
==== Front
CMAJ
CMAJ
9711805
CMAJ : Canadian Medical Association Journal
0820-3946
1488-2329
CMA Impact Inc.

10.1503/cmaj.240452
196e989
Research
Respiratory syncytial virus vaccination strategies for older Canadian adults: a cost–utility analysis
Tuite Ashleigh R. PhD MPH
Simmons Alison E. MPH
Rudd Monica MMath
Cernat Alexandra MSc
Gebretekle Gebremedhin B. PhD
Yeung Man Wah MSc
Killikelly April PhD
Siu Winnie MD
Buchan Sarah A. PhD MSc
Brousseau Nicholas MD
Tunis Matthew PhD
Centre for Immunization Programs (Tuite, Simmons, Rudd, Cernat, Gebretekle, Yeung, Killikelly, Siu, Tunis), Public Health Agency of Canada, Ottawa, Ont.; Dalla Lana School of Public Health (Tuite, Simmons, Rudd, Buchan), University of Toronto, Toronto, Ont.; Health Policy PhD Program (Cernat), Faculty of Health Sciences, McMaster University, Hamilton, Ont.; School of Epidemiology and Public Health (Siu), Faculty of Medicine, University of Ottawa, Ottawa, Ont.; Health Protection (Buchan), Public Health Ontario, Toronto, Ont.; Direction des risques biologiques (Brousseau), Institut national de santé publique du Québec, Québec, Que.
Correspondence to: Ashleigh Tuite, ashleigh.tuite@phac-aspc.gc.ca
9 9 2024
09 9 2024
196 29 E989E1005
11 6 2024
© 2024 CMA Impact Inc. or its licensors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/
Background:

Respiratory syncytial virus (RSV) vaccines could reduce disease burden and costs in older Canadian adults, but vaccination program cost-effectiveness is unknown. We evaluated the cost-effectiveness of different age cut-offs for RSV adult vaccination programs, with or without a focus on people with higher disease risk due to chronic medical conditions.

Methods:

We developed a static individual-based model of medically attended RSV disease to compare alternative age-, medical risk–, and age-plus medical risk–based vaccination policies. The model followed a multiage population of 100 000 people aged 50 years and older. Vaccine characteristics were based on RSV vaccines authorized in Canada as of May 2024, with vaccine protection assumed to last 2 years (or 3 years in scenario analyses). We calculated sequential incremental cost-effectiveness ratios in 2023 Canadian dollars per quality-adjusted life year (QALY) from the health-system and societal perspectives, discounted at 1.5%.

Results:

Although all vaccination strategies averted medically attended RSV disease, universal age-based strategies were not an efficient use of resources compared with medical risk–based strategies. Vaccinating adults aged 70 years and older with 1 or more chronic medical condition was the optimal strategy for a cost-effectiveness threshold of $50 000 per QALY. Results were sensitive to assumptions about vaccine price, but medical risk–based approaches remained optimal compared with age-based strategies, even when vaccine prices were low. Findings were robust to a range of alternative assumptions.

Interpretation:

Vaccination programs for RSV in some groups of older Canadians with underlying medical conditions are likely cost-effective. These findings can inform the design of vaccination programs.
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pmcRespiratory syncytial virus (RSV) infections cause a substantial burden of disease, particularly at the extremes of age, with rates of medically attended RSV highest among infants and older adults.1–4 Among adults, the incidence of medically attended RSV increases with age.5,6 The presence of underlying medical conditions, such as chronic obstructive pulmonary disease, congestive heart failure, diabetes, asthma, and immunodeficiency, is associated with more severe RSV disease in adults.7,8 Prevention of RSV disease has evolved markedly in the past several years, with multiple immunization products now authorized for infants and adults.9

Vaccines for RSV have the potential to reduce health care and related costs in older Canadians, but the introduction of publicly funded vaccination programs may be costly. Based on available epidemiologic data, not all older adults derive equal benefit from vaccination; those who are younger and without underlying medical conditions are expected to have a lower risk of severe RSV disease and may benefit less from vaccination. Cost-effectiveness analysis can be used to quantify the costs and benefits of potential vaccination programs for RSV. These analyses generate an incremental cost-effectiveness ratio (ICER) that estimates the additional cost for 1 additional unit of health outcome for an intervention relative to a comparator and helps assess value for money.10 To date, most economic analyses of RSV vaccination programs in older adults have focused on cost-effectiveness in adults aged 60 or 65 years and older.11 Given the elevated risk of RSV disease with increasing age and in people with underlying medical conditions, the objective of this study was to evaluate the optimal use of RSV vaccines in the Canadian population. Specifically, we evaluated the cost-effectiveness of different age cut-offs for programs that were either focused on people at high risk of RSV disease or offered to the entire age group regardless of medical risk status.

Methods

Setting

As of May 2024, 2 RSV vaccines were approved for use in Canada in adults aged 60 years and older (RSVPreF3 [recombinant, AS01E adjuvanted vaccine] and RSVpreF [RSV prefusion F subunit vaccine]) 9 and another was under review (mRNA-1345).12 At the time of this analysis, Canada’s National Advisory Committee on Immunization (NACI) had not yet published its recommendations for the use of RSV vaccines in adults, and most Canadian provinces and territories did not have publicly funded programs. One exception was the province of Ontario, which announced a publicly funded vaccination program for adults aged 60 years and older living in long-term care homes, Elder care lodges, and some retirement homes in fall of 2023.13 In jurisdictions without publicly funded programs, authorized vaccines are available for purchase out of pocket.

Model overview

We conducted a model-based cost–utility analysis (i.e., a cost-effectiveness analysis with quality-adjusted life years [QALYs] as a measure of health outcome) of RSV vaccination programs in the Canadian population aged 50 years and older. We developed a static individual-based model of medically attended RSV disease to explore the impact of alternative age-, medical risk–, and age- plus medical risk–based vaccination policies on RSV-associated outcomes. We measured costs in 2023 Canadian dollars and, where necessary, we adjusted them using the Canadian Consumer Price Index.14 We used a discount rate of 1.5% for costs and outcomes, and assessed cost-effectiveness from both the health-system and societal perspectives.15 We constructed and analyzed the model using R.16 Full model details are provided in Appendix 1, Supplementary Material (available at www.cmaj.ca/lookup/doi/10.1503/cmaj.240452/tab-related-content).

Model structure

The model followed a multi-age closed population of 100 000 people over a 3-year period that included 3 full RSV seasons, with the age group distribution based on projections of the Canadian population aged 50 years and older.17 We further characterized individuals by the presence or absence of 1 or more chronic medical condition.18 Model start time was September, at the onset of a new RSV season, and the model used monthly time steps. A portion of the population was vaccinated with 1 vaccine dose (per the recommended schedule19,20) in the first 2 months of model entry, with vaccination coverage based on influenza vaccine uptake, which varied by age and chronic medical condition status.21 We included risks of solicited severe local and severe systemic adverse events following immunization (AEFI). Respiratory syncytial virus infection could occur at any month during the 3-year period and was assumed to follow seasonal trends, with peak activity occurring from January to March. We studied a 3-year period based on currently available data showing that vaccine protection wanes over time but lasts for at least 2 RSV seasons.22–24 The 3-year period allowed for investigation of vaccine protection that potentially lasts through 3 RSV seasons in a scenario analysis. Once vaccine protection waned, there was no difference in RSV disease risk between vaccinated and unvaccinated people. We included lifetime costs and QALY losses for people with RSV-attributable mortality during the modelled period.

We modelled medically attended RSV disease only, with individuals requiring 1 of the following levels of care: outpatient (health care provider visit or emergency department visit), or inpatient (hospital admission, with or without intensive care unit [ICU] admission) (Figure 1). Although multiple RSV infections are possible within a season and in subsequent seasons,25 for simplicity, we assumed a maximum of 1 medically attended RSV infection per person over the model period.

Figure 1: Health states included in the model associated with medically attended respiratory syncytial virus (RSV). Arrows indicate possible transitions between health states. Individuals can transition to death from any of the other health states owing to background mortality (arrows not shown). Risk of experiencing any medically attended RSV outcome varies by age, chronic medical condition status, and vaccination status. Note: ICU = intensive care unit.

We obtained model parameters describing RSV epidemiology, vaccine characteristics, costs, and health utilities from published studies and available data when possible, and by assumption or expert opinion otherwise (Table 1 and Table 2). We preferentially used Canadian data and used estimates that were specific for age and chronic medical condition status, when available. Ranges in Table 1 and Table 2 indicate parameters that were drawn from distributions for the analysis, with β distributions used for probabilities and utilities, and γ distributions used for costs.

Table 1: Population, respiratory syncytial virus epidemiology, and vaccine characteristics input parameters

Parameter	Base	Range	Reference	
Population distribution, %	
 50–59 yr	31.7	–	Statistics Canada17	
 60–64 yr	17.5	–		
 65–69 yr	15.8	–		
 70–74 yr	12.8	–		
 75–79 yr	9.9	–		
 ≥ 80 yr	12.2	–		
% of population with ≥ 1 chronic medical condition	
 50–59 yr	38.4	–	Statistics Canada18	
 60–79 yr	60.1	–		
 ≥ 80 yr	72.1	–		
Monthly % of annual RSV cases	
 September	1.2	–	Respiratory Virus Detection Surveillance System (average of 9 seasons, 2010–2011 to 2018–2019)26	
 October	1.9	–		
 November	5.5	–		
 December	14.2	–		
 January	17.6	–		
 February	21.1	–		
 March	17.0	–		
 April	11.0	–		
 May	5.6	–		
 June	2.6	–		
 July	1.3	–		
 August	1.1	–		
Odds ratio for medically attended outpatient care in adults with ≥ 1 chronic medical condition	
 All ages	1.1	–	Shi et al.7	
% of patients requiring hospital admission who had ≥ 1 chronic medical condition	
 All ages	98.2	–	ElSherif et al.27	
Underdetection factor for medically attended RSV in adults	
 All ages	1.5	1–2	McLaughlin et al.8	
Annual incidence of medically attended RSV requiring outpatient health care provider visit per 100 000 population (unadjusted for underdetection)	
 50–59 yr	261.9	186.5–337.3	ElSherif et al.;27 McLaughlin et al.;8 Respiratory Virus Detection Surveillance System26	
 60–69 yr	604.1	472.8–707.8		
 70–79 yr	780.0	625.1–934.1		
 ≥ 80 yr	2487.1	2097.1–2877.2		
Annual incidence of medically attended RSV requiring emergency department visit per 100 000 population (unadjusted for underdetection)	
 50–59 yr	16.8	12.0–21.6	ElSherif et al.;27 McLaughlin et al.;8 Respiratory Virus Detection Surveillance System26	
 60–69 yr	43.3	33.9–50.7		
 70–79 yr	68.5	54.9–82.0		
 ≥ 80 yr	218.3	184.1–252.5		
Annual incidence of RSV-attributable hospital admission per 100 000 population (unadjusted for underdetection)	
 50–59 yr	15.1	10.8–19.5	ElSherif et al.;27 Respiratory Virus Detection Surveillance System26	
 60–69 yr	47.5	37.2–55.7		
 70–79 yr	96.4	77.3–115.4		
 ≥ 80 yr	307.4	259.2–355.6		
% of patients admitted to hospital with RSV requiring ICU admission	
 All ages	13.7	10.2–17.9	ElSherif et al.27	
Medically attended outpatient RSV disease duration, d	
 50–64 yr	7	6–9	Gessner;28 assumption	
 ≥ 65 yr	15	13–18	Falsey et al.29	
% of patients with medically attended RSV prescribed an antimicrobial	
 All ages	50	14–89	Bernardo et al.;30 ElSherif et al.27	
Length of stay in hospital, d	
 50–64 yr	6	3–13	Chen et al.31	
 65–74 yr	6	4–13		
 ≥ 75 yr	7	4–13		
Length of stay in ICU, d	
 All ages	5	3–9	ElSherif et al.27	
RSV mortality per hospital admission, %	
 50–64 yr	7.2	5.4–9.5	Chen et al.31	
 65–74 yr	6.6	5.2–8.4		
 ≥ 75 yr	10.1	9.0–11.3		
All-cause mortality rate, per year, per 1000 population	
 All ages	Age-specific rates	–	Statistics Canada32	
Vaccination coverage, %, with chronic medical conditions	
 50–59 yr	58.6	–	Seasonal Influenza Vaccination Coverage Survey, 2022–202321	
 60–64 yr	59.9	–		
 65–69 yr	65.2	–		
 70–79 yr	82.7	–		
 ≥ 80 yr	83.4	–		
Vaccination coverage, %, without chronic medical conditions	
 50–59 yr	36.7	–	Seasonal Influenza Vaccination Coverage Survey 2022–202321	
 60–64 yr	49.4	–		
 65–69 yr	61.1	–		
 70–79 yr	74.9	–		
 ≥ 80 yr	74.8	–		
Time to receive vaccine, including travel and waiting time, h	
 All ages	2	1.5–2.5	Canada Health Infoway;33 Ray et al.34	
Vaccine effectiveness, %, RSVPreF3 (recombinant, AS01E adjuvanted vaccine)	
 Outpatient RSV — season 1 (7 mo follow-up)	82.6	–	Friedland;23 Ison et al.;24 assumption for season 3	
 Outpatient RSV — season 2 (6 mo follow-up)	56.1	–		
 Outpatient RSV — season 3	18.7	–		
 Hospital-admitted RSV — season 1 (7 mo follow-up)	94.1	–		
 Hospital-admitted RSV — season 2 (6 mo follow-up)	64.2	–		
 Hospital-admitted RSV — season 3	21.4	–		
Vaccine effectiveness, %, RSVpreF (RSV prefusion F subunit vaccine)	
 Outpatient RSV — season 1 (7 mo follow-up)	65.1	–	Gurtman;22 assumption for season 3	
 Outpatient RSV — season 2 (4 mo follow-up)	48.9	–		
 Outpatient RSV — season 3	16.3	–		
 Hospital-admitted RSV — season 1 (7 mo follow-up)	88.9	–		
 Hospital-admitted RSV — season 2 (4 mo follow-up)	78.6	–		
 Hospital-admitted RSV — season 3	26.2	–		
Vaccine wastage rate, %	
 All ages	5	–	World Health Organization35	
Adverse events after vaccination, %	
 Severe local adverse event	0.51	0.16–1.84	Melgar et al.36	
 Severe systemic adverse event	0.57	0.10–2.35		
Duration of adverse event after vaccination, d	
 Severe local adverse event	1	1–4	Papi et al.;37 Walsh et al.;38 Lee et al.39	
 Severe systemic adverse event	2	1–4	Papi et al.;37 Walsh et al.;38 Lee et al.39	
Note: ICU = intensive care unit, RSV = respiratory syncytial virus.

Table 2: Cost and utility input parameters

Parameter	Base	Range	Reference	
Cost of vaccine administration per dose, $	
 All ages	18	13–22	O’Reilly et al.40	
Vaccination cost per dose, $	
 RSVPreF3 (recombinant, AS01E adjuvanted vaccine)	230	100–230	Grant41	
 RSVpreF (RSV prefusion F subunit vaccine)	230	100–230		
Attributable health care costs per person admitted to hospital with RSV, $	
 Do not die in hospital, first 6 months after hospital admission	32 228	31 622–32 836	Mac et al.42	
 Die in hospital	27 534	22 027–33 041*		
Costs per person with RSV treated in the outpatient setting, $	
 Health care provider visit	62	48–82	Sander et al.;43 CIHI;44 Alliance for Healthier Communities45	
 Emergency department visit	340	302–509		
Direct medical costs for severe local adverse event after vaccination, $	
 < 65 yr	62	48–82	Sander et al.;43 CIHI;44 Lee et al.39	
 ≥ 65 yr	63	49–83		
Direct medical costs for severe systemic adverse event after vaccination, $	
 < 65 yr	62	48–82	Sander et al.;43 CIHI;44 Lee et al.39	
 ≥ 65 yr	66	51–87		
Transportation costs, $	
 Cost of 2-way travel to vaccination or outpatient care (out of pocket)	14	11–16*	Canada Health Infoway;33 NACI46	
 Cost of travel to inpatient care	417	210–623	NACI46	
Copay per prescription, $	
 50–64 yr	10	5–12	Western University47	
 ≥ 65 yr	10	7–34	The Commonwealth Fund;48 assumption	
Patient-borne medication costs, $	
 Over-the-counter medication costs for medically attended RSV case	12	3–20	Federici et al.49	
 Prescription medication costs for medically attended RSV case (< 65 yr)	14	6–22	Federici et al.49	
 Prescription medication costs for severe local adverse event after vaccination (< 65 yr)	1.05	0.79–1.31	Lee et al.39	
 Prescription medication costs for severe systemic adverse event after vaccination (< 65 yr)	4.19	3.14–5.24	Lee et al.39	
Caregiver reduction in productivity	
 % of reduction in productivity	33	–	Keita Fakeye et al.50	
Labour force participation, %	
 50–59 yr	82.6	–	Statistics Canada51	
 60–64 yr	58.5	–		
 65–69 yr	29.3	–		
 ≥ 70 yr	8.2	–		
 Caregiver	88.8	–		
Average employment income, $	
 50–59 yr	65 466	–	Statistics Canada52	
 60–64 yr	62 674	–		
 ≥ 70 yr	27 721	–		
 Caregiver (age 25–54 yr)	68 372	–		
Background health utility	
 50–59 yr	0.848	–	Yan et al.53	
 60–64 yr	0.839	–		
 65–74 yr	0.867	–		
 ≥ 75 yr	0.861	–		
QALY loss, outpatient, with or without emergency department visit	
 All ages	0.0056	0.0037–0.0075	Herring et al.;54 Mao et al.;55 Zeevat et al.;56 Meijboom et al.57	
QALY loss, hospital admission	
 All ages	0.020	0.017–0.030	Herring et al.;54 Mao et al.;55 Zeevat et al.;56 Meijboom et al.57	
QALY loss, death	
 50–59 yr	20.26	–	Yan et al.;53 Statistics Canada32,58	
 60–64 yr	16.74	–		
 65–69 yr	14.29	–		
 70–74 yr	11.75	–		
 75–79 yr	9.38	–		
 ≥ 80 yr	5.84	–		
QALY loss, adverse event after vaccination	
 Serious local adverse event	0.0003	0.0002–0.0004	Prosser et al.;59 assumption	
 Serious systemic adverse event	0.0004	0.0003–0.0005		
Note: CIHI = Canadian Institute for Health Information, NACI = National Advisory Committee on Immunization, QALY = quality-adjusted life year, RSV = respiratory syncytial virus.

* Range defined as ± 20% of the base value.

Respiratory syncytial virus epidemiology

We estimated the proportion of annual cases occurring each month from reported RSV tests and positive detections for all of Canada.26 We obtained incidence of hospital-admitted RSV and risk of ICU admission from a Canadian study.27 We estimated outpatient incidence of medically attended RSV disease by applying rate ratios of health care provider or emergency department visits to hospital-admitted cases from a meta-analysis8 to Canadian hospital admission rates. We accounted for the association of chronic medical conditions with increased risk of medically attended RSV4,7 by adjusting age-specific outpatient and inpatient incidence estimates to be consistent with the reported fractions of people receiving outpatient care or who were admitted to hospital with RSV with at least 1 chronic medical condition. 7,27 We adjusted all RSV outcome estimates by an under-detection ratio of 1.5 in the base-case analysis.8

Vaccine characteristics

We used data for the 2 RSV vaccines (RSVPreF3 and RSVpreF) currently authorized for use in Canada to estimate vaccine effectiveness and rates of AEFIs.22–24,36 Since randomized controlled trial (RCT) data were available for only up to 2 RSV seasons, in our base-case analysis we conservatively assumed that vaccine effectiveness in season 3 was 0. We modelled vaccine effectiveness extending through to season 3 in a scenario analysis. Data on average vaccine effectiveness and average duration of follow-up for each season were used to generate step functions, with protection assumed to wane linearly between seasons. We used a cubic polynomial regression model to obtain smoothed estimates of vaccine effectiveness over 36 months (Appendix 1, Supplementary Figure 1); in the absence of data for season 3, we assumed that vaccine effectiveness reached one-third of season 2 vaccine effectiveness by the end of the season (i.e., month 36) to model waning effectiveness past the end of RCT data. We assumed that vaccine effectiveness did not vary by age or chronic medical condition status.

Costs

We based costs following hospital admission for RSV on attributable costs derived from a retrospective population-based cohort study in Ontario, Canada,42 and costs for outpatient cases on estimates for patients with influenza.43 Vaccination costs included administration costs and Canadian list prices.40,41 Direct costs for AEFIs included a health care provider visit and treatment costs.39,43,44 Costs for the societal perspective included patient productivity loss due to AEFIs and RSV-attributable illness and death, caregiver productivity loss, and out-of-pocket medical costs.

Utilities

We based age-specific utilities for the general population on EuroQol 5-dimension, 5-level (EQ-5D-5L) health-related quality-of-life index scores for the Canadian population.53 We derived losses in QALYs associated with the modelled health outcomes from published studies and assumption.54–57,59

Vaccination strategies

We evaluated a combination of age-only, medical risk–only, and age- plus medical risk–based single-dose vaccination strategies (Table 3). For age-based strategies, all people the same age or older than the specified age cut-off (i.e., 60 yr, 65 yr, 70 yr, 75 yr, or 80 yr) were eligible to receive the vaccine. For medical risk–based strategies, only people aged greater than or equal to the specified age cut-off who also had 1 or more chronic medical condition were eligible to receive the vaccine. For age- plus medical risk–based strategies, people were eligible to receive the vaccine if they met an age requirement, or if they were younger and had at least 1 chronic medical condition. For age- plus medical risk–based strategies, we evaluated a lower age bound for people with chronic medical conditions aged either 50 years or 60 years. Although the vaccines are currently authorized for use in adults aged 60 years and older, we considered a lower age limit of 50 years because a lower age indication is currently under review.60

Table 3: Vaccination strategies evaluated in the model

Strategy type	Without chronic medical conditions (average risk)	With chronic medical conditions (high risk)	50–59 yr	60–64 yr	65–69 yr	70–74 yr	75–79 yr	≥ 80 yr	
No vaccination	None	None	*	*	*	*	*	*	
Risk based	None	Age ≥ 60 yr	*	†	†	†	†	†	
Age based	Age ≥ 60 yr	Age ≥ 60 yr	*	‡	‡	‡	‡	‡	
Age plus risk based	Age ≥ 60 yr	Age ≥ 50 yr	†	‡	‡	‡	‡	‡	
Risk based	None	Age ≥ 65 yr	*	*	†	†	†	†	
Age based	Age ≥ 65 yr	Age ≥ 65 yr	*	*	‡	‡	‡	‡	
Age plus risk based	Age ≥ 65 yr	Age ≥ 60 yr	*	†	‡	‡	‡	‡	
Age plus risk based	Age ≥ 65 yr	Age ≥ 50 yr	†	†	‡	‡	‡	‡	
Risk based	None	Age ≥ 70 yr	*	*	*	†	†	†	
Age based	Age ≥ 70 yr	Age ≥ 70 yr	*	*	*	‡	‡	‡	
Age plus risk based	Age ≥ 70 yr	Age ≥ 60 yr	*	†	†	‡	‡	‡	
Age plus risk based	Age ≥ 70 yr	Age ≥ 50 yr	†	†	†	‡	‡	‡	
Risk based	None	Age ≥ 75 yr	*	*	*	*	†	†	
Age based	Age ≥ 75 yr	Age ≥ 75 yr	*	*	*	*	‡	‡	
Age plus risk based	Age ≥ 75 yr	Age ≥ 60 yr	*	†	†	†	‡	‡	
Age plus risk based	Age ≥ 75 yr	Age ≥ 50 yr	†	†	†	†	‡	‡	
Risk based	None	Age ≥ 80 yr	*	*	*	*	*	†	
Age based	Age ≥ 80 yr	Age ≥ 80 yr	*	*	*	*	*	‡	
Age plus risk based	Age ≥ 80 yr	Age ≥ 60 yr	*	†	†	†	†	‡	
Age plus risk based	Age ≥ 80 yr	Age ≥ 50 yr	†	†	†	†	†	‡	
* Not included in vaccination program.

† Included in vaccination program if ≥ 1 chronic medical condition.

‡ Included in vaccination program regardless of chronic medical condition status.

Model validation

We used estimates of RSV burden in adults aged 60 years and older in high-income countries from a meta-analysis3 to assess the validity of our approach for estimating RSV disease burden. Although our model included adults aged 50 years and older, we focused on the population aged 60 years and older for model validation, to align with estimates from the meta-analysis. We compared our model-derived estimates of medically attended RSV cases, hospital admissions, and deaths in the absence of vaccination to estimates for the US population aged 60 years and older3 that were adjusted for the relative sizes of Canada and the United States.

Analysis

We used model-projected incidence of RSV treated in outpatient and inpatient settings and vaccination program costs for different vaccination strategies to estimate QALYs, costs, and ICERs. We also calculated outcomes averted compared with no vaccination and number needed to vaccinate to avert each modelled health outcome. Because measured trial end points were different for the 2 vaccines and there were no studies directly comparing outcomes between vaccines, we conducted separate analyses assuming vaccines with the characteristics of either RSVPreF3 or RSVpreF. We conducted a sequential analysis to compare ICERs for the vaccination strategies.10 A strategy is eliminated in a sequential analysis if there are other strategies that are projected to result in more QALYs gained at lower costs (i.e., the eliminated strategy is dominated) or there is a combination of other strategies that would result in more QALYs gained at lower costs, such that the excluded strategy would never be the optimal intervention, regardless of the cost-effectiveness threshold used (i.e., the strategy is subject to extended dominance). Model estimates were based on 20 000 simulations (400 draws of parameters from distributions and 50 stochastic simulations per parameter set). Outcomes across strategies were compared within each model simulation, and summary results across the simulations were calculated as medians and 95% credible intervals. Unless otherwise stated, results are provided for the health-system perspective, with results for the societal perspective provided in Appendix 1, Supplementary Material.

Sensitivity and scenario analyses

We performed probabilistic sensitivity analyses and generated cost-effectiveness acceptability curves to visualize the probability that competing vaccination strategies were preferred at varying cost-effectiveness thresholds.

Though the main analysis included all vaccination strategies when estimating ICERs, we also conducted subanalyses restricted to age-based strategies only, recognizing that medical risk–based strategies may be challenging to implement.

We conducted several scenario analyses, with details provided in Appendix 1, Supplementary Table 1. Briefly, we considered more optimistic scenarios for vaccine effectiveness, including less rapid waning during season 2 or protection that extended through a third season. We also evaluated the impact of varying assumptions about the amount of underdetection of RSV disease by assuming no underdetection or more underdetection than used in the base case. We reduced the proportion of people admitted to hospital with RSV with 1 or more chronic medical condition from 98% to 90%. Finally, we evaluated the impact of RSV vaccination strategies in a setting of higher disease incidence61 and higher costs associated with medical care, including transportation to receive medical care,46 which may reflect the context of some remote and isolated communities. We used the age distribution of the Canadian territories for this analysis, to reflect the younger age of the population in Northern Canada.17

To address uncertainty in vaccine price, we identified the optimal strategy at different vaccine prices for different cost-effectiveness thresholds for the base-case and scenario analyses. The optimal strategy was the strategy with the largest sequential ICER that was lower than the specified cost-effectiveness threshold. Finally, we re-estimated production losses using the friction cost approach62 with a 3-month friction period, rather than the human capital method15 that was used in the main analysis.

Ethics approval

No ethics approval was required or obtained for this modelling study.

Results

Model validation

Model-estimated cases of medically attended RSV disease in the Canadian population aged 60 years and older for the base-case analysis were consistent with expected cases derived using alternative estimates of RSV disease burden in high-income settings (Figure 2). Without vaccination, we projected 131 389 (95% credible interval 120 070–143 581) medically attended RSV cases, 12 068 (95% credible interval 10 324–13 883) hospital admissions, and 1015 (95% credible interval 617–1450) deaths annually among Canadians aged 60 years and older.

Figure 2: Comparison of model-projected annual respiratory syncytial virus (RSV) disease in the absence of vaccination in the Canadian population aged 60 years and older to estimates from the United States, adjusted to reflect the Canadian population size. Coloured violin plots show the distribution of model estimates for the base-case and scenario analyses in the absence of vaccination, and black points and bars (validation data) show the mean and 95% confidence interval, respectively, of the adjusted US estimates from Savic et al.3 Results are plotted on a log scale. Scenarios that altered vaccine-effectiveness assumptions are not shown, as they had no impact on the incidence of RSV outcomes in the absence of vaccination.

Base case

For all strategies, number of cases averted was largest when vaccination included younger ages (Figure 3 and Appendix 1, Supplementary Table 2). Age-based strategies were projected to avert a median of 12%–30% of outpatient cases, 20%–40% of hospital-admitted cases, and 23%–41% of deaths. Using medical risk–based strategies, vaccination was projected to avert a median of 9%–21% of outpatient cases, 20%–39% of hospital-admitted cases, and 22%–40% of deaths in the population, depending on the vaccine used and the assumed age recommendation. Age- plus risk-based strategies were projected to avert a median of 20%–31% of outpatient cases, 38%–42% of hospital-admitted cases, and 39%–42% of deaths.

Figure 3: Model-projected outcomes averted and number needed to vaccinate for different respiratory syncytial virus (RSV) vaccination strategies. (A) Median values of RSV-attributable outpatient cases, inpatient cases, and deaths averted compared with no vaccination over a 3-year period. (B) Median values of number needed to vaccinate to avert 1 RSV-attributable outpatient case, inpatient case, or death. The x-axis scales are different for the different outcomes in panel B. Colours represent the type of strategy used and shading is used to differentiate between the vaccines that were modelled. Y-axis labels indicate the age group cut-off used for the different strategies. Note: AR = average risk (no chronic medical conditions), HR = high risk (≥ 1 chronic medical condition).

Estimates of number needed to vaccinate to avert 1 outpatient visit, hospital admission, or death tended to be largest for the age- plus risk-based strategies and were smallest for risk-based strategies (Figure 3; Appendix 1, Supplementary Table 2). For all strategies, number needed to vaccinate increased as the age cut-off for vaccination was lowered, though this gradient was less apparent for the age- plus risk-based strategies.

Results were not appreciably different for the 2 vaccines evaluated. For both vaccines, a program focused on vaccinating people with at least 1 chronic medical condition aged 70 years and older was the optimal strategy for a cost-effectiveness threshold of $50 000 per QALY (Figure 4 and Table 4). Lowering the age recommendation to people with at least 1 chronic medical condition aged 60 years and older resulted in sequential ICERs of approximately $100 000 per QALY gained compared with a medical risk–based policy for those aged 70 years and older. Sequential ICERs for age- plus risk-based strategies that used different age cut-offs depending on the presence or absence of chronic medical conditions exceeded commonly used cost-effectiveness thresholds.63,64 No vaccination was dominated by (i.e., was more costly and less effective than) other vaccination strategies.

Figure 4: Costs and quality-adjusted life year (QALY) losses associated with respiratory syncytial virus (RSV) vaccination strategies. Vaccine characteristics were based on available data for (A) RSVPreF3 (recombinant, AS01E adjuvanted vaccine) or (B) RSVpreF (RSV prefusion F subunit vaccine). Dominated or extended dominated strategies are excluded. The solid line shows the cost-effectiveness frontier, which connects nondominated strategies. Labels indicate the sequential incremental cost-effectiveness ratios (ICERs) for these strategies. Results are shown for the base-case analysis for the health-system perspective. Values represent the mean of 20 000 simulations per strategy. Additional details about the strategies are provided in Table 3, and costs, QALYs, and ICERs are provided in Table 4 for all strategies, including dominated ones. Note: AR = average risk (no chronic medical conditions), HR = high risk (≥ 1 chronic medical condition).

Table 4: Costs, quality-adjusted life years, and incremental cost-effectiveness ratios for all vaccination strategies with vaccine-effectiveness estimates based on (A) RSVPreF3 and (B) RSVpreF, for the health-system perspective

Strategy*	Costs, $	Effect (QALYs lost)	Incremental costs, $	Incremental effect (QALYs gained)	Sequential ICER* ($ per QALY)	
(A) RSVPreF3 (recombinant, AS01E adjuvanted vaccine)	
80 yr HR	11 093 616	251.7969	–	–	–	
75 yr HR	11 789 187	235.0853	695 572	16.7117	41 622	
70 yr HR	12 694 094	216.7820	904 907	18.3033	49 439	
60 yr HR	15 211 110	192.2692	2 517 016	24.5127	102 682	
80 yr AR and 50 yr HR	17 464 260	181.5907	2 253 150	10.6786	210 998	
75 yr AR and 50 yr HR	18 217 831	181.0419	753 571	0.5487	1 373 259	
70 yr AR and 50 yr HR	19 190 540	180.3799	972 709	0.6620	1 469 301	
60 yr AR and 50 yr HR	21 062 420	179.4767	1 871 880	0.9031	2 072 630	
80 yr all	11 691 842	250.3266	–	–	Extended dominated	
65 yr HR	13 933 048	205.8000	–	–	Extended dominated	
80 yr AR and 60 yr HR	15 809 336	190.7989	–	–	Extended dominated	
75 yr AR and 60 yr HR	16 562 907	190.2501	–	–	Extended dominated	
65 yr AR and 50 yr HR	20 176 398	179.9373	–	–	Extended dominated	
No vaccination	11 462 844	293.0558	–	–	Dominated	
75 yr all	13 140 984	233.0662	–	–	Dominated	
70 yr all	15 018 600	214.1009	–	–	Dominated	
65 yr all	17 243 412	202.6763	–	–	Dominated	
70 yr AR and 60 yr HR	17 535 616	189.5881	–	–	Dominated	
65 yr AR and 60 yr HR	18 521 474	189.1455	–	–	Dominated	
60 yr all	19 407 496	188.6850	–	–	Dominated	
(B) RSVpreF (RSV prefusion F subunit vaccine)	
80 yr HR	11 005 219	250.5372	–	–	–	
75 yr HR	11 677 018	233.2090	671 800	17.3283	38 769	
70 yr HR	12 555 211	214.3400	878 192	18.8690	46 542	
60 yr HR	15 048 253	189.2850	2 493 042	25.0550	99 503	
80 yr AR and 50 yr HR	17 295 502	178.4421	2 247 249	10.8429	207 256	
75 yr AR and 50 yr HR	18 049 620	177.9290	754 117	0.5131	1 469 731	
70 yr AR and 50 yr HR	19 022 818	177.3123	973 198	0.6167	1 578 164	
60 yr AR and 50 yr HR	20 895 542	176.4777	1 872 724	0.8346	2 243 725	
80 yr all	11 603 970	249.1642	–	–	Extended dominated	
65 yr HR	13 781 691	203.1625	–	–	Extended dominated	
80 yr AR and 60 yr HR	15 647 004	187.9120	–	–	Extended dominated	
75 yr AR and 60 yr HR	16 401 122	187.3989	–	–	Extended dominated	
65 yr AR and 50 yr HR	20 009 151	176.9007	–	–	Extended dominated	
No vaccination	11 462 844	293.0558	–	–	Dominated	
75 yr all	13 029 887	231.3228	–	–	Dominated	
70 yr all	14 881 277	211.8372	–	–	Dominated	
65 yr all	17 094 090	200.2481	–	–	Dominated	
70 yr AR and 60 yr HR	17 374 320	186.7822	–	–	Dominated	
65 yr AR and 60 yr HR	18 360 653	186.3706	–	–	Dominated	
60 yr all	19 247 044	185.9475	–	–	Dominated	
Note: AR = average risk (no chronic medical condition), HR = high risk (≥ 1 chronic medical condition), ICER = incremental cost-effectiveness ratio, QALY = quality-adjusted life year, RSV = respiratory syncytial virus.

* Dominated: this strategy is more costly and less effective than alternative strategies. Extended dominated: there is a combination of other strategies that are less costly and more effective than this strategy. Sequential ICER: each strategy is compared to the next most costly strategy, and all dominated or extended dominated strategies are excluded.

Results for the societal perspective were qualitatively similar regardless of whether we used the human capital (Appendix 1, upplementary Table 3) or friction cost (Appendix 1, Supplementary Table 4) approach for estimating production losses, though the estimated ICERs were lower than those for the health-system perspective.

Probabilistic sensitivity analysis identified some uncertainty about the optimal strategy around the $50 000 per QALY threshold, with the risk-based strategy most likely to be cost-effective shifting from age 80 years to age 70 years for both vaccines near this threshold (Appendix 1, Supplementary Figure 2). Risk-based vaccination of people aged 70 years and older had the largest probability of being cost-effective from $50 000 up to a threshold of $80 000 per QALY. Beyond $80 000 per QALY, there was a less clear difference between the age 60 years and age 70 years risk-based strategies.

Age-only strategies were never identified as cost-effective options regardless of the cost-effectiveness threshold used, when compared with other strategies. When evaluating only age-based strategies, vaccinating adults aged 80 years and older resulted in sequential ICERs of $3261–$5391 per QALY gained. Lowering the age recommendation for all adults from 80 years and older to 75 years and older required a cost-effectiveness threshold of approximately $80 000 per QALY (Appendix 1, Supplementary Table 5).

With a 40% reduction in vaccine price per dose (from the list price of $230 to $135–$140), the optimal strategy remained a risk-based one, but the optimal age cut-off was lowered from age 70 years to age 60 years, when using a cost-effectiveness threshold of $50 000 per QALY and base-case assumptions (Figure 5).

Figure 5: Impact of vaccine price on optimal vaccination strategy for different scenarios and cost-effectiveness thresholds. For a given vaccine price per dose (x-axis), the optimal vaccination strategy is shown for cost-effectiveness thresholds of $30 000, $50 000, or $100 000 per quality-adjusted life year (QALY). The base-case vaccine price was $230 per dose (maximum value on the x-axis). Scenario details are provided in Appendix 1, Supplementary Table 1. Results are shown for the health-system perspective for the indicated vaccines. Note: AR = average risk (no chronic medical conditions), HR = high risk (≥ 1 chronic medical condition, RSV = respiratory syncytial virus, VE = vaccine effectiveness.

Scenario analyses

Whereas most of the scenario analyses generated estimates of RSV outcomes that were compatible with expected RSV burden, the no RSV underdetection scenario appeared to underestimate burden, and the higher incidence and higher medical costs scenario overestimated burden (Figure 2).

Medical risk–based strategies were generally preferred across most scenarios, except with substantial vaccine-price reductions and a higher cost-effectiveness threshold (Figure 5). However, in the higher incidence and higher medical costs scenario, age- plus medical risk–based strategies were optimal even at higher vaccine prices and lower thresholds. At vaccine list prices and a $50 000 per QALY threshold, an older age cut-off for risk-based strategies was optimal in scenarios assuming a lower proportion of people with chronic medical conditions among hospital-admitted cases or no underdetection of RSV disease.

Assumptions that vaccine protection either extended into a third season or waned more slowly in the second season had little impact on results. For both scenarios, at the vaccine list prices, vaccinating high-risk adults aged 70 years and older remained optimal at a $50 000 per QALY threshold. If vaccine protection extends through a third RSV season, a 25% reduction in vaccine price (to $165–$175 per dose) would be required for the age recommendation for a risk-based strategy to be lowered from 70 years to 60 years and older.

In a subanalysis of age-based strategies only, we observed similar trends as for the full analysis, with a lower age cut-off preferrable when the cost-effectiveness threshold was increased, the vaccine price was lowered, or both (Appendix 1, Supplementary Figure 3).

Interpretation

Our model-based cost-effectiveness analysis of RSV vaccination for the Canadian population shows that strategies focused on adults with underlying medical conditions that place them at increased risk of RSV disease are more likely to be cost-effective than general age-based strategies. We found that vaccination of older adults may be less costly and more effective than no vaccination and that vaccinating people aged 70 years and older with chronic medical conditions is likely to be cost-effective based on commonly used cost-effectiveness thresholds. Our finding that medical risk–based policies were preferred over age-based ones was robust to a range of alternative assumptions, including vaccine protection that extends into a third RSV season or a lower proportion of people with chronic medical conditions among hospital-admitted patients. Our results were sensitive to assumptions about vaccine price, but risk-based approaches were preferred even at lower vaccine prices. We found that broader programs may be cost-effective in settings where the risk of disease and health care costs are higher, such as some remote communities in Northern Canada.

Age-based strategies were never cost-effective compared with risk-based or age- plus risk-based strategies, regardless of the cost-effectiveness threshold used or the vaccine price considered; age-based strategies were either dominated or extendedly dominated. Although age-based strategies would not result in the optimal use of resources when risk-based vaccination strategies are an option, we did a subanalysis evaluating only age-based strategies because there may be other reasons why such an approach would be desirable, such as ease of identification of people recommended for vaccination by health care providers. Of note, our vaccination-coverage estimates, which were based on influenza vaccination, assumed that for all age groups, uptake is higher for people with chronic medical conditions; as such, even the age-based strategies we evaluated include an element of risk-focused vaccination.

A recent review identified 5 economic evaluations for RSV vaccines in high-income countries (excluding Canada),11 all of which evaluated age-based strategies only in the population aged 60 years or 65 years and older. Without a substantial reduction in vaccine price, all of the non–industry funded analyses estimated ICERs exceeding $100 000 per QALY gained.65–67 Similarly, a Canadian economic evaluation68 assessed the vaccine price required for an RSV vaccination program to be cost-effective at a threshold of $50 000 per QALY and found that substantial vaccine price reductions would be required to be cost-effective for use in the general population. By contrast, in this same study, smaller price reductions were required for the vaccine to be cost-effective for a program for residents of long-term care homes.68 Overall, these findings are consistent with our analysis, suggesting a risk-focused vaccination program may be optimal.

Limitations

Our model-based analysis has several limitations. In the absence of data showing that RSV vaccines prevent onward transmission after infection, we used a static model to estimate the impact of RSV vaccination programs. Absent indirect effects, our estimates of cost-effectiveness of RSV vaccination programs may be overly conservative, though a recent dynamic model showed that assumptions about vaccine effectiveness for reducing transmission are not expected to substantially influence the estimated impact of RSV vaccination programs in older adults.69 Vaccine effectiveness and waning assumptions were based on data for 2 RSV seasons, and we assumed a single vaccine effectiveness for all ages and risk groups, given available data. As additional data on durability of vaccine protection and vaccine effectiveness in different population groups accumulate, we can refine our estimates of vaccination program impact. In particular, if vaccine effectiveness is found to be reduced with increasing age or presence of chronic medical conditions, the preference for risk-based strategies may be diminished. Uptake for a new RSV vaccination program is also unknown. Because our model does not assume indirect effects associated with vaccination, estimated cost-effectiveness would not change if coverage were lower than assumed in the model. However, our estimates of RSV disease potentially averted would be overly optimistic. The finding that risk-based strategies are optimal is informed by data showing higher incidence of severe RSV disease in people with underlying medical conditions. In our analysis, estimates of the proportion of the population with 1 or more chronic medical condition were based on underlying health conditions that could place individuals at elevated risk of complications after SARS-CoV-2 infection, 18 which may not align with risk of medically attended RSV disease. In general, additional data on the burden of RSV disease in Canadian adults, particularly in the outpatient setting, would contribute to an improved understanding of the potential benefits of vaccination programs.

Conclusion

Vaccination programs for RSV have the potential to avert a substantial burden of RSV diseases in older adults. Based on currently available data, RSV vaccination programs in some groups of older Canadians are expected to be cost-effective, with programs focusing on people with underlying medical conditions that place them at increased risk of severe RSV disease expected to provide the best value for money.

Acknowledgements

The authors thank Ruoke Chen from the Public Health Agency of Canada for providing estimates of influenza vaccination coverage and members of the National Advisory Committee on Immunization RSV Working Group for providing feedback during model development.

Competing interests: Sarah Buchan declares funds from the Canadian Institutes of Health Research and SickKids to support work on the burden of respiratory syncytial virus (RSV) in older adults and young children. Dr. Buchan is a member of the National Advisory Committee on Immunization (NACI) RSV Working Group and liaison member to NACI for the Canadian Association for Immunization Research, Evaluation and Education. Nicholas Brousseau is a member of NACI and the Quebec Immunization Committee. No other competing interests were declared.

This article has been peer reviewed.

Contributors: All authors were involved in the conception and design of the study and critical revision of the manuscript for important intellectual content. Ashleigh Tuite, Alison Simmons, Monica Rudd, Alexandra Cernat, Gebremedhin Gebretekle, and Man Yeung contributed to the acquisition of data. Ashleigh Tuite was primarily responsible for the analysis and interpretation of results and drafting the first version of the manuscript. All authors provided final approval of the version to be published and agreed to be accountable for all aspects of the work.

Data sharing: The data available from this modelling study are presented in the tables and appendix of this article.
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