An official website of the United States government
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Authors; Samantha Verbrugghe, Quenby Mahood, and Sean Tiggelaar.
Respiratory syncytial virus (RSV), a common respiratory illness, infects almost all children worldwide by 2 years of age.1,2 Most infections occur in annual epidemics, which occur seasonally from fall to early spring in temperate climates and during the rainy season in tropical climates.1,2 RSV is a significant cause of morbidity and mortality in infants and is the leading cause of lower respiratory tract infections (LRTIs), such as bronchiolitis and pneumonia, and the leading cause of hospitalizations in children younger than 2 years of age.3 Risk factors for developing severe RSV in infants include premature birth, congenital heart disease, chronic lung disease, cystic fibrosis, Down syndrome, immunocompromising conditions, and severe neuromuscular disease.4,5
Passive RSV prophylaxis has been available; palivizumab (Synagis), a humanized monoclonal antibody (mAb), was approved for use by Health Canada for the prevention of serious LRTIs caused by RSV in pediatric patients at high risk of RSV disease.6 The recommended dosing of palivizumab typically consists of 4 injections given monthly at the onset of and continuing throughout the RSV season, with an extra dose considered in remote Northern areas of Canada that have longer RSV outbreaks.7 A long-acting mAb, nirsevimab (Beyfortus), was recently approved by Health Canada8 for the prevention of LRTIs caused by RSV in neonates and infants during their first RSV season or children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. Nirsevimab has similarly been approved by the European Medicines Agency (EMA)9 and is under review by the US FDA.10 Nirsevimab can be given as a single dose at birth or just before (or at) the commencement of the RSV season.8,9
Currently, no vaccines have been authorized for the prevention of RSV disease. In November 2022, Pfizer announced the results of the MATISSE trial, a phase III trial assessing a candidate known as RSVpreF, a bivalent RSV prefusion F protein-based vaccine (Abrysvo) for use during pregnancy for RSV prevention in infants up to 6 months of age.11 As of May 2023, the EMA, the FDA, and Health Canada have all accepted market authorization submissions for RSVpreF immunization during pregnancy as well as for the immunization of older adults.12-14
What is the cost-effectiveness of RSVpreF immunization during pregnancy for infants and for people who are pregnant?
A review of the economic literature was undertaken to identify previously published economic evidence regarding the cost-effectiveness of RSV immunization during pregnancy for infants and for people who are pregnant.
An information specialist conducted a literature search on key resources, including MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search approach was customized to retrieve a limited set of results, balancing comprehensiveness with relevancy. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. Search concepts were developed based on the elements of the research questions and selection criteria. The main search concepts were RSVpreF or respiratory syncytial virus vaccines. CADTH-developed search filters were applied to limit retrieval to economic studies, citations related to health utilities or quality of life, and for background, health technology assessments, systematic reviews, meta-analyses, or indirect treatment comparisons. No limits were applied. The search was completed on March 24, 2023. Regular alerts updated the search until May 8, 2023.
One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.
Selection Criteria.
Studies were excluded based on the following:
During data extraction, the following were collected: author, publication year, country, currency, source of funding, study design, modelling approach, study perspective, discounting, time horizon, outcomes, source of clinical efficacy, study population characteristics, and results. The quality of included studies were critically appraised by 1 reviewer using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Economic Evaluations.16 Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.
Cost-effectiveness outcomes were reported as unadjusted and adjusted. If adjusted, outcomes were adjusted to 2023 Canadian dollars using Organisation for Economic Co-operation and Development (OECD) purchasing power parity rates17 and inflation rates from the Bank of Canada.18
A total of 242 citations were identified in the literature search. Following screening of titles and abstracts, 218 citations were excluded and 24 potentially relevant reports from the electronic search were retrieved for full-text review. Additionally, 1 potentially relevant publication was retrieved from the grey literature search for full-text review. Of these articles, 21 publications were excluded for various reasons, and 4 publications met the inclusion criteria and were included in this report. Appendix 1 presents the PRISMA flow chart of the study selection.
Of the 4 economic evaluations identified, 2 used static cohort models,19,20 1 used a discrete-event agent-based simulation,2 and 1 used a decision-tree model.21 All 4 were model-based studies. One study was set in Norway,20 1 was in 6 European countries,19 1 was in the Nunavik region of Canada,2 and 1 was in the US.21 Table 2 in Appendix 1 provides an overview of the characteristics of the 4 included studies.
The 4 studies ranged from meeting 5 to 8 of the 11 JBI quality appraisal checklist criteria16 (Appendix 1, Table 3) when considering their applicability to assessing the cost-effectiveness of immunization during pregnancy using the product RSVpreF. None of the studies were based on well-established clinical efficacy for RSVpreF, none included all issues of concern to users (e.g., none considered the cost-effectiveness of immunizing during pregnancy, including costs and benefits, to the people who are pregnant), and it was unclear whether the studies were generalizable to the Canadian population or to the Canadian population as a whole in the case of the study set in Nunavik, Quebec.
Base-case analyses for all studies were conducted from the health care payer perspective, with 1 study also reporting a societal perspective alongside its health care base case21 and another reporting 2 different societal perspectives as scenario analyses.19 One study incorporated increased risk of long-term sequelae (i.e., asthma and recurrent wheezing) in the base case,21 and 2 studies considered such sequelae in scenario analyses.19,20 The models supporting the economic evaluations all followed a cohort of infants born during 1 year until they reached 1 year2 or 5 years of age,19,20 except for 1 study that considered a time horizon of 5 years for health care utilization, 10 years for impact on asthma or/or wheezing, and lifetime for loss of productivity due to premature death (loss of productivity applies to societal perspective only).21 Discount rates ranged from 3% to 4% for costs and 1.5% to 4% for effects, with 1 study not discounting due to its 1-year time horizon.2 One study reported direct industry funding for editorial support,21 while the remaining 3 reported arms-length funding through national or international RSV research consortia and networks that had governmental, academic, and industry partners.2,19,20 Cost-effectiveness was reported as incremental cost-effectiveness ratios (ICERs), mostly represented as the incremental cost per additional quality-adjusted life-year (QALY), and through cost-effectiveness acceptability frontiers in which sequential analyses were conducted. For the remainder of this review, reported ICERs and cost-effectiveness acceptability frontier thresholds are reported as 2023 Canadian dollars, with conversion conducted using OECD Purchasing Price Parity rates for the year of the original currency17 and then inflated to 2023 dollars using the Bank of Canada inflation calculator.18 A summary table of the main findings of each identified economic study, including the original unadjusted results, is available in Appendix 1, Table 4.
Two studies,19,20 reporting results for 7 modelled countries, directly compared year-round immunization during pregnancy to no intervention and to long-acting mAb interventions. These mAb interventions included various seasonal strategies in which a long-acting mAb was given to infants born in some range of months during local RSV season, as well as to programs in which infants born in October through April received the mAb at birth, while those born in May through September received a “catch-up” dose of the mAb in their first October. Both of these studies assumed that the efficacy of immunization during pregnancy would be equivalent to Preferred Product Characteristics (PPCs) for RSV vaccinations in pregnancy published by WHO, which call for a product with a 70% efficacy lasting at least 4 months.22 One of the studies also conducted a scenario analysis incorporating recently reported efficacy results from the RSVpreF MATISSE trial, in which 6-month data reported a reduction of medically attended RSV of 51.3% and of severe medically attended RSV of 69.4%.11 The efficacy of long-acting mAbs was derived from the MELODY nirsevimab trial.23
One study2 compared various individual strategies (i.e., seasonal immunization during pregnancy, seasonal immunization during pregnancy plus a long-acting mAb for preterm and chronically ill infants, a short-acting mAb for preterm and chronically ill infants, and a long-acting mAb for preterm and chronically ill infants) to no intervention. Immunization during pregnancy was not directly compared with mAb-based interventions, and mAb-based interventions for healthy infants were only compared with the same intervention given to only preterm and chronically ill infants. The efficacy of immunization during pregnancy in this study was derived from the ResVax trial, PREPARE, which failed to meet its primary end point for reduction in RSV-associated, medically significant LRTIs at 3 months.24 In this model, the efficacy of immunization during pregnancy was predicted to be 14% for preventing outpatient visits, 24.7% to 61.9% for preventing pediatric ward stays, and 31.9% to 75.0% for preventing intensive care unit (ICU) stays.
The final study21 compared a hypothetical vaccine that prevented RSV starting at birth, either in the form of immunization during pregnancy or a vaccine given to neonates, with no intervention. The efficacy of this vaccine was assumed to be 50% for all RSV-related outcomes and was predicted to have a half-life of 12 months in the base case, with 1-way sensitivity analyses varying efficacy and duration.
Influential parameters reported as affecting results within studies included underlying differences between modelled countries in terms of RSV burden and health care system organization,19 effectiveness and duration of effect used for the interventions,19-21 severity of RSV season,2,20 and the acquisition costs of immunization during pregnancy and mAbs.19-21
All 4 studies compared immunization during pregnancy to no intervention, although ICERs for this comparison were manually recalculated within the current review for 2 of the studies using reported incremental costs and QALYs.19,20 Estimated ICERs, when considering a health care system perspective, ranged widely from immunization during pregnancy being dominant (less costly, more effective) compared with no treatment in Nunavik during moderate and severe RSV seasons2 and in Finland19 to costing more than $200,000 per QALY gained in Nunavik during mild RSV seasons2 as well as in the Netherlands19 and Norway.20 When considering a societal perspective that added direct nonmedical costs (travel, meals, lodging) per hospitalization, parental income loss per RSV event, and lifetime income loss for infants who died, 1 study reported an ICER of $105,022 per QALY gained for immunization during pregnancy compared with no intervention.21 Further details can be found in Appendix 1, Table 4. Reasons for this range of ICERs include differences in model parameter inputs, such as immunization during pregnancy efficacy and duration assumptions; underlying rates of RSV-related primary care visits, hospitalizations, and recurrent wheezing or asthma; QALY decrements attributed to primary care visits, hospitalizations, and recurrent wheezing or asthma; and the associated costs of treatment.
One study21 also reported ICERs for immunization during pregnancy compared with no treatment of $348,573 per life-year gained, and $30,921 per hospitalization avoided when considering the health care system perspective. Another study reported that when seasonal immunization during pregnancy was combined with a seasonal long-acting mAb for preterm and chronically ill infants, immunization during pregnancy plus mAb was dominant (less costly, more effective) over no treatment in RSV seasons of all severities.2
Two studies19,20 conducted sequential analyses in which, in addition to no treatment, year-round immunization during pregnancy was directly compared with 1 or more year-round and seasonal long-acting mAb strategies as well as to seasonal mAb strategies that included a catch-up dose at the start of RSV season for infants born outside of RSV season. The studies reported cost-effectiveness acceptability frontiers outlining the most cost-effective strategy across a range of willingness-to-pay per QALY thresholds.
Both of these studies assumed an immunization during pregnancy efficacy of 70% lasting for 4 months in their base case, and long-acting mAb efficacy and duration was represented by nirsevimab data. In all 7 countries modelled within these 2 studies, year-round immunization during pregnancy was dominated (i.e., was more costly and less effective) by various seasonal mAb strategies and thus was not the most cost-effective strategy at any willingness-to-pay threshold. Results reportedly did not substantially differ in the study, which included a scenario that incorporated recently released RSVpreF data, because the longer (6 month) duration of action was offset by lower efficacy rates for primary care visits at 6 months compared with WHO PPC efficacy at 4 months used in the base case.18 Sequential results also did not substantially differ from those of the base case when partial societal (including caregiver productivity loss) or full societal (including caregiver productivity and leisure time loss) perspectives were taken within this study; immunization during pregnancy was still not the most cost-effective strategy at any willingness-to-pay threshold.19 A summary of the cost-effectiveness frontier in each modelled country within these studies can be found in Appendix 1, Table 4.
Of particular interest is that these 2 studies conducted pricing threshold analyses, with 1 study reporting that immunization during pregnancy would be a cost-effective option compared with a long-acting mAb if the immunization during pregnancy was priced at least 50% lower per dose than the mAb,19 while the other study estimated that immunization during pregnancy would need to be priced 2 to 5 times lower than the long-acting mAb to be cost-effective.20 These results are similar to 2 economic studies that estimated that the maximum cost-effective purchase price per person or per fully protected person was lower for year-round immunization during pregnancy compared with seasonal long-acting mAb for newborns (i.e., immunization during pregnancy needed to be priced lower than the mAb to be cost-effective),25,26 although 1 of these studies reported that when immunization during pregnancy was used seasonally, the maximum cost-effective price per person was similar to that of seasonal mAb.26
The review identified 4 economic evaluations conducted in high-income countries that assessed the cost-effectiveness of RSV immunization during pregnancy compared with no intervention; of these, 2 economic evaluations compared immunization during pregnancy with long-acting mAb intervention strategies. All studies evaluated the benefits and costs of RSV immunization during pregnancy for infants, but none considered the potential benefit of RSV immunization during pregnancy to the people who are pregnant. Although health benefits and potential cost offsets in people who are pregnant may be relatively limited due to low rates of RSV-related morbidity and mortality in healthy adults younger than 50 years, it is likely the overall cost-effectiveness of RSV immunization during pregnancy was slightly underestimated due to this omission, and the cost-effectiveness of RSV prevention in people who are pregnant is unknown.
The identified studies used a range of inputs to estimate the efficacy of immunization during pregnancy and duration within their models, including WHO PPC recommendations, data from the failed ResVax PREPARE trial, and author assumptions. Data from the MATISSE RSVpreF trial was new at the time of this review, and only available as part of a press release from its sponsor, Pfizer.11 Only 1 of the included studies incorporated data from this trial, and only as a scenario analysis with incomplete reporting.19 This scenario applied efficacy over a 6-month duration using rates reported for the 6-month follow-up period of the MATISSE trial (medically attended RSV of 51.3%; severe medically attended RSV of 69.4%).11 The study did not conduct a scenario incorporating the higher efficacy rates reported at the 90-day primary end point of the trial over a 3-month duration (medically attended RSV of 57.1%; severe medically attended RSV of 81.8%).11 Very young infants are at higher risk of severe RSV disease than those approaching 6 months of age,19,22 thus an alternate scenario considering these higher efficacy rates over a shorter duration may have been informative. As such, the efficacy inputs used in the included studies may not be reflective of the efficacy of RSVpreF in preventing severe RSV outcomes in very young infants.
Most studies19-21 (n = 3) did not consider the cost-effectiveness of seasonal immunization during pregnancy strategies in which only persons due to give birth during, just before, and/or just after (to ensure preterm infants would also be protected) RSV season would be vaccinated. Because year-round immunization during pregnancy was dominated by seasonal long-acting mAb strategies in the studies directly comparing them,19,20 a comparison of seasonal immunization during pregnancy compared with seasonal mAb strategies may have been of interest. Conversely, the included study set in Nunavik only considered seasonal immunization during pregnancy, thus the cost-effectiveness of year-round immunization during pregnancy was not assessed in this setting.2
The included studies used a range of sources to estimate QALY decrements associated with RSV-related primary care visits, hospitalizations, ICU stays, and recurrent wheezing or asthma. Measuring QALY loss in very young children is challenging, increasing the uncertainty in resulting estimates of cost-effectiveness for interventions, including RSVpreF, aimed at improving quality of life in young pediatric populations. Most studies did not incorporate deaths avoided due to RSV prevention strategies because of very low rates of RSV-related deaths in high-income countries20 (such deaths occur primarily in critically ill infants who were likely to experience premature death even without RSV infection)19 or for unstated reasons.2 This may underestimate the cost-effectiveness of RSVpreF should a portion of these deaths be avoided in clinical practice. The model that did include RSV-related mortality prevention estimated that 66 deaths would be avoided in the US by vaccinating 4.2 million live births.21 These deaths avoided accounted for 21% of the QALY gains in the model, a figure which likely overestimates any potential mortality benefit that might be realized with RSV immunization during pregnancy in practice, thus the model likely underestimates the ICER.
Most of the included studies may be broadly generalizable to the Canadian health care system because the eligibility criteria screened for economic evaluations conducted in high-income countries, as defined by the World Bank.15 Further, 3 of the included studies were set in countries with public health care systems similar to Canada,27 with the exception of a single study set in the US.21
The assumed price per dose of immunization during pregnancy varied widely within the included studies, ranging from $73 to $1,736 (2023 Canadian dollars). At the time of this review, RSVpreF was under review but not yet approved or available in Canada, the US, or the European Union.12-14 As such, the price at which RSVpreF will be available is unknown, increasing uncertainty in its cost-effectiveness.
The sole economic model set in Canada considered the population of Nunavik, Quebec.2 Although highly relevant to decision-makers in Nunavik and similar regions, the high rates of RSV infections and associated hospitalizations, as well as the high costs and family burden associated with potential medical transport from remote Arctic regions,2 likely reduces generalizability of cost-effectiveness results to non-Arctic regions of Canada. Additionally, the estimated cost per immunization during pregnancy dose was very high in this study compared with the others and may not be reflective of future costs that would be paid by Canadian health care payers for RSVpreF.
Four economic studies were identified regarding the cost-effectiveness of RSV immunization during pregnancy in high-income countries. All 4 identified studies that evaluated the cost-effectiveness of RSV immunization during pregnancy modelled outcomes for infants. However, there is a lack of evidence on outcomes for the persons who are pregnant.
When compared to no intervention, the cost-effectiveness of immunization during pregnancy ranged from dominant (more effective and less costly) to more than $200,000 per QALY gained, depending on the modelled region, efficacy, pricing, and severity of the RSV season.
When compared with seasonal RSV prophylaxis with long-acting mAbs such as nirsevimab, year-round immunization during pregnancy was not considered cost-effective when the price per dose was the same as that of the long-acting mAb. Immunization during pregnancy was estimated to become cost-effective when its acquisition cost per dose was 2 to 5 times lower than that of the long-acting mAb.
Most studies did not incorporate efficacy data from immunization during pregnancy trials, and only 1 study included data specific to the product RSVpreF in a scenario analysis. Given the between-study variation in assumed immunization during pregnancy efficacy, immunization during pregnancy acquisition costs, QALY measures, mortality assumptions, and setting, substantial uncertainty remains regarding the cost-effectiveness of immunization during pregnancy with RSVpreF in Canada.
European Medicines Agency
incremental cost-effectiveness ratio
intensive care unit
Joanna Briggs Institute
lower respiratory tract infection
monoclonal antibody
Organisation for Economic Co-operation and Development
Preferred Product Characteristics
respiratory syncytial virus
RSV prefusion F protein-based vaccine
Note this appendix has not been copy-edited.
Selection of Included Studies.
Characteristics of Included Economic Evaluations.
Quality Appraisal Results.
Main Results of Included Economic Evaluations.
Interface: Ovid
Databases:
Date of search: March 24, 2023
Alerts: Biweekly search updates until May 8, 2023.
Search filters applied: Systematic reviews; meta-analyses; network meta-analyses; health technology assessments; economic evaluations; costs and cost analysis studies, and quality of life studies.
Limits: None
Syntax Guide.
Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.
While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH.
CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the contents of this document or any of the source materials.
This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the third-party website owners’ own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites.
Subject to the aforementioned limitations, the views expressed herein do not necessarily reflect the views of Health Canada, Canada’s provincial or territorial governments, other CADTH funders, or any third-party supplier of information.
This document is prepared and intended for use in the context of the Canadian health care system. The use of this document outside of Canada is done so at the user’s own risk.
This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada.
The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.
About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.
Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.
Questions or requests for information about this report can be directed to requests@cadth.ca
Copyright © 2023 - Canadian Agency for Drugs and Technologies in Health. Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND).
Your browsing activity is empty.
Activity recording is turned off.
See more...
