.6381
pCAP	PNEU-C-20 + PNEU-P-23	309.6834
Hospitalization	PNEU-C-15	28.53096
Hospitalization	PNEU-C-20	89.20836
Hospitalization	PNEU-C-15 + PNEU-P-23	81.0254
Hospitalization	PNEU-C-20 + PNEU-P-23	114.0592
Death	PNEU-C-15	1.27263
Death	PNEU-C-20	5.397521
Death	PNEU-C-15 + PNEU-P-23	5.312283
Death	PNEU-C-20 + PNEU-P-23	7.330628

Health outcomes averted with different vaccination strategies compared to PNEU-P-23 use in the age 50 cohort, in the rest of Canada

Outcome	Strategy	Mean lifetime outcomes averted per 100,000 population
IPD	PNEU-C-15	-0.64397
IPD	PNEU-C-20	7.549912
IPD	PNEU-C-15 + PNEU-P-23	9.343773
IPD	PNEU-C-20 + PNEU-P-23	12.26972
pCAP	PNEU-C-15	78.89242
pCAP	PNEU-C-20	182.3706
pCAP	PNEU-C-15 + PNEU-P-23	150.6069
pCAP	PNEU-C-20 + PNEU-P-23	216.7382
Hospitalization	PNEU-C-15	20.76439
Hospitalization	PNEU-C-20	56.97985
Hospitalization	PNEU-C-15 + PNEU-P-23	50.25161
Hospitalization	PNEU-C-20 + PNEU-P-23	71.10063
Death	PNEU-C-15	0.950296
Death	PNEU-C-20	3.190357
Death	PNEU-C-15 + PNEU-P-23	3.025681
Death	PNEU-C-20 + PNEU-P-23	4.198087

Health outcomes averted with different vaccination strategies compared to PNEU-P-23 use in the age 65 cohort, in Northern Canada

Outcome	Strategy	Mean lifetime outcomes averted per 100,000 population
IPD	PNEU-C-15	4.897155
IPD	PNEU-C-20	22.06517
IPD	PNEU-C-15 + PNEU-P-23	24.90282
IPD	PNEU-C-20 + PNEU-P-23	30.94968
pCAP	PNEU-C-15	119.8787
pCAP	PNEU-C-20	217.1269
pCAP	PNEU-C-15 + PNEU-P-23	185.7728
pCAP	PNEU-C-20 + PNEU-P-23	247.1149
Hospitalization	PNEU-C-15	59.21648
Hospitalization	PNEU-C-20	120.5447
Hospitalization	PNEU-C-15 + PNEU-P-23	109.21
Hospitalization	PNEU-C-20 + PNEU-P-23	143.0488
Death	PNEU-C-15	6.206004
Death	PNEU-C-20	13.5131
Death	PNEU-C-15 + PNEU-P-23	12.60291
Death	PNEU-C-20 + PNEU-P-23	16.38384

Health outcomes averted with different vaccination strategies compared to PNEU-P-23 use in the age 65 cohort, in the rest of Canada

Outcome	Strategy	Mean lifetime outcomes averted per 100,000 population
IPD	PNEU-C-15	2.75027
IPD	PNEU-C-20	10.16716
IPD	PNEU-C-15 + PNEU-P-23	11.57536
IPD	PNEU-C-20 + PNEU-P-23	14.20708
pCAP	PNEU-C-15	100.2026
pCAP	PNEU-C-20	176.5893
pCAP	PNEU-C-15 + PNEU-P-23	152.5603
pCAP	PNEU-C-20 + PNEU-P-23	201.1869
Hospitalization	PNEU-C-15	48.79631
Hospitalization	PNEU-C-20	91.27524
Hospitalization	PNEU-C-15 + PNEU-P-23	81.75827
Hospitalization	PNEU-C-20 + PNEU-P-23	106.6863
Death	PNEU-C-15	4.980975
Death	PNEU-C-20	9.702638
Death	PNEU-C-15 + PNEU-P-23	8.881972
Death	PNEU-C-20 + PNEU-P-23	11.5212

Health outcomes averted with different vaccination strategies compared to PNEU-P-23 use in the age 75 cohort, in Northern Canada

Outcome	Strategy	Mean lifetime outcomes averted per 100,000 population
IPD	PNEU-C-15	2.40475
IPD	PNEU-C-20	21.21687
IPD	PNEU-C-15 + PNEU-P-23	25.10092
IPD	PNEU-C-20 + PNEU-P-23	31.30868
pCAP	PNEU-C-15	139.4398
pCAP	PNEU-C-20	261.0044
pCAP	PNEU-C-15 + PNEU-P-23	224.0451
pCAP	PNEU-C-20 + PNEU-P-23	299.4194
Hospitalization	PNEU-C-15	71.49773
Hospitalization	PNEU-C-20	150.7938
Hospitalization	PNEU-C-15 + PNEU-P-23	136.4431
Hospitalization	PNEU-C-20 + PNEU-P-23	180.0896
Death	PNEU-C-15	7.235044
Death	PNEU-C-20	16.43263
Death	PNEU-C-15 + PNEU-P-23	15.30166
Death	PNEU-C-20 + PNEU-P-23	20.06082

Health outcomes averted with different vaccination strategies compared to PNEU-P-23 use in the age 75 cohort, in the rest of Canada

Outcome	Strategy	Mean lifetime outcomes averted per 100,000 population
IPD	PNEU-C-15	3.895045
IPD	PNEU-C-20	15.52716
IPD	PNEU-C-15 + PNEU-P-23	17.56409
IPD	PNEU-C-20 + PNEU-P-23	21.69746
pCAP	PNEU-C-15	187.6316
pCAP	PNEU-C-20	333.7505
pCAP	PNEU-C-15 + PNEU-P-23	285.8358
pCAP	PNEU-C-20 + PNEU-P-23	379.074
Hospitalization	PNEU-C-15	98.20861
Hospitalization	PNEU-C-20	183.3103
Hospitalization	PNEU-C-15 + PNEU-P-23	161.2181
Hospitalization	PNEU-C-20 + PNEU-P-23	212.2464
Death	PNEU-C-15	9.899365
Death	PNEU-C-20	19.11666
Death	PNEU-C-15 + PNEU-P-23	17.11785
Death	PNEU-C-20 + PNEU-P-23	22.42586

Outcomes are summed across the lifespan of the individuals in the indicated age cohort for the different vaccination strategies and compared to rates in a cohort vaccinated with PNEU-P-23. Results are shown separately for the North and rest of Canada. For the vaccinate at age 50 strategy, use of PNEU-C-15 was projected to result in more IPD cases than current recommendations (outlined in red). Note that the x-axes vary across graphs.

Unless noted otherwise, results are presented for the health system perspective. Mean costs, QALYs, and ICERs from the base case health system perspective are presented in Table 9. Incremental cost-effectiveness ratios show the costs per QALY gained when comparing each vaccination strategy directly to current recommendations (PNEU-P-23). The sequential ICERs compare all of the different possible vaccination strategies for a given age cohort and geographic region, excluding those that are either dominated or subject to extended dominance. In the sequential analysis, strategies that, when compared to the current recommendation only, may have ICERs considered cost-effective by commonly used thresholds, may be excluded because there are other strategies that represent better value for money, regardless of the cost-effectiveness threshold used. For instance, for the rest of Canada, the ICER for vaccinating at age 65 with PNEU-C-15 compared to PNEU-P-23 is $34,852 per QALY gained. However, compared to PNEU-C-20 use in the same population, PNEU-C-15 is dominated, because it is more costly and results in fewer QALYs gained than PNEU-C-20. If PNEU-C-20 is available, it would be the preferred option based on the parameters and assumptions used for this analysis.

Mean costs and QALYs are also displayed graphically in Figure 3 by cohort age, region, and perspective. Across cohort ages, regions, and perspective, the efficiency frontier consisted of PNEU-P-23 and PNEU-C-20 (either alone or in series with PNEU-P-23). ICERs ranging from $6,529 to $113,514 per QALY from the health system perspective. ICERs were higher in younger age cohorts due to lower risk of disease and waning vaccine protection as risk increased with age. ICERs were generally lower in Northern Canada due to the higher burden of disease and higher costs associated with illness. Higher ICERs in the Northern Canada age 75 years cohort were likely due to lower life expectancy in this region.

Figure 3 - Text description

Figure 3 is a multi-panel figure showing mean costs and QALYs for different vaccination strategies, with results separated by age cohort, region, and perspective. The figure consists of 6 scatter plots arranged in two rows and three columns. Each graph shows results for an age cohort (50, 65, or 75 years) and geographic region (Rest of Canada or Northern Canada). The x-axis is labelled "Total QALYs (per capita)" and the y-axis is labelled "Total costs (per capita)". The scales for the x- and y-axis are different across the graphs. There are symbols on the graphs that represent the total QALYs and total costs for a specified vaccination strategy. The vaccination strategies are: PNEU-P-23 (red), PNEU-C-15 (yellow), PNEU-C-20 (green), PNEU-C-15+PNEU-P-23 (blue), and PNEU-C-20+PNEU-P-23 (purple).There are two symbols representing the health system perspective (triangle) and societal perspective (square). The total costs are higher for the societal perspective than the health system perspective. There are solid lines connecting some of the symbols on the graph. The line is known as the efficiency frontier and the symbols on the efficiency frontier have numbers associated with them, representing the incremental cost-effectiveness ratios. In all of the graphs, the efficiency frontier includes PNEU-P-23, PNEU-C-20, and PNEU-C-20+PNEU-P-23. PNEU-C-15 and PNEU-C20+PNEU-P-23 are not on the efficiency frontier. The values of the incremental cost-effectiveness ratios are provided in Table 9 for the health system perspective.

Base case mean costs and QALYs over 2,000 simulations in the age 50 cohort, in the rest of Canada

Perspective	Strategy	Total costs (per capita)	Total QALYs (per capita)	ICER	Sequential ICER
Health system	PNEU-P-23	504.84	20.77705	0	0
Health system	PNEU-C-20	525.97	20.77765	35618.87	35618.87
Health system	PNEU-C-20 + PNEU-P-23	541.44	20.77784	46786.72	81866.14
Health system	PNEU-C-15	525.92	20.77722	127064.8	Weakly dominated
Health system	PNEU-C-15 + PNEU-P-23	538.78	20.77762	60515.2	Dominated
Societal	PNEU-P-23	734.32	20.77705	0	0
Societal	PNEU-C-20	751.07	20.77765	28232.13	28232.13
Societal	PNEU-C-20 + PNEU-P-23	838.41	20.77784	133096.7	462487.8
Societal	PNEU-C-15	754.62	20.77722	122418.8	Dominated
Societal	PNEU-C-15 + PNEU-P-23	837.43	20.77762	183888.4	Dominated

Base case mean costs and QALYs over 2,000 simulations in the age 65 cohort, in the rest of Canada

Perspective	Strategy	Total costs (per capita)	Total QALYs (per capita)	ICER	Sequential ICER
Health system	PNEU-P-23	468.33	13.69927	0	0
Health system	PNEU-C-20	486.02	13.70029	17379.41	17379.41
Health system	PNEU-C-20 + PNEU-P-23	501.52	13.70049	27408.62	80343.78
Health system	PNEU-C-15	486.14	13.69979	34852.38	Dominated
Health system	PNEU-C-15 + PNEU-P-23	499.09	13.70020	33077.01	Dominated
Societal	PNEU-P-23	568.23	13.69927	0	0
Societal	PNEU-C-20	583.69	13.70029	15180.3	15180.3
Societal	PNEU-C-20 + PNEU-P-23	609.45	13.70049	34040.85	133588.7
Societal	PNEU-C-15	585.14	13.69979	33082.75	Dominated
Societal	PNEU-C-15 + PNEU-P-23	607.64	13.70020	42364.2	Dominated

Base case mean costs and QALYs over 2,000 simulations in the age 75 cohort, in the rest of Canada

Perspective	Strategy	Total costs (per capita)	Total QALYs (per capita)	ICER	Sequential ICER
Health system	PNEU-P-23	397.33	9.07517	0	0
Health system	PNEU-C-20	416.04	9.07652	13853.65	13853.65
Health system	PNEU-C-20 + PNEU-P-23	436.03	9.07676	24353.21	83787.72
Health system	PNEU-C-15	418.48	9.07586	30816.98	Dominated
Health system	PNEU-C-15 + PNEU-P-23	434.28	9.07638	30550.64	Dominated
Societal	PNEU-P-23	474.48	9.07517	0	0
Societal	PNEU-C-20	489.73	9.07652	11295.77	11295.77
Societal	PNEU-C-20 + PNEU-P-23	519.81	9.07676	28527.96	126073.7
Societal	PNEU-C-15	494.09	9.07586	28573.77	Dominated
Societal	PNEU-C-15 + PNEU-P-23	519.03	9.07638	36829.13	Dominated

Base case mean costs and QALYs over 2,000 simulations in the age 50 cohort, in Northern Canada

Perspective	Strategy	Total costs (per capita)	Total QALYs (per capita)	ICER	Sequential ICER
Health system	PNEU-P-23	616.32	11.15424	0	0
Health system	PNEU-C-20	625.15	11.15478	16299.63	16299.63
Health system	PNEU-C-20 + PNEU-P-23	636.19	11.15498	27027.56	57003.37
Health system	PNEU-C-15	634.39	11.15436	153969.7	Dominated
Health system	PNEU-C-15 + PNEU-P-23	638.19	11.15477	41367.37	Dominated
Societal	PNEU-P-23	843.42	11.15424	0	0
Societal	PNEU-C-20	845.40	11.15478	3668.979	3668.979
Societal	PNEU-C-20 + PNEU-P-23	927.35	11.15498	114188	422998.3
Societal	PNEU-C-15	860.37	11.15436	144467.5	Dominated
Societal	PNEU-C-15 + PNEU-P-23	931.99	11.15477	167588.6	Dominated

Base case mean costs and QALYs over 2,000 simulations in the age 65 cohort, in Northern Canada

Perspective	Strategy	Total costs (per capita)	Total QALYs (per capita)	ICER	Sequential ICER
Health system	PNEU-P-23	521.51	5.52531	0	0
Health system	PNEU-C-20	525.64	5.52594	6528.941	6528.941
Health system	PNEU-C-20 + PNEU-P-23	536.67	5.52608	19703.73	79986.27
Health system	PNEU-C-15	533.68	5.52559	43038.09	Dominated
Health system	PNEU-C-15 + PNEU-P-23	538.15	5.52590	28178.42	Dominated
Societal	PNEU-P-23	589.83	5.52531	0	0
Societal	PNEU-C-20	591.21	5.52594	2190.275	2190.275
Societal	PNEU-C-20 + PNEU-P-23	612.41	5.52608	29351.2	153628.7
Societal	PNEU-C-15	600.89	5.52559	39141.45	Dominated
Societal	PNEU-C-15 + PNEU-P-23	614.66	5.52590	42058.08	Dominated

Base case mean costs and QALYs over 2,000 simulations in the age 75 cohort, in Northern Canada

Perspective	Strategy	Total costs (per capita)	Total QALYs (per capita)	ICER	Sequential ICER
Health system	PNEU-P-23	440.83	2.95298	0	0
Health system	PNEU-C-20	448.71	2.95348	15756.56	15756.56
Health system	PNEU-C-20 + PNEU-P-23	461.37	2.95359	33567.12	113514
Health system	PNEU-C-15	458.20	2.95320	79463.2	Dominated
Health system	PNEU-C-15 + PNEU-P-23	463.00	2.95344	47582.26	Dominated
Societal	PNEU-P-23	492.23	2.95298	0	0
Societal	PNEU-C-20	497.26	2.95348	10046.29	10046.29
Societal	PNEU-C-20 + PNEU-P-23	520.09	2.95359	45527.47	204793.1
Societal	PNEU-C-15	508.42	2.95320	74040.71	Dominated
Societal	PNEU-C-15 + PNEU-P-23	522.55	2.95344	65077.3	Dominated

Each plot shows the efficiency frontier from the health system perspective (▲) and the societal perspective (■). The efficiency frontier is marked by a solid line connecting the set of potentially cost-effective strategies, depending on the cost-effectiveness threshold value. ICERs are labelled below each strategy on the efficiency frontier and are represented by the slope of the line connecting the strategy with the next most effective strategy on the frontier. Strategies that are not on the efficiency frontier are not considered cost-effective at any threshold value and for this reason, ICERs are not shown. Note that the scales for the x- and y-axes vary across graphs.

Figure 4 displays the proportion of simulations for which each strategy was the optimal strategy over a range of cost-effectiveness threshold values. In Northern Canada, PNEU-C-20 was the optimal strategy in greater than 50% of simulations at threshold ranges of $16,700-58,800, $7,400-87,100, and $16,600-125,600, in the age 50, 65, and 75 years cohorts, respectively. In ROC, PNEU-C-20 was the optimal strategy in greater than 50% of simulations at threshold ranges of $36,000-85,100, $17,400-87,900, and $14,100-93,100, in the age 50, 65, and 75 years cohorts, respectively. In Northern Canada, PNEU-C-20 in series with PNEU-P-23 was the optimal strategy in the majority of simulations at thresholds above $67,100 (age 50 years), $92,800 (age 65 years), and $141,000 (age 75 years). In ROC, PNEU-C-20 in series with PNEU-P-23 was the optimal strategy in the majority of simulations at thresholds above $92,800 (age 50 years), $90,700 (age 65 years), and $97,100 (age 75 years). PNEU-C-15 did not appear as the optimal strategy in any of the simulations. PNEU-C-15 in series with PNEU-P-23 was the optimal strategy in <1-2% of simulations and at thresholds >$100,000 per QALY gained.

Results are shown for each age cohort and geographic region.

Figure 4 - Text description

Figure 4 is a multi-panel line graph. There are two rows. The top row shows results for the rest of Canada and the bottom row for Northern Canada. The columns show results for the age 50 years, 65 years, and 75 years cohorts. The x-axis is labelled "Cost-effectiveness threshold, Canadian dollars per QALY gained" and the scale ranges from 0 to 200,000. The y-axis is labelled "Percent of simulations each strategy is optimal" and ranges from 0 to 100. Lines on the graph are colored by vaccination strategy: PNEU-P-23 (red), PNEU-C-15 (yellow), PNEU-C-20 (green); PNEU-C-15+PNEU-P-23 (blue); and PNEU-C-20+PNEU-P-23 (purple) and show percent of simulations that a given strategy is optimal for a given cost-effectiveness threshold. At low threshold values, PNEU-P-23 has the highest values for percent of simulations that it is the optimal strategy. At threshold values in the $20,000 to $100,000 range, PNEU-C-20 is most frequently the strategy with the highest values for percent of simulations for which it is the optimal strategy. Above the $100,000 to $150,000 threshold, PNEU-C-20+PNEU-P-23 is most frequently the optimal strategy. The precise values vary across age cohorts and regions.

Percent of simulations that each strategy was the optimal strategy at a given cost-effectiveness threshold in the age 50 cohort, in the rest of Canada

Cost-effectiveness threshold ($ per QALY gained)	Strategy	% of simulations each strategy is optimal
0	PNEU-P-23	100%
10000	PNEU-P-23	100%
20000	PNEU-P-23	85%
30000	PNEU-P-23	62%
40000	PNEU-P-23	43%
50000	PNEU-P-23	32%
60000	PNEU-P-23	23%
70000	PNEU-P-23	17%
80000	PNEU-P-23	12%
90000	PNEU-P-23	9%
100000	PNEU-P-23	7%
110000	PNEU-P-23	5%
120000	PNEU-P-23	4%
130000	PNEU-P-23	3%
140000	PNEU-P-23	2%
150000	PNEU-P-23	1%
160000	PNEU-P-23	1%
170000	PNEU-P-23	1%
180000	PNEU-P-23	1%
190000	PNEU-P-23	0%
200000	PNEU-P-23	0%
0	PNEU-C-15	0%
10000	PNEU-C-15	0%
20000	PNEU-C-15	0%
30000	PNEU-C-15	0%
40000	PNEU-C-15	0%
50000	PNEU-C-15	0%
60000	PNEU-C-15	0%
70000	PNEU-C-15	0%
80000	PNEU-C-15	0%
90000	PNEU-C-15	0%
100000	PNEU-C-15	0%
110000	PNEU-C-15	0%
120000	PNEU-C-15	0%
130000	PNEU-C-15	0%
140000	PNEU-C-15	0%
150000	PNEU-C-15	0%
160000	PNEU-C-15	0%
170000	PNEU-C-15	0%
180000	PNEU-C-15	0%
190000	PNEU-C-15	0%
200000	PNEU-C-15	0%
0	PNEU-C-20	0%
10000	PNEU-C-20	1%
20000	PNEU-C-20	15%
30000	PNEU-C-20	38%
40000	PNEU-C-20	57%
50000	PNEU-C-20	67%
60000	PNEU-C-20	71%
70000	PNEU-C-20	66%
80000	PNEU-C-20	57%
90000	PNEU-C-20	45%
100000	PNEU-C-20	33%
110000	PNEU-C-20	22%
120000	PNEU-C-20	14%
130000	PNEU-C-20	9%
140000	PNEU-C-20	6%
150000	PNEU-C-20	4%
160000	PNEU-C-20	2%
170000	PNEU-C-20	1%
180000	PNEU-C-20	1%
190000	PNEU-C-20	0%
200000	PNEU-C-20	0%
0	PNEU-C-15 + PNEU-P-23	0%
10000	PNEU-C-15 + PNEU-P-23	0%
20000	PNEU-C-15 + PNEU-P-23	0%
30000	PNEU-C-15 + PNEU-P-23	0%
40000	PNEU-C-15 + PNEU-P-23	0%
50000	PNEU-C-15 + PNEU-P-23	0%
60000	PNEU-C-15 + PNEU-P-23	0%
70000	PNEU-C-15 + PNEU-P-23	0%
80000	PNEU-C-15 + PNEU-P-23	0%
90000	PNEU-C-15 + PNEU-P-23	0%
100000	PNEU-C-15 + PNEU-P-23	0%
110000	PNEU-C-15 + PNEU-P-23	0%
120000	PNEU-C-15 + PNEU-P-23	0%
130000	PNEU-C-15 + PNEU-P-23	0%
140000	PNEU-C-15 + PNEU-P-23	0%
150000	PNEU-C-15 + PNEU-P-23	0%
160000	PNEU-C-15 + PNEU-P-23	0%
170000	PNEU-C-15 + PNEU-P-23	1%
180000	PNEU-C-15 + PNEU-P-23	1%
190000	PNEU-C-15 + PNEU-P-23	1%
200000	PNEU-C-15 + PNEU-P-23	1%
0	PNEU-C-20 + PNEU-P-23	0%
10000	PNEU-C-20 + PNEU-P-23	0%
20000	PNEU-C-20 + PNEU-P-23	0%
30000	PNEU-C-20 + PNEU-P-23	0%
40000	PNEU-C-20 + PNEU-P-23	0%
50000	PNEU-C-20 + PNEU-P-23	1%
60000	PNEU-C-20 + PNEU-P-23	6%
70000	PNEU-C-20 + PNEU-P-23	17%
80000	PNEU-C-20 + PNEU-P-23	31%
90000	PNEU-C-20 + PNEU-P-23	47%
100000	PNEU-C-20 + PNEU-P-23	61%
110000	PNEU-C-20 + PNEU-P-23	73%
120000	PNEU-C-20 + PNEU-P-23	82%
130000	PNEU-C-20 + PNEU-P-23	88%
140000	PNEU-C-20 + PNEU-P-23	92%
150000	PNEU-C-20 + PNEU-P-23	94%
160000	PNEU-C-20 + PNEU-P-23	96%
170000	PNEU-C-20 + PNEU-P-23	97%
180000	PNEU-C-20 + PNEU-P-23	98%
190000	PNEU-C-20 + PNEU-P-23	99%
200000	PNEU-C-20 + PNEU-P-23	99%

Percent of simulations that each strategy was the optimal strategy at a given cost-effectiveness threshold in the age 65 cohort, in the rest of Canada

Outcome	Strategy	Mean lifetime outcomes averted per 100,000 population
0	PNEU-P-23	100%
10000	PNEU-P-23	81%
20000	PNEU-P-23	42%
30000	PNEU-P-23	23%
40000	PNEU-P-23	15%
50000	PNEU-P-23	10%
60000	PNEU-P-23	7%
70000	PNEU-P-23	5%
80000	PNEU-P-23	3%
90000	PNEU-P-23	2%
100000	PNEU-P-23	1%
110000	PNEU-P-23	1%
120000	PNEU-P-23	0%
130000	PNEU-P-23	0%
140000	PNEU-P-23	0%
150000	PNEU-P-23	0%
160000	PNEU-P-23	0%
170000	PNEU-P-23	0%
180000	PNEU-P-23	0%
190000	PNEU-P-23	0%
200000	PNEU-P-23	0%
0	PNEU-C-15	0%
10000	PNEU-C-15	0%
20000	PNEU-C-15	0%
30000	PNEU-C-15	0%
40000	PNEU-C-15	0%
50000	PNEU-C-15	0%
60000	PNEU-C-15	0%
70000	PNEU-C-15	0%
80000	PNEU-C-15	0%
90000	PNEU-C-15	0%
100000	PNEU-C-15	0%
110000	PNEU-C-15	0%
120000	PNEU-C-15	0%
130000	PNEU-C-15	0%
140000	PNEU-C-15	0%
150000	PNEU-C-15	0%
160000	PNEU-C-15	0%
170000	PNEU-C-15	0%
180000	PNEU-C-15	0%
190000	PNEU-C-15	0%
200000	PNEU-C-15	0%
0	PNEU-C-20	0%
10000	PNEU-C-20	19%
20000	PNEU-C-20	58%
30000	PNEU-C-20	77%
40000	PNEU-C-20	84%
50000	PNEU-C-20	86%
60000	PNEU-C-20	82%
70000	PNEU-C-20	72%
80000	PNEU-C-20	60%
90000	PNEU-C-20	47%
100000	PNEU-C-20	37%
110000	PNEU-C-20	28%
120000	PNEU-C-20	20%
130000	PNEU-C-20	14%
140000	PNEU-C-20	10%
150000	PNEU-C-20	7%
160000	PNEU-C-20	6%
170000	PNEU-C-20	4%
180000	PNEU-C-20	2%
190000	PNEU-C-20	2%
200000	PNEU-C-20	1%
0	PNEU-C-15 + PNEU-P-23	0%
10000	PNEU-C-15 + PNEU-P-23	0%
20000	PNEU-C-15 + PNEU-P-23	0%
30000	PNEU-C-15 + PNEU-P-23	0%
40000	PNEU-C-15 + PNEU-P-23	0%
50000	PNEU-C-15 + PNEU-P-23	0%
60000	PNEU-C-15 + PNEU-P-23	0%
70000	PNEU-C-15 + PNEU-P-23	0%
80000	PNEU-C-15 + PNEU-P-23	1%
90000	PNEU-C-15 + PNEU-P-23	1%
100000	PNEU-C-15 + PNEU-P-23	2%
110000	PNEU-C-15 + PNEU-P-23	2%
120000	PNEU-C-15 + PNEU-P-23	2%
130000	PNEU-C-15 + PNEU-P-23	2%
140000	PNEU-C-15 + PNEU-P-23	2%
150000	PNEU-C-15 + PNEU-P-23	1%
160000	PNEU-C-15 + PNEU-P-23	1%
170000	PNEU-C-15 + PNEU-P-23	1%
180000	PNEU-C-15 + PNEU-P-23	1%
190000	PNEU-C-15 + PNEU-P-23	1%
200000	PNEU-C-15 + PNEU-P-23	1%
0	PNEU-C-20 + PNEU-P-23	0%
10000	PNEU-C-20 + PNEU-P-23	0%
20000	PNEU-C-20 + PNEU-P-23	0%
30000	PNEU-C-20 + PNEU-P-23	0%
40000	PNEU-C-20 + PNEU-P-23	1%
50000	PNEU-C-20 + PNEU-P-23	4%
60000	PNEU-C-20 + PNEU-P-23	11%
70000	PNEU-C-20 + PNEU-P-23	22%
80000	PNEU-C-20 + PNEU-P-23	36%
90000	PNEU-C-20 + PNEU-P-23	49%
100000	PNEU-C-20 + PNEU-P-23	61%
110000	PNEU-C-20 + PNEU-P-23	70%
120000	PNEU-C-20 + PNEU-P-23	78%
130000	PNEU-C-20 + PNEU-P-23	84%
140000	PNEU-C-20 + PNEU-P-23	88%
150000	PNEU-C-20 + PNEU-P-23	91%
160000	PNEU-C-20 + PNEU-P-23	93%
170000	PNEU-C-20 + PNEU-P-23	95%
180000	PNEU-C-20 + PNEU-P-23	97%
190000	PNEU-C-20 + PNEU-P-23	97%
200000	PNEU-C-20 + PNEU-P-23	98%

Percent of simulations that each strategy was the optimal strategy at a given cost-effectiveness threshold in the age 75 cohort, in the rest of Canada

Outcome	Strategy	Mean lifetime outcomes averted per 100,000 population
0	PNEU-P-23	98%
10000	PNEU-P-23	64%
20000	PNEU-P-23	35%
30000	PNEU-P-23	21%
40000	PNEU-P-23	15%
50000	PNEU-P-23	11%
60000	PNEU-P-23	8%
70000	PNEU-P-23	7%
80000	PNEU-P-23	5%
90000	PNEU-P-23	3%
100000	PNEU-P-23	2%
110000	PNEU-P-23	1%
120000	PNEU-P-23	1%
130000	PNEU-P-23	0%
140000	PNEU-P-23	0%
150000	PNEU-P-23	0%
160000	PNEU-P-23	0%
170000	PNEU-P-23	0%
180000	PNEU-P-23	0%
190000	PNEU-P-23	0%
200000	PNEU-P-23	0%
0	PNEU-C-15	0%
10000	PNEU-C-15	0%
20000	PNEU-C-15	0%
30000	PNEU-C-15	0%
40000	PNEU-C-15	0%
50000	PNEU-C-15	0%
60000	PNEU-C-15	0%
70000	PNEU-C-15	0%
80000	PNEU-C-15	0%
90000	PNEU-C-15	0%
100000	PNEU-C-15	0%
110000	PNEU-C-15	0%
120000	PNEU-C-15	0%
130000	PNEU-C-15	0%
140000	PNEU-C-15	0%
150000	PNEU-C-15	0%
160000	PNEU-C-15	0%
170000	PNEU-C-15	0%
180000	PNEU-C-15	0%
190000	PNEU-C-15	0%
200000	PNEU-C-15	0%
0	PNEU-C-20	2%
10000	PNEU-C-20	36%
20000	PNEU-C-20	65%
30000	PNEU-C-20	79%
40000	PNEU-C-20	84%
50000	PNEU-C-20	85%
60000	PNEU-C-20	82%
70000	PNEU-C-20	74%
80000	PNEU-C-20	63%
90000	PNEU-C-20	53%
100000	PNEU-C-20	44%
110000	PNEU-C-20	36%
120000	PNEU-C-20	28%
130000	PNEU-C-20	21%
140000	PNEU-C-20	16%
150000	PNEU-C-20	12%
160000	PNEU-C-20	10%
170000	PNEU-C-20	7%
180000	PNEU-C-20	6%
190000	PNEU-C-20	5%
200000	PNEU-C-20	4%
0	PNEU-C-15 + PNEU-P-23	0%
10000	PNEU-C-15 + PNEU-P-23	0%
20000	PNEU-C-15 + PNEU-P-23	0%
30000	PNEU-C-15 + PNEU-P-23	0%
40000	PNEU-C-15 + PNEU-P-23	0%
50000	PNEU-C-15 + PNEU-P-23	0%
60000	PNEU-C-15 + PNEU-P-23	0%
70000	PNEU-C-15 + PNEU-P-23	0%
80000	PNEU-C-15 + PNEU-P-23	1%
90000	PNEU-C-15 + PNEU-P-23	1%
100000	PNEU-C-15 + PNEU-P-23	1%
110000	PNEU-C-15 + PNEU-P-23	1%
120000	PNEU-C-15 + PNEU-P-23	2%
130000	PNEU-C-15 + PNEU-P-23	2%
140000	PNEU-C-15 + PNEU-P-23	2%
150000	PNEU-C-15 + PNEU-P-23	2%
160000	PNEU-C-15 + PNEU-P-23	2%
170000	PNEU-C-15 + PNEU-P-23	2%
180000	PNEU-C-15 + PNEU-P-23	1%
190000	PNEU-C-15 + PNEU-P-23	1%
200000	PNEU-C-15 + PNEU-P-23	1%
0	PNEU-C-20 + PNEU-P-23	0%
10000	PNEU-C-20 + PNEU-P-23	0%
20000	PNEU-C-20 + PNEU-P-23	0%
30000	PNEU-C-20 + PNEU-P-23	0%
40000	PNEU-C-20 + PNEU-P-23	1%
50000	PNEU-C-20 + PNEU-P-23	4%
60000	PNEU-C-20 + PNEU-P-23	10%
70000	PNEU-C-20 + PNEU-P-23	20%
80000	PNEU-C-20 + PNEU-P-23	32%
90000	PNEU-C-20 + PNEU-P-23	43%
100000	PNEU-C-20 + PNEU-P-23	52%
110000	PNEU-C-20 + PNEU-P-23	62%
120000	PNEU-C-20 + PNEU-P-23	69%
130000	PNEU-C-20 + PNEU-P-23	76%
140000	PNEU-C-20 + PNEU-P-23	82%
150000	PNEU-C-20 + PNEU-P-23	86%
160000	PNEU-C-20 + PNEU-P-23	89%
170000	PNEU-C-20 + PNEU-P-23	91%
180000	PNEU-C-20 + PNEU-P-23	93%
190000	PNEU-C-20 + PNEU-P-23	94%
200000	PNEU-C-20 + PNEU-P-23	95%

Percent of simulations that each strategy was the optimal strategy at a given cost-effectiveness threshold in the age 50 cohort, in Northern Canada

Outcome	Strategy	Mean lifetime outcomes averted per 100,000 population
0	PNEU-P-23	84%
10000	PNEU-P-23	61%
20000	PNEU-P-23	45%
30000	PNEU-P-23	33%
40000	PNEU-P-23	25%
50000	PNEU-P-23	18%
60000	PNEU-P-23	13%
70000	PNEU-P-23	10%
80000	PNEU-P-23	7%
90000	PNEU-P-23	5%
100000	PNEU-P-23	4%
110000	PNEU-P-23	3%
120000	PNEU-P-23	2%
130000	PNEU-P-23	1%
140000	PNEU-P-23	1%
150000	PNEU-P-23	1%
160000	PNEU-P-23	1%
170000	PNEU-P-23	0%
180000	PNEU-P-23	0%
190000	PNEU-P-23	0%
200000	PNEU-P-23	0%
0	PNEU-C-15	0%
10000	PNEU-C-15	0%
20000	PNEU-C-15	0%
30000	PNEU-C-15	0%
40000	PNEU-C-15	0%
50000	PNEU-C-15	0%
60000	PNEU-C-15	0%
70000	PNEU-C-15	0%
80000	PNEU-C-15	0%
90000	PNEU-C-15	0%
100000	PNEU-C-15	0%
110000	PNEU-C-15	0%
120000	PNEU-C-15	0%
130000	PNEU-C-15	0%
140000	PNEU-C-15	0%
150000	PNEU-C-15	0%
160000	PNEU-C-15	0%
170000	PNEU-C-15	0%
180000	PNEU-C-15	0%
190000	PNEU-C-15	0%
200000	PNEU-C-15	0%
0	PNEU-C-20	16%
10000	PNEU-C-20	39%
20000	PNEU-C-20	55%
30000	PNEU-C-20	64%
40000	PNEU-C-20	65%
50000	PNEU-C-20	60%
60000	PNEU-C-20	48%
70000	PNEU-C-20	35%
80000	PNEU-C-20	26%
90000	PNEU-C-20	18%
100000	PNEU-C-20	13%
110000	PNEU-C-20	8%
120000	PNEU-C-20	6%
130000	PNEU-C-20	4%
140000	PNEU-C-20	3%
150000	PNEU-C-20	2%
160000	PNEU-C-20	1%
170000	PNEU-C-20	1%
180000	PNEU-C-20	1%
190000	PNEU-C-20	0%
200000	PNEU-C-20	0%
0	PNEU-C-15 + PNEU-P-23	0%
10000	PNEU-C-15 + PNEU-P-23	0%
20000	PNEU-C-15 + PNEU-P-23	0%
30000	PNEU-C-15 + PNEU-P-23	0%
40000	PNEU-C-15 + PNEU-P-23	0%
50000	PNEU-C-15 + PNEU-P-23	0%
60000	PNEU-C-15 + PNEU-P-23	0%
70000	PNEU-C-15 + PNEU-P-23	0%
80000	PNEU-C-15 + PNEU-P-23	0%
90000	PNEU-C-15 + PNEU-P-23	0%
100000	PNEU-C-15 + PNEU-P-23	0%
110000	PNEU-C-15 + PNEU-P-23	0%
120000	PNEU-C-15 + PNEU-P-23	0%
130000	PNEU-C-15 + PNEU-P-23	0%
140000	PNEU-C-15 + PNEU-P-23	0%
150000	PNEU-C-15 + PNEU-P-23	0%
160000	PNEU-C-15 + PNEU-P-23	0%
170000	PNEU-C-15 + PNEU-P-23	1%
180000	PNEU-C-15 + PNEU-P-23	0%
190000	PNEU-C-15 + PNEU-P-23	0%
200000	PNEU-C-15 + PNEU-P-23	1%
0	PNEU-C-20 + PNEU-P-23	0%
10000	PNEU-C-20 + PNEU-P-23	0%
20000	PNEU-C-20 + PNEU-P-23	1%
30000	PNEU-C-20 + PNEU-P-23	3%
40000	PNEU-C-20 + PNEU-P-23	11%
50000	PNEU-C-20 + PNEU-P-23	22%
60000	PNEU-C-20 + PNEU-P-23	39%
70000	PNEU-C-20 + PNEU-P-23	55%
80000	PNEU-C-20 + PNEU-P-23	67%
90000	PNEU-C-20 + PNEU-P-23	77%
100000	PNEU-C-20 + PNEU-P-23	83%
110000	PNEU-C-20 + PNEU-P-23	89%
120000	PNEU-C-20 + PNEU-P-23	92%
130000	PNEU-C-20 + PNEU-P-23	94%
140000	PNEU-C-20 + PNEU-P-23	96%
150000	PNEU-C-20 + PNEU-P-23	97%
160000	PNEU-C-20 + PNEU-P-23	98%
170000	PNEU-C-20 + PNEU-P-23	98%
180000	PNEU-C-20 + PNEU-P-23	99%
190000	PNEU-C-20 + PNEU-P-23	99%
200000	PNEU-C-20 + PNEU-P-23	99%

Percent of simulations that each strategy was the optimal strategy at a given cost-effectiveness threshold in the age 65 cohort, in Northern Canada

Outcome	Strategy	Mean lifetime outcomes averted per 100,000 population
0	PNEU-P-23	66%
10000	PNEU-P-23	45%
20000	PNEU-P-23	30%
30000	PNEU-P-23	21%
40000	PNEU-P-23	15%
50000	PNEU-P-23	12%
60000	PNEU-P-23	9%
70000	PNEU-P-23	7%
80000	PNEU-P-23	6%
90000	PNEU-P-23	5%
100000	PNEU-P-23	4%
110000	PNEU-P-23	3%
120000	PNEU-P-23	2%
130000	PNEU-P-23	2%
140000	PNEU-P-23	2%
150000	PNEU-P-23	1%
160000	PNEU-P-23	1%
170000	PNEU-P-23	1%
180000	PNEU-P-23	0%
190000	PNEU-P-23	0%
200000	PNEU-P-23	0%
0	PNEU-C-15	0%
10000	PNEU-C-15	0%
20000	PNEU-C-15	0%
30000	PNEU-C-15	0%
40000	PNEU-C-15	0%
50000	PNEU-C-15	0%
60000	PNEU-C-15	0%
70000	PNEU-C-15	0%
80000	PNEU-C-15	0%
90000	PNEU-C-15	0%
100000	PNEU-C-15	0%
110000	PNEU-C-15	0%
120000	PNEU-C-15	0%
130000	PNEU-C-15	0%
140000	PNEU-C-15	0%
150000	PNEU-C-15	0%
160000	PNEU-C-15	0%
170000	PNEU-C-15	0%
180000	PNEU-C-15	0%
190000	PNEU-C-15	0%
200000	PNEU-C-15	0%
0	PNEU-C-20	34%
10000	PNEU-C-20	55%
20000	PNEU-C-20	69%
30000	PNEU-C-20	77%
40000	PNEU-C-20	80%
50000	PNEU-C-20	78%
60000	PNEU-C-20	73%
70000	PNEU-C-20	66%
80000	PNEU-C-20	56%
90000	PNEU-C-20	48%
100000	PNEU-C-20	39%
110000	PNEU-C-20	32%
120000	PNEU-C-20	25%
130000	PNEU-C-20	20%
140000	PNEU-C-20	15%
150000	PNEU-C-20	12%
160000	PNEU-C-20	9%
170000	PNEU-C-20	7%
180000	PNEU-C-20	6%
190000	PNEU-C-20	5%
200000	PNEU-C-20	3%
0	PNEU-C-15 + PNEU-P-23	0%
10000	PNEU-C-15 + PNEU-P-23	0%
20000	PNEU-C-15 + PNEU-P-23	0%
30000	PNEU-C-15 + PNEU-P-23	0%
40000	PNEU-C-15 + PNEU-P-23	0%
50000	PNEU-C-15 + PNEU-P-23	0%
60000	PNEU-C-15 + PNEU-P-23	0%
70000	PNEU-C-15 + PNEU-P-23	0%
80000	PNEU-C-15 + PNEU-P-23	0%
90000	PNEU-C-15 + PNEU-P-23	0%
100000	PNEU-C-15 + PNEU-P-23	0%
110000	PNEU-C-15 + PNEU-P-23	1%
120000	PNEU-C-15 + PNEU-P-23	1%
130000	PNEU-C-15 + PNEU-P-23	1%
140000	PNEU-C-15 + PNEU-P-23	1%
150000	PNEU-C-15 + PNEU-P-23	1%
160000	PNEU-C-15 + PNEU-P-23	1%
170000	PNEU-C-15 + PNEU-P-23	1%
180000	PNEU-C-15 + PNEU-P-23	1%
190000	PNEU-C-15 + PNEU-P-23	1%
200000	PNEU-C-15 + PNEU-P-23	1%
0	PNEU-C-20 + PNEU-P-23	0%
10000	PNEU-C-20 + PNEU-P-23	0%
20000	PNEU-C-20 + PNEU-P-23	0%
30000	PNEU-C-20 + PNEU-P-23	2%
40000	PNEU-C-20 + PNEU-P-23	4%
50000	PNEU-C-20 + PNEU-P-23	10%
60000	PNEU-C-20 + PNEU-P-23	17%
70000	PNEU-C-20 + PNEU-P-23	26%
80000	PNEU-C-20 + PNEU-P-23	38%
90000	PNEU-C-20 + PNEU-P-23	47%
100000	PNEU-C-20 + PNEU-P-23	57%
110000	PNEU-C-20 + PNEU-P-23	65%
120000	PNEU-C-20 + PNEU-P-23	72%
130000	PNEU-C-20 + PNEU-P-23	77%
140000	PNEU-C-20 + PNEU-P-23	82%
150000	PNEU-C-20 + PNEU-P-23	86%
160000	PNEU-C-20 + PNEU-P-23	89%
170000	PNEU-C-20 + PNEU-P-23	91%
180000	PNEU-C-20 + PNEU-P-23	93%
190000	PNEU-C-20 + PNEU-P-23	94%
200000	PNEU-C-20 + PNEU-P-23	95%

Percent of simulations that each strategy was the optimal strategy at a given cost-effectiveness threshold in the age 75 cohort, in Northern Canada

Outcome	Strategy	Mean lifetime outcomes averted per 100,000 population
0	PNEU-P-23	71%
10000	PNEU-P-23	57%
20000	PNEU-P-23	46%
30000	PNEU-P-23	38%
40000	PNEU-P-23	32%
50000	PNEU-P-23	28%
60000	PNEU-P-23	23%
70000	PNEU-P-23	19%
80000	PNEU-P-23	16%
90000	PNEU-P-23	14%
100000	PNEU-P-23	12%
110000	PNEU-P-23	10%
120000	PNEU-P-23	9%
130000	PNEU-P-23	8%
140000	PNEU-P-23	6%
150000	PNEU-P-23	6%
160000	PNEU-P-23	5%
170000	PNEU-P-23	4%
180000	PNEU-P-23	4%
190000	PNEU-P-23	3%
200000	PNEU-P-23	3%
0	PNEU-C-15	0%
10000	PNEU-C-15	0%
20000	PNEU-C-15	0%
30000	PNEU-C-15	0%
40000	PNEU-C-15	0%
50000	PNEU-C-15	0%
60000	PNEU-C-15	0%
70000	PNEU-C-15	0%
80000	PNEU-C-15	0%
90000	PNEU-C-15	0%
100000	PNEU-C-15	0%
110000	PNEU-C-15	0%
120000	PNEU-C-15	0%
130000	PNEU-C-15	0%
140000	PNEU-C-15	0%
150000	PNEU-C-15	0%
160000	PNEU-C-15	0%
170000	PNEU-C-15	0%
180000	PNEU-C-15	0%
190000	PNEU-C-15	0%
200000	PNEU-C-15	0%
0	PNEU-C-20	29%
10000	PNEU-C-20	43%
20000	PNEU-C-20	54%
30000	PNEU-C-20	62%
40000	PNEU-C-20	66%
50000	PNEU-C-20	70%
60000	PNEU-C-20	72%
70000	PNEU-C-20	73%
80000	PNEU-C-20	71%
90000	PNEU-C-20	67%
100000	PNEU-C-20	63%
110000	PNEU-C-20	58%
120000	PNEU-C-20	53%
130000	PNEU-C-20	48%
140000	PNEU-C-20	43%
150000	PNEU-C-20	39%
160000	PNEU-C-20	34%
170000	PNEU-C-20	31%
180000	PNEU-C-20	28%
190000	PNEU-C-20	24%
200000	PNEU-C-20	21%
0	PNEU-C-15 + PNEU-P-23	0%
10000	PNEU-C-15 + PNEU-P-23	0%
20000	PNEU-C-15 + PNEU-P-23	0%
30000	PNEU-C-15 + PNEU-P-23	0%
40000	PNEU-C-15 + PNEU-P-23	0%
50000	PNEU-C-15 + PNEU-P-23	0%
60000	PNEU-C-15 + PNEU-P-23	0%
70000	PNEU-C-15 + PNEU-P-23	0%
80000	PNEU-C-15 + PNEU-P-23	0%
90000	PNEU-C-15 + PNEU-P-23	0%
100000	PNEU-C-15 + PNEU-P-23	0%
110000	PNEU-C-15 + PNEU-P-23	1%
120000	PNEU-C-15 + PNEU-P-23	1%
130000	PNEU-C-15 + PNEU-P-23	1%
140000	PNEU-C-15 + PNEU-P-23	1%
150000	PNEU-C-15 + PNEU-P-23	1%
160000	PNEU-C-15 + PNEU-P-23	1%
170000	PNEU-C-15 + PNEU-P-23	1%
180000	PNEU-C-15 + PNEU-P-23	1%
190000	PNEU-C-15 + PNEU-P-23	1%
200000	PNEU-C-15 + PNEU-P-23	1%
0	PNEU-C-20 + PNEU-P-23	0%
10000	PNEU-C-20 + PNEU-P-23	0%
20000	PNEU-C-20 + PNEU-P-23	0%
30000	PNEU-C-20 + PNEU-P-23	1%
40000	PNEU-C-20 + PNEU-P-23	1%
50000	PNEU-C-20 + PNEU-P-23	3%
60000	PNEU-C-20 + PNEU-P-23	5%
70000	PNEU-C-20 + PNEU-P-23	9%
80000	PNEU-C-20 + PNEU-P-23	13%
90000	PNEU-C-20 + PNEU-P-23	19%
100000	PNEU-C-20 + PNEU-P-23	25%
110000	PNEU-C-20 + PNEU-P-23	31%
120000	PNEU-C-20 + PNEU-P-23	38%
130000	PNEU-C-20 + PNEU-P-23	43%
140000	PNEU-C-20 + PNEU-P-23	50%
150000	PNEU-C-20 + PNEU-P-23	55%
160000	PNEU-C-20 + PNEU-P-23	60%
170000	PNEU-C-20 + PNEU-P-23	64%
180000	PNEU-C-20 + PNEU-P-23	68%
190000	PNEU-C-20 + PNEU-P-23	72%
200000	PNEU-C-20 + PNEU-P-23	75%

II.4 Sensitivity Analysis

Deterministic univariate sensitivity analysis was performed for key model parameters by varying model parameters one at a time over the ranges listed in Tables 3-8 while holding all other parameter values at their base case values (Figures 5 and 6). Vaccine effectiveness parameters were tested differently, with values for PNEU-C-15/20 and PNEU-P-23 constrained to ensure that PNEU-C-15/20 would not be less effective than PNEU-P-23 during this test. The low effectiveness value of PNEU-C-15/20 was constrained to be no less than the base case value of the PNEU-P-23 and the high effectiveness value of PNEU-P-23 was constrained to be no greater than the base case value of PNEU-C-15/20. Vaccine prices were varied by ±50% of the base case value. Results are presented as ICERs of PNEU-C-15 + PNEU-P-23 or PNEU-C-20 compared to PNEU-P-23.

The model showed greater sensitivity to vaccination parameters, particularly when vaccine effectiveness against CAP was similar between the polysaccharide and conjugate vaccines. In addition, the model showed greater sensitivity to vaccine price and discount rate. Larger variations in the ICER were observed in Northern Canada compared to the rest of Canada.

Figure 5 - Text description

Figure 5 is a multi-panel figure showing tornado diagrams for a sensitivity analysis comparing PNEU-C-15 + PNEU-P-23 to PNEU-P-23. There are 2 rows. The top row shows results for the rest of Canada and the bottom row shows results for Northern Canada. There are three columns, with the following headings: Epidemiological parameters, Vaccination parameters, and Economic parameters. The x-axis shows the ICER and the y-axis is labelled with different model input parameters. For each figure, there is a bar for each model input parameter and the bar is colored to represent low (yellow) and high (blue) values of the input parameter values used. The bars are centered on the base case estimate of the ICER and the width of the bars represents the range of ICER values when a given parameter is varied from its low to high values. For each graph the bars are ordered by width, with the widest bars at the top, indicating parameters that when varied across their low and high values resulted in the largest change in the value of the ICER.

Deterministic univariate sensitivity analysis comparing PNEU-C-15 + PNEU-P-23 with PNEU-P-23 in the rest of Canada

Parameter type	Parameter name	Base case ICER	ICER for low value	ICER for high value
Epidemiological parameter	CFR, CAP	32943	37270.71	29239.03
Epidemiological parameter	% pCAP/CAP	32943	36502.12	29751.33
Epidemiological parameter	Incidence IPD	32943	33431.74	32459.01
Epidemiological parameter	CFR, IPD	32943	33239.45	32622.09
Epidemiological parameter	Incidence CAP (inpatient)	32943	33166.49	32719.63
Epidemiological parameter	Prob sequelae (severe)	32943	33055.81	32829.86
Epidemiological parameter	Odds CAP is outpatient	32943	32995.56	32850.81
Epidemiological parameter	Prob sequelae (mild)	32943	32989.53	32880.13
Vaccination parameter	VE CAP, PNEU-C	32943	76814.58	20728.3
Vaccination parameter	VE CAP, PNEU-P	32943	23982.29	48534.51
Vaccination parameter	VE IPD, PNEU-C	32943	36931.66	28788.43
Vaccination parameter	VE ST3-CAP, PNEU-C	32943	38539.65	30511.88
Vaccination parameter	VE ST3-IPD, PNEU-C	32943	36016.26	29861.64
Vaccination parameter	VE IPD, PNEU-P	32943	30209.25	35566.29
Vaccination parameter	VE ST3-CAP, PNEU-P	32943	32413.46	36911.21
Vaccination parameter	VE ST3-IPD, PNEU-P	32943	32763.88	34708.83
Vaccination parameter	Coverage	32943	32942.58	32942.58
Economic parameter	Price, PNEU-C-15	32943	15274.56	50610.6
Economic parameter	Discount rate	32943	25632.98	55067.23
Economic parameter	Cost, vaccine administration	32943	30868.53	35016.62
Economic parameter	Utility, inpatient	32943	30714.68	34768.91
Economic parameter	Cost, IPD	32943	33127.13	32750.74
Economic parameter	Cost, transportation (inpatient)	32943	33096.19	32789.74
Economic parameter	Utility, outpatient	32943	32793.72	33041.2
Economic parameter	Cost, sequelae (severe)	32943	33005.05	32880.11
Economic parameter	Utility, sequelae (severe)	32943	32891.48	32994.34
Economic parameter	Utility, sequelae (mild)	32943	32892.41	32990.12
Economic parameter	Cost, CAP (inpatient)	32943	32982.3	32902.86
Economic parameter	Cost, sequelae (mild)	32943	32963.33	32921.83
Economic parameter	Cost, CAP (outpatient)	32943	32961.47	32923.68

Deterministic univariate sensitivity analysis comparing PNEU-C-15 + PNEU-P-23 with PNEU-P-23 in Northern Canada

Parameter type	Parameter name	Base case ICER	ICER for low value	ICER for high value
Epidemiological parameter	Incidence IPD	28087	41153.12	15760.63
Epidemiological parameter	% pCAP/CAP	28087	33562.21	23196.25
Epidemiological parameter	Incidence CAP (inpatient)	28087	33017.77	23594.88
Epidemiological parameter	CFR, CAP	28087	31392.36	25194.08
Epidemiological parameter	CFR, IPD	28087	28469.69	27677.09
Epidemiological parameter	Odds CAP is outpatient	28087	28365.92	27606.4
Epidemiological parameter	Prob sequelae (severe)	28087	28218.38	27955.72
Epidemiological parameter	Prob sequelae (mild)	28087	28140.12	28015.62
Vaccination parameter	VE CAP, PNEU-C	28087	83621.18	10741.69
Vaccination parameter	VE CAP, PNEU-P	28087	14685.57	51440.06
Vaccination parameter	VE IPD, PNEU-C	28087	37394.81	19250.88
Vaccination parameter	VE ST3-IPD, PNEU-C	28087	35143.63	21465.78
Vaccination parameter	VE IPD, PNEU-P	28087	21831.94	34599.04
Vaccination parameter	VE ST3-CAP, PNEU-C	28087	35731.86	24709.27
Vaccination parameter	VE ST3-CAP, PNEU-P	28087	27322.52	33816.3
Vaccination parameter	VE ST3-IPD, PNEU-P	28087	27675.08	32257.08
Vaccination parameter	Coverage	28087	28086.67	28086.67
Economic parameter	Price, PNEU-C-15	28087	112.1939	56061.14
Economic parameter	Discount rate	28087	22379.1	43535.62
Economic parameter	Cost, transportation (inpatient)	28087	35821.56	20277.33
Economic parameter	Utility, inpatient	28087	24254.93	31714.93
Economic parameter	Cost, vaccine administration	28087	25056.75	31116.58
Economic parameter	Cost, CAP (inpatient)	28087	29053.65	27078.96
Economic parameter	Cost, IPD	28087	28825.34	27318.82
Economic parameter	Utility, outpatient	28087	27829.56	28258.33
Economic parameter	Cost, sequelae (severe)	28087	28166.88	28006.45
Economic parameter	Utility, sequelae (severe)	28087	28030.24	28143.88
Economic parameter	Utility, sequelae (mild)	28087	28031.27	28139.22
Economic parameter	Cost, transportation subsidy (outpatient)	28087	28136.41	28038.53
Economic parameter	Cost, accommodation subsidy (outpatient)	28087	28189.36	28091.48
Economic parameter	Cost, CAP (outpatient)	28087	28132.06	28041.27
Economic parameter	Cost, sequelae (mild)	28087	28113.31	28060.02

Each parameter value was varied between a low and high value while holding all other parameters at their base case values. Differences in the base case ICERs compared to Table 9 are a result of deterministic (rather than probabilistic) estimates in the univariate sensitivity analysis.

CAP

community-acquired pneumonia

CFR

case fatality rate

IPD

invasive pneumococcal disease

% pCAP/CAP

proportion of CAP cases attributable to S. pneumoniae

VE

vaccine effectiveness

PCV

pneumococcal conjugate vaccine

PPV

pneumococcal polysaccharide vaccine

ST3

serotype 3

Figure 6 - Text description

Figure 6 is a multi-panel figure showing tornado diagrams for a sensitivity analysis comparing PNEU-C-20 to PNEU-P-23. There are 2 rows. The top row shows results for the rest of Canada and the bottom row shows results for Northern Canada. There are three columns, with the following headings: Epidemiological parameters, Vaccination parameters, and Economic parameters. The x-axis shows the ICER and the y-axis is labelled with different model input parameters. For each figure, there is a bar for each model input parameter and the bar is colored to represent low (yellow) and high (blue) values of the input parameter values used. The bars are centered on the base case estimate of the ICER and the width of the bars represents the range of ICER values when a given parameter is varied from its low to high values. For each graph the bars are ordered by width, with the widest bars at the top, indicating parameters that when varied across their low and high values resulted in the largest change in the value of the ICER.

Deterministic univariate sensitivity analysis comparing PNEU-C-20 with PNEU-P-23 in the rest of Canada

Parameter type	Parameter name	Base case ICER	ICER for low value	ICER for high value
Epidemiological parameter	% pCAP/CAP	16898	19253.44	14810.6
Epidemiological parameter	CFR, CAP	16898	19294.71	14882.18
Epidemiological parameter	Incidence IPD	16898	17162.11	16635.97
Epidemiological parameter	Incidence CAP (inpatient)	16898	17045.35	16751.45
Epidemiological parameter	CFR, IPD	16898	17021.27	16764.5
Epidemiological parameter	Odds CAP is outpatient	16898	16945.35	16816.05
Epidemiological parameter	Prob sequelae (severe)	16898	16960.16	16836.12
Epidemiological parameter	Prob sequelae (mild)	16898	16921.98	16866.15
Vaccination parameter	VE CAP, PNEU-C	16898	67289.08	7922.267
Vaccination parameter	VE CAP, PNEU-P	16898	8487.277	41027.76
Vaccination parameter	VE IPD, PNEU-C	16898	20405.93	13445.22
Vaccination parameter	VE IPD, PNEU-P	16898	13881.84	20089.49
Vaccination parameter	VE ST3-CAP, PNEU-C	16898	19974.86	15537.06
Vaccination parameter	VE ST3-IPD, PNEU-C	16898	18715.62	15052.79
Vaccination parameter	VE ST3-CAP, PNEU-P	16898	16601.19	19115.35
Vaccination parameter	VE ST3-IPD, PNEU-P	16898	16791.19	17950.95
Vaccination parameter	Coverage	16898	16898.02	16898.02
Economic parameter	Price, PNEU-C-20	16898	-1547.19	35343.24
Economic parameter	Discount rate	16898	12628.76	30249.21
Economic parameter	Utility, inpatient	16898	15734.19	17854.41
Economic parameter	Cost, transportation (inpatient)	16898	17054.63	16742.21
Economic parameter	Cost, IPD	16898	17049.34	16740.74
Economic parameter	Utility, outpatient	16898	16817.3	16951.53
Economic parameter	Cost, sequelae (severe)	16898	16948.29	16847.76
Economic parameter	Cost, CAP (inpatient)	16898	16940.61	16855.44
Economic parameter	Utility, sequelae (severe)	16898	16876.93	16919.38
Economic parameter	Cost, CAP (outpatient)	16898	16918.28	16877.77
Economic parameter	Utility, sequelae (mild)	16898	16877.32	16917.64
Economic parameter	Cost, sequelae (mild)	16898	16914.72	16881.33
Economic parameter	Cost, vaccine administration	16898	16898.02	16898.02

Deterministic univariate sensitivity analysis comparing PNEU-C-20 with PNEU-P-23 in Northern Canada

Parameter type	Parameter name	Base case ICER	ICER for low value	ICER for high value
Epidemiological parameter	Incidence IPD	5851	12920	-1286.28
Epidemiological parameter	% pCAP/CAP	5851	9753.419	2418.012
Epidemiological parameter	Incidence CAP (inpatient)	5851	9362.508	2695.969
Epidemiological parameter	CFR, CAP	5851	6602.032	5206.31
Epidemiological parameter	Odds CAP is outpatient	5851	6123.009	5382.365
Epidemiological parameter	CFR, IPD	5851	5914.509	5781.997
Epidemiological parameter	Prob sequelae (severe)	5851	5905.025	5796.534
Epidemiological parameter	Prob sequelae (mild)	5851	5868.967	5826.295
Vaccination parameter	VE CAP, PNEU-C	5851	71930.16	-7877.39
Vaccination parameter	VE CAP, PNEU-P	5851	-7241.68	42075.76
Vaccination parameter	VE IPD, PNEU-C	5851	14591.63	-1773.46
Vaccination parameter	VE IPD, PNEU-P	5851	-1029.26	14068.75
Vaccination parameter	VE ST3-IPD, PNEU-C	5851	10242.7	1666.169
Vaccination parameter	VE ST3-CAP, PNEU-C	5851	10402.76	3812.619
Vaccination parameter	VE ST3-CAP, PNEU-P	5851	5392.792	9261.133
Vaccination parameter	VE ST3-IPD, PNEU-P	5851	5593.172	8446.69
Vaccination parameter	Coverage	5851	5850.651	5850.651
Economic parameter	Price, PNEU-C-20	5851	-24028.8	35730.1
Economic parameter	Cost, transportation (inpatient)	5851	13822.28	-2197.69
Economic parameter	Discount rate	5851	2360.459	15668.19
Economic parameter	Cost, CAP (inpatient)	5851	6908.196	4748.564
Economic parameter	Utility, inpatient	5851	5031.426	6632.717
Economic parameter	Cost, IPD	5851	6457.344	5219.996
Economic parameter	Cost, sequelae (severe)	5851	5915.764	5785.538
Economic parameter	Cost, transportation subsidy (outpatient)	5851	5904.895	5798.157
Economic parameter	Cost, accommodation subsidy (outpatient)	5851	5962.638	5855.901
Economic parameter	Cost, CAP (outpatient)	5851	5900.297	5801.006
Economic parameter	Utility, outpatient	5851	5792.29	5889.67
Economic parameter	Cost, sequelae (mild)	5851	5872.277	5829.025
Economic parameter	Utility, sequelae (severe)	5851	5841.11	5860.317
Economic parameter	Utility, sequelae (mild)	5851	5841.284	5859.531
Economic parameter	Cost, vaccine administration	5851	5850.651	5850.651

Each parameter value was varied between a low and high value while holding all other parameters at their base case values. Differences in the base case ICERs compared to Table 9 are a result of deterministic (rather than probabilistic) estimates in the univariate sensitivity analysis.

CAP

community-acquired pneumonia

CFR

case fatality rate

IPD

invasive pneumococcal disease

% pCAP/CAP

proportion of CAP cases attributable to S. pneumoniae

VE

vaccine effectiveness

PCV

pneumococcal conjugate vaccine

PPV

pneumococcal polysaccharide vaccine

ST3

serotype 3

II.5 Scenario Analyses

Extensive scenario analyses were conducted to account for uncertainty in base case assumptions. Some key analysis are described below.

Indirect effects of a pediatric vaccination program with PNEU-C-15 and/or PNEU-C-20

Incidence of pneumococcal disease associated with serotypes unique to PNEU-C-15 or PNEU-C-20 were decreased to approximate indirect effects of a potential pediatric vaccination program with PNEU-C-15 or PNEU-C-20. Indirect effects were assumed to begin four years after vaccination of adults to account for a delay in initiating a pediatric program and time to observe an effect of reduced carriage. Indirect effects were modelled as a simple linear decline in PD incidence from unique PNEU-C-15/20 serotypes by 50% over 5 years. Potential serotype replacement was not modelled. Figure 7 shows that inclusion of indirect effects resulted in ICERs that were higher compared to the base case. No change to the strategies on the efficiency frontier was observed compared to the base case.

Figure 7 - Text description

Figure 7 is a multi-panel figure showing mean costs and QALYs for different vaccination strategies under a scenario analysis looking at the impact of indirect effects from a pediatric vaccination program. The graphs are separated by age cohort, region, and include the results for two perspectives. The figure consists of four scatter plots arranged in two rows and three columns. Each graph shows results for an age cohort (50 or 65 years) and geographic region (Rest of Canada or Northern Canada). The x-axis is labelled "Total QALYs (per capita)" and the y-axis is labelled "Total costs (per capita)". The scales for the x- and y-axis are different across the graphs. There are symbols on the graphs that represent the total QALYs and total costs for a specified vaccination strategy. The vaccination strategies are: PNEU-P-23 (red), PNEU-C-15 (yellow), PNEU-C-20 (green), PNEU-C-15+PNEU-P-23 (blue), and PNEU-C-20+PNEU-P-23 (purple).There are two symbols representing the health system perspective (triangle) and societal perspective (square). The total costs are higher for the societal perspective than the health system perspective. There are solid lines connecting some of the symbols on the graph. The line is known as the efficiency frontier and the symbols on the efficiency frontier have numbers associated with them, representing the incremental cost-effectiveness ratios. In all of the graphs, the efficiency frontier includes PNEU-P-23, PNEU-C-20, and PNEU-C-20+PNEU-P-23. PNEU-C-15 and PNEU-C20+PNEU-P-23 are not on the efficiency frontier.

Scenario analysis: Indirect effects from a pediatric vaccination program in the age 50 cohort, in the rest of Canada

Perspective	Strategy	Total costs (per capita)	Total QALYs (per capita)	ICER	Sequential ICER
Health system	PNEU-P-23	442.93	20.78185	0	0
Health system	PNEU-C-20	464.97	20.78237	42251.9	42251.9
Health system	PNEU-C-20 + PNEU-P-23	480.46	20.78255	53026.96	83231.79
Health system	PNEU-C-15	463.97	20.78201	126552.6	Weakly dominated
Health system	PNEU-C-15 + PNEU-P-23	477.32	20.78237	65527.74	Weakly dominated
Societal	PNEU-P-23	655.73	20.78185	0	0
Societal	PNEU-C-20	673.94	20.78237	34908.42	34908.42
Societal	PNEU-C-20 + PNEU-P-23	761.33	20.78255	149192.8	469556.6
Societal	PNEU-C-15 + PNEU-P-23	759.57	20.78237	197867.4	Weakly dominated
Societal	PNEU-C-15	675.97	20.78201	121690.5	Dominated

Scenario analysis: Indirect effects from a pediatric vaccination program in the age 65 cohort, in the rest of Canada

Perspective	Strategy	Total costs (per capita)	Total QALYs (per capita)	ICER	Sequential ICER
Health system	PNEU-P-23	418.29	13.70260	0	0
Health system	PNEU-C-20	437.39	13.70350	21316.42	21316.42
Health system	PNEU-C-20 + PNEU-P-23	452.92	13.70369	31881.02	81612.41
Health system	PNEU-C-15	436.46	13.70308	38018.23	Weakly dominated
Health system	PNEU-C-15 + PNEU-P-23	449.92	13.70346	36932.73	Dominated
Societal	PNEU-P-23	508.90	13.70260	0	0
Societal	PNEU-C-20	526.05	13.70350	19143.66	19143.66
Societal	PNEU-C-20 + PNEU-P-23	551.86	13.70369	39551.61	135619.3
Societal	PNEU-C-15	526.21	13.70308	36234.83	Dominated
Societal	PNEU-C-15 + PNEU-P-23	549.35	13.70346	47235.11	Dominated

Scenario analysis: Indirect effects from a pediatric vaccination program in the age 50 cohort, in Northern Canada

Perspective	Strategy	Total costs (per capita)	Total QALYs (per capita)	ICER	Sequential ICER
Health system	PNEU-P-23	562.99	11.15560	0	0
Health system	PNEU-C-20	573.14	11.15610	19975.74	19975.74
Health system	PNEU-C-20 + PNEU-P-23	584.24	11.15630	30350.42	57806.58
Health system	PNEU-C-15	581.02	11.15571	151839.4	Dominated
Health system	PNEU-C-15 + PNEU-P-23	585.54	11.15611	44131.95	Dominated
Societal	PNEU-P-23	780.56	11.15560	0	0
Societal	PNEU-C-20	784.31	11.15610	7375.954	7375.954
Societal	PNEU-C-20 + PNEU-P-23	866.32	11.15630	122490.8	427137.6
Societal	PNEU-C-15	797.45	11.15571	142242.7	Dominated
Societal	PNEU-C-15 + PNEU-P-23	870.04	11.15611	175110	Dominated

Scenario analysis: Indirect effects from a pediatric vaccination program in the age 65 cohort, in Northern Canada

Perspective	Strategy	Total costs (per capita)	Total QALYs (per capita)	ICER	Sequential ICER
Health system	PNEU-P-23	501.31	5.52569	0	0
Health system	PNEU-C-20	506.61	5.52629	8750.289	8750.289
Health system	PNEU-C-20 + PNEU-P-23	517.66	5.52643	21989.27	80283.02
Health system	PNEU-C-15	513.74	5.52596	44969.29	Dominated
Health system	PNEU-C-15 + PNEU-P-23	518.65	5.52626	30139.73	Dominated
Societal	PNEU-P-23	567.56	5.52569	0	0
Societal	PNEU-C-20	570.25	5.52629	4440.515	4440.515
Societal	PNEU-C-20 + PNEU-P-23	591.47	5.52643	32138.18	154096.2
Societal	PNEU-C-15	578.92	5.52596	41082.05	Dominated
Societal	PNEU-C-15 + PNEU-P-23	593.17	5.52626	44510.92	Dominated

Each plot shows the efficiency frontier from the health system perspective (▲) and the societal perspective (■). The efficiency frontier is marked by a solid line connecting the set of potentially cost-effective strategies, depending on the cost-effectiveness threshold value. ICERs are labelled below each strategy on the efficiency frontier and are represented by the slope of the line connecting the strategy with the next most effective strategy on the frontier. Strategies that are not on the efficiency frontier are not considered cost-effective at any threshold value.

Faster waning of vaccine protection

This scenario examined the potential impact of faster waning protection compared to the base case. In this scenario, protection by the polysaccharide vaccine declined linearly to 0% over seven years (compared to 15 years in the base case). Protection by the conjugate vaccine was assumed to remain stable for the first five years and then declined to 0% over the next seven years (compared to 10 years in the base case). Lower ICERs were observed compared to the base case (Figure 8) and PNEU-P-23 was dominated by PNEU-C-20 at age 65 years in Northern Canada and at age 50 years in Northern Canada from the societal perspective.

Figure 8 - Text description

Figure 8 is a multi-panel figure showing mean costs and QALYs for different vaccination strategies under a scenario analysis looking at the impact of faster waning of vaccine protection. The graphs are separated by age cohort, region, and include the results for two perspectives. The figure consists of four scatter plots arranged in two rows and two columns. Each graph shows results for an age cohort (50 or 65 years) and geographic region (Rest of Canada or Northern Canada). The x-axis is labelled "Total QALYs (per capita)" and the y-axis is labelled "Total costs (per capita)". The scales for the x- and y-axis are different across the graphs. There are symbols on the graphs that represent the total QALYs and total costs for a specified vaccination strategy. The vaccination strategies are: PNEU-P-23 (red), PNEU-C-15 (yellow), PNEU-C-20 (green), PNEU-C-15+PNEU-P-23 (blue), and PNEU-C-20+PNEU-P-23 (purple).There are two symbols representing the health system perspective (triangle) and societal perspective (square). The total costs are higher for the societal perspective than the health system perspective. There are solid lines connecting some of the symbols on the graph. The line is known as the efficiency frontier and the symbols on the efficiency frontier have numbers associated with them, representing the incremental cost-effectiveness ratios. In the graphs for the Rest of Canada, the efficiency frontier includes PNEU-P-23, PNEU-C-20, and PNEU-C-20+PNEU-P-23. PNEU-C-15 and PNEU-C20+PNEU-P-23 are not on the efficiency frontier. In the graphs for Northern Canada, the efficiency frontier includes only PNEU-C-20 and PNEU-C-20+PNEU-P-23 for both perspectives for the age 65 years cohort and for the societal perspective for the age 50 years cohort. PNEU-P-23 is included on the efficiency frontier, along with PNEU-C-20 and PNEU-C-20+PNEU-P-23, for the age 50 cohort for the health system perspective.

Scenario analysis: faster waning of vaccine protection in the age 50 cohort, in the rest of Canada

Perspective	Strategy	Total costs (per capita)	Total QALYs (per capita)	ICER	Sequential ICER
Health system	PNEU-P-23	509.49	20.7767	0	0
Health system	PNEU-C-20	528.17	20.77748	23838.53	23838.53
Health system	PNEU-C-20 + PNEU-P-23	544.83	20.77758	40209.17	174517
Health system	PNEU-C-15	527.37	20.77711	43469.32	Weakly dominated
Health system	PNEU-C-15 + PNEU-P-23	542.68	20.77732	53634.26	Dominated
Societal	PNEU-P-23	742.23	20.7767	0	0
Societal	PNEU-C-20	754.55	20.77748	15733.22	15733.22
Societal	PNEU-C-20 + PNEU-P-23	843.89	20.77758	115686.5	935722.3
Societal	PNEU-C-15	756.93	20.77711	35760.31	Dominated
Societal	PNEU-C-15 + PNEU-P-23	843.83	20.77732	164211.1	Dominated

Scenario analysis: faster waning of vaccine protection in the age 65 cohort, in the rest of Canada

Perspective	Strategy	Total costs (per capita)	Total QALYs (per capita)	ICER	Sequential ICER
Health system	PNEU-P-23	473.63	13.69883	0	0
Health system	PNEU-C-20	489.43	13.70002	13294.69	13294.69
Health system	PNEU-C-20 + PNEU-P-23	506.08	13.70011	25243.49	171272.8
Health system	PNEU-C-15	488.62	13.69958	19818.06	Weakly dominated
Health system	PNEU-C-15 + PNEU-P-23	503.99	13.6998	31114.19	Dominated
Societal	PNEU-P-23	574.98	13.69883	0	0
Societal	PNEU-C-20	587.85	13.70002	10826.28	10826.28
Societal	PNEU-C-20 + PNEU-P-23	615.08	13.70011	31188.54	280040.8
Societal	PNEU-C-15	588.17	13.69958	17437.37	Dominated
Societal	PNEU-C-15 + PNEU-P-23	613.73	13.6998	39707.12	Dominated

Scenario analysis: faster waning of vaccine protection in the age 50 cohort, in Northern Canada

Perspective	Strategy	Total costs (per capita)	Total QALYs (per capita)	ICER	Sequential ICER
Health system	PNEU-P-23	628.62	11.1539	0	0
Health system	PNEU-C-20	630.30	11.15466	2221.118	2221.118
Health system	PNEU-C-20 + PNEU-P-23	644.40	11.15477	18164.03	129176.3
Health system	PNEU-C-15	637.81	11.15427	24320.02	Dominated
Health system	PNEU-C-15 + PNEU-P-23	647.89	11.15451	31277.33	Dominated
Societal	PNEU-C-20	852.19	11.15466	-10960.3	0
Societal	PNEU-C-20 + PNEU-P-23	938.30	11.15477	89519.62	789172.1
Societal	PNEU-P-23	860.52	11.1539	0	Dominated
Societal	PNEU-C-15	864.87	11.15427	11510.01	Dominated
Societal	PNEU-C-15 + PNEU-P-23	945.11	11.15451	137261.2	Dominated

Scenario analysis: faster waning of vaccine protection in the age 65 cohort, in Northern Canada

Perspective	Strategy	Total costs (per capita)	Total QALYs (per capita)	ICER	Sequential ICER
Health system	PNEU-C-20	529.55	5.525862	-3599.2	0
Health system	PNEU-C-20 + PNEU-P-23	542.63	5.525953	11225.58	143739.3
Health system	PNEU-P-23	532.48	5.525049	0	Dominated
Health system	PNEU-C-15	536.53	5.525534	8344.917	Dominated
Health system	PNEU-C-15 + PNEU-P-23	545.40	5.525741	18666.65	Dominated
Societal	PNEU-C-20	595.54	5.525862	-8136.98	0
Societal	PNEU-C-20 + PNEU-P-23	619.03	5.525953	18660.67	258195.9
Societal	PNEU-P-23	602.16	5.525049	0	Dominated
Societal	PNEU-C-15	604.05	5.525534	3882.236	Dominated
Societal	PNEU-C-15 + PNEU-P-23	622.75	5.525741	29748.14	Dominated

Each plot shows the efficiency frontier from the health system perspective (▲) and the societal perspective (■). The efficiency frontier is marked by a solid line connecting the set of potentially cost-effective strategies, depending on the cost-effectiveness threshold value. ICERs are labelled below each strategy on the efficiency frontier and are represented by the slope of the line connecting the strategy with the next most effective strategy on the frontier. Strategies that are not on the efficiency frontier are not considered cost-effective at any threshold value.

PNEU-C-15 effectiveness versus serotype 3

This scenario examined the potential impact of higher effectiveness of PNEU-C-15 for preventing pneumococcal disease due to serotype 3, based on GMT ratios^{Footnote 78}. Vaccine effectiveness values for this scenario are listed in Table 10. Higher effectiveness of PNEU-C-15 against serotype 3 PD resulted in lower ICERs of PNEU-C-15 (alone or in series with PNEU-P-23) compared to PNEU-P-23 than in the base case analysis but did not result in PNEU-C-15 appearing on the efficiency frontier (Figure 9). No other changes to the strategies on the efficiency frontier were observed.

Figure 9 - Text description

Figure 9 is a multi-panel figure showing mean costs and QALYs for different vaccination strategies under a scenario analysis looking at the impact of higher PNEU-C-vaccine effectiveness against pneumococcal disease caused by serotype 3. The graphs are separated by age cohort, region, and include the results for two perspectives. The figure consists of four scatter plots arranged in two rows and two columns. Each graph shows results for an age cohort (50 or 65 years) and geographic region (Rest of Canada or Northern Canada). The x-axis is labelled "Total QALYs (per capita)" and the y-axis is labelled "Total costs (per capita)". The scales for the x- and y-axis are different across the graphs. There are symbols on the graphs that represent the total QALYs and total costs for a specified vaccination strategy. The vaccination strategies are: PNEU-P-23 (red), PNEU-C-15 (yellow), PNEU-C-20 (green), PNEU-C-15+PNEU-P-23 (blue), and PNEU-C-20+PNEU-P-23 (purple). There are two symbols representing the health system perspective (triangle) and societal perspective (square). The total costs are higher for the societal perspective than the health system perspective. There are solid lines connecting some of the symbols on the graph. The line is known as the efficiency frontier and the symbols on the efficiency frontier have numbers associated with them, representing the incremental cost-effectiveness ratios. In all of the graphs, the efficiency frontier includes PNEU-P-23, PNEU-C-20, and PNEU-C-20+PNEU-P-23. PNEU-C-15 and PNEU-C20+PNEU-P-23 are not on the efficiency frontier.

Scenario analysis: higher PNEU-C-15 vaccine effectiveness against pneumococcal disease caused by serotype 3 in the age 50 cohort, in the rest of Canada

Perspective	Strategy	Total costs (per capita)	Total QALYs (per capita)	ICER	Sequential ICER
Health system	PNEU-P-23	504.84	20.77705	0	0
Health system	PNEU-C-20	525.97	20.77765	35618.87	35618.87
Health system	PNEU-C-20 + PNEU-P-23	541.44	20.77784	46786.72	81866.14
Health system	PNEU-C-15	524.99	20.7773	83639.69	Weakly dominated
Health system	PNEU-C-15 + PNEU-P-23	537.86	20.77769	52018.32	Weakly dominated
Societal	PNEU-P-23	734.32	20.77705	0	0
Societal	PNEU-C-20	751.07	20.77765	28232.13	28232.13
Societal	PNEU-C-20 + PNEU-P-23	838.41	20.77784	133096.7	462487.8
Societal	PNEU-C-15 + PNEU-P-23	835.85	20.77769	159986.5	Weakly dominated
Societal	PNEU-C-15	753.03	20.7773	77688.08	Dominated

Scenario analysis: higher PNEU-C-15 vaccine effectiveness against pneumococcal disease caused by serotype 3 in the age 65 cohort, in the rest of Canada

Perspective	Strategy	Total costs (per capita)	Total QALYs (per capita)	ICER	Sequential ICER
Health system	PNEU-P-23	468.33	13.69927	0	0
Health system	PNEU-C-20	486.02	13.70029	17379.41	17379.41
Health system	PNEU-C-20 + PNEU-P-23	501.52	13.70049	27408.62	80343.78
Health system	PNEU-C-15	484.59	13.69993	24867.23	Weakly dominated
Health system	PNEU-C-15 + PNEU-P-23	497.57	13.70035	27307.56	Weakly dominated
Societal	PNEU-P-23	568.23	13.69927	0	0
Societal	PNEU-C-20	583.69	13.70029	15180.3	15180.3
Societal	PNEU-C-20 + PNEU-P-23	609.45	13.70049	34040.85	133588.7
Societal	PNEU-C-15	583.18	13.69993	22862.02	Weakly dominated
Societal	PNEU-C-15 + PNEU-P-23	605.71	13.70035	34999.91	Weakly dominated

Scenario analysis: higher PNEU-C-15 vaccine effectiveness against pneumococcal disease caused by serotype 3 in the age 50 cohort, in Northern Canada

Perspective	Strategy	Total costs (per capita)	Total QALYs (per capita)	ICER	Sequential ICER
Health system	PNEU-P-23	616.32	11.15424	0	0
Health system	PNEU-C-20	625.15	11.15478	16299.63	16299.63
Health system	PNEU-C-20 + PNEU-P-23	636.19	11.15498	27027.56	57003.37
Health system	PNEU-C-15 + PNEU-P-23	635.68	11.15484	32138.56	Weakly dominated
Health system	PNEU-C-15	631.85	11.15443	80821.26	Dominated
Societal	PNEU-P-23	843.42	11.15424	0	0
Societal	PNEU-C-20	845.40	11.15478	3668.979	3668.979
Societal	PNEU-C-20 + PNEU-P-23	927.35	11.15498	114188	422998.3
Societal	PNEU-C-15	856.80	11.15443	69666.38	Dominated
Societal	PNEU-C-15 + PNEU-P-23	928.46	11.15484	141218.4	Dominated

Scenario analysis: higher PNEU-C-15 vaccine effectiveness against pneumococcal disease caused by serotype 3 in the age 65 cohort, in Northern Canada

Perspective	Strategy	Total costs (per capita)	Total QALYs (per capita)	ICER	Sequential ICER
Health system	PNEU-P-23	521.51	5.525308	0	0
Health system	PNEU-C-20	525.64	5.525939	6528.941	6528.941
Health system	PNEU-C-20 + PNEU-P-23	536.67	5.526077	19703.73	79986.27
Health system	PNEU-C-15 + PNEU-P-23	534.42	5.525995	18760.1	Weakly dominated
Health system	PNEU-C-15	529.89	5.525689	21951.39	Dominated
Societal	PNEU-P-23	589.83	5.525308	0	0
Societal	PNEU-C-20	591.21	5.525939	2190.275	2190.275
Societal	PNEU-C-20 + PNEU-P-23	612.41	5.526077	29351.2	153628.7
Societal	PNEU-C-15 + PNEU-P-23	610.45	5.525995	29989	Weakly dominated
Societal	PNEU-C-15	596.62	5.525689	17809.61	Dominated

Each plot shows the efficiency frontier from the health system perspective (▲) and the societal perspective (■). The efficiency frontier is marked by a solid line connecting the set of potentially cost-effective strategies, depending on the cost-effectiveness threshold value. ICERs are labelled below each strategy on the efficiency frontier and are represented by the slope of the line connecting the strategy with the next most effective strategy on the frontier. Strategies that are not on the efficiency frontier are not considered cost-effective at any threshold value.

Vaccine price

Given the sensitivity of model results to vaccine prices and uncertainty about prices for PNEU-C-15 and PNEU-C-20, the influence of vaccine prices on optimal vaccination strategy was further explored in a two-way sensitivity analysis. We determined the point at which the prices for PNEU-C-15, PNEU-C-20, and PNEU-P-23 would have equivalent cost-effectiveness (i.e., the use of one particular vaccination strategy was no longer preferred). The vaccine prices for PNEU-C-15 and PNEU-C-20 were varied relative to the assumed price for PNEU-P-23. The optimal strategies were determined for the age 50 and 65 years cohorts for cost-effectiveness thresholds of $30,000 and $60,000 per QALY gained. At a threshold of $30,000 per QALY gained, PNEU-P-23, PNEU-C-15, and PNEU-C-20 would be equivalent cost-effective strategies at incremental prices (relative to an assumed fixed price for PNEU-P-23) of PNEU-C-15 and PNEU-C-20 of $14 and $51 per dose, respectively, in the age 50 years cohort. In the age 65 years cohort, the strategies would be equivalent at incremental prices of $41 (PNEU-C-15) and $84 (PNEU-C-20) per dose. At a threshold of $60,000 per QALY gained, PNEU-P-23, PNEU-C-15 + PNEU-P-23, and PNEU-C-20 would be equivalent strategies at incremental prices of $46 (PNEU-C-15) and $88 (PNEU-C-20) per dose in the age 50 years cohort. In the age 65 years cohort, the strategies would be equivalent at incremental prices of $99 (PNEU-C-15) and $148 (PNEU-C-20) per dose. Based on this analysis, the price per dose of PNEU-C-15 may need to be approximately $40-50 less than that of PNEU-C-20 for the use of PNEU-C-15 to be cost effective.

II.6 Study limitations

There are a number of limitations to this study. A significant limitation is the lack of comparative effectiveness data between PNEU-C-15 and PNEU-C-20. As a result, the dominance of PNEU-C-20 is driven by the broader serotype coverage under an assumption of equivalent effectiveness to PNEU-C-13 serotypes. In addition, the nature of waning protection with PNEU-C-15 and PNEU-C-20 are unknown. Although the model results appear robust in scenario analysis of vaccine waning, the strategies on the efficiency frontier may change if waning is markedly different between the two conjugate vaccines.

The effect of vaccination on transmission could not be assessed due to the static cohort design. There is considerable uncertainty associated with the possible future use of higher valency pneumococcal vaccines in pediatric vaccination programs, in terms of reduction in vaccine-type PD and potential serotype replacement, which could influence the cost-effectiveness of an adult program.

The model did not stratify the population by underlying medical conditions or immunocompromised status due to limited data in these groups at the national level. These groups may have a higher burden of disease and higher medical costs per case. Cost-effectiveness of the conjugate vaccines in groups without underlying medical or immunocompromising conditions may be overestimated as the costs and benefits are aggregated over the entire population.

There is some data suggesting that vaccination may reduce the occurrence of cardiac events following pneumonia^{Footnote 79 Footnote 80}. Due to uncertainty about the nature of this protective effect, this outcome was not included in the model and this exclusion may underestimate the benefits of vaccination with PNEU-C-15 or PNEU-C-20. In this case, these study results would be a conservative estimate of the cost-effectiveness of PNEU-C-15 and PNEU-C-20.

Societal costs were likely underestimated as non-medical consumption and caregiver costs associated with auditory sequelae were not included due to uncertainty about the effect of pneumococcal disease and auditory sequelae on these costs. Given these limitations, the study results may be viewed as a conservative estimate of the cost-effectiveness of PNEU-C-15 and PNEU-C-20 from a societal perspective.

II.7 Conclusions

The base case model and scenario analyses indicate that PNEU-C-20 (either alone or in series with PNEU-P-23) is likely a cost-effective strategy at age 65 or age 75 years. In the base case, using a health system perspective, ICERs for the use of PNEU-C-20 alone ranged from $6530 to $17,400 per QALY gained in these age cohorts. Base case ICERs for PNEU-C-20 at age 50 years ranged from $16,300 to $35,600 per QALY gained using the health system perspective. PNEU-C-15 was dominated or subject to extended dominance across most scenarios and does not appear to be a cost-effective strategy while PNEU-P-23 or PNEU-C-20 are available.

Multi-model Comparison

III.1 Approach

To evaluate the robustness of the cost-utility model described in Section 2, a multi-model comparison was conducted. Outputs from different economic models were compared to identify areas of consistency and difference across models with different structures and assumptions. Two additional cost-utility models were identified that were adapted to evaluate the cost-effectiveness of age-based vaccination strategies in the Canadian population. Both models were funded by industry. Versions of the Merck^{Footnote 8} and Pfizer^{Footnote 9} models were described in the systematic review (Section 1) and were used in economic evaluations of PNEU-C-15 and/or PNEU-C-20 in the United States. Wherever possible, these models incorporated the same parameters as used in the previously described Canadian cost-utility model, although differences in the model structures required some modifications or simplifying assumptions, as described in Table 11. All models were adapted to represent a general population and did not include stratification by chronic medical or immunocompromising conditions.

For the multi-model comparison, results from a single base case were generated and sensitivity analysis were not conducted. A health system perspective was adopted and all models used a lifetime time horizon. Indirect effects of a potential pediatric vaccination program were not included for this comparison. For a given age recommendation and region, sequential ICERs were calculated, to allow for a comparison across different vaccination strategies and identify options that would be most cost-effective. Results for the multi-model comparison are summarized in aggregate below to avoid possible disclosure of confidential information.

III.2 Multi-Model Comparison Results

Results were broadly consistent across the different models. Differences in estimates across models likely reflected differences in model structure and simplifying assumptions made for the purposes of the multi-model comparison. Despite quantitative variability in ICER estimates across models, qualitative results were consistent.

In the sequential analysis of all vaccination strategies, all models estimated that PNEU-C-15 or PNEU-C-15 in series with PNEU-P-23 would be dominated or subject to extended dominance by PNEU-C-20. This was consistent across ages and regions.

All three models indicated that use of PNEU-C-20 is likely a cost-effective strategy at age 50 years and 65 years, with ICERs ranging from $5,000 to $40,000 per QALY across models and geographic regions. At age 75, results for the use of PNEU-C-20 were variable, with ICERs ranging from $11,000 to $105,000 per QALY gained. All models placed PNEU-C-20 in series with PNEU-P-23 on the efficiency frontier for all ages and regions, suggesting that this strategy could be considered cost-effective, depending on the threshold used.

III.3 Conclusions

Three cost-utility models with harmonized parameter values showed qualitatively consistent results despite differing model structures and assumptions. The comparison supported the finding that, based on currently available data, PNEU-C-20, used alone or in series with PNEU-P-23 could be a cost-effective strategy for use in the adult Canadian population.

List of Abbreviations

ACIP

Advisory Committee on Immunization Practices

CADTH

Canadian Agency for Drugs and Technologies in Health

CAP

Community-acquired pneumonia

CFR

Case fatality rate

CMC

Chronic medical conditions

CNDSS

Canadian Notifiable Disease Surveillance System

DAD

Discharge Abstract Database

IC

Immunocompromising conditions

ICER

Incremental cost-effectiveness ratio

ICS

International Circumpolar Surveillance

IPD

Invasive pneumococcal disease

NVT

Non-vaccine type

pCAP

Pneumococcal Community Acquired Pneumonia

PCV

Pneumococcal conjugate vaccine

PD

Pneumococcal disease

PNEU-C-13

13-valent pneumococcal conjugate vaccine

PNEU-C-15

15-valent conjugate pneumococcal vaccine

PNEU-C-20

20-valent conjugate pneumococcal vaccine

PNEU-P-23

23-valent pneumococcal polysaccharide vaccine

PPV

Pneumococcal polysaccharide vaccine

QALY

Quality-adjusted life year

ROC

Rest of Canada

ST3

Serotype 3

US

United States

VE

Vaccine effectiveness

VT

Vaccine-type