Statement on the prevention of respiratory syncytial virus disease in infants: Supplementary systematic review of economic evidence

On this page

• Preamble
• Overview of economic evidence
• Systematic review of economic evidence
• Summary of included studies
  • Model-specific appraisal
  • Summary of results
  • Discussion
• 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 or monoclonal antibody 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.

Overview of economic evidence

Systematic reviews and a de novo model-based cost-utility analysis were used as economic evidence to support decision-making for the use of a bivalent RSV prefusion F protein–based (RSVpreF) vaccine and a long-acting monoclonal antibody (nirsevimab) in pregnant women and infants, respectively, for the prevention of RSV-related outcomes in the pediatric population. The systematic reviews are published^{Footnote 1Footnote 2}, and summarized below, along with an additional review of the grey literature. Details of the model-based cost-utility analysis are published elsewhere^{Footnote 3}. All costs are reported in 2023 Canadian dollars unless otherwise specified.

A note on language

NACI recognizes that not all people giving birth or breastfeeding will identify as women or mothers. Much of the research available currently refers only to "women" when discussing pregnancy. When citing research, NACI refers to the language used in the study. In these cases, "woman" refers to someone who was assigned female at birth and "maternal" is used to identify the person who is pregnant or postpartum. For the purposes of this statement, the terms "woman", "women", and "maternal" should be considered to also apply to those individuals who do not specifically identify as female gender but are the parent gestating the fetus or breastfeeding or chestfeeding the infant.

Systematic reviews of economic evaluations

Separate systematic reviews were conducted for the cost-effectiveness of (1) RSV immunization during pregnancy to prevent RSV outcomes in infants and women who are pregnant, and (2) nirsevimab in infants. The peer-reviewed literature searches were updated May 8, 2023, and June 13, 2023, respectively. The grey literature search was updated November 15, 2023. The included studies were limited to high income countries and to studies published in English or French.

Summary of included studies

Table 1 summarizes the six studies included in the systematic reviews ^{Footnote 4Footnote 5Footnote 6Footnote 7Footnote 8Footnote 9}, and the five models included in the grey literature review^{Footnote 10Footnote 11Footnote 12Footnote 13Footnote 14Footnote 15}. Note that the grey literature review accepted preprints and slide decks presented to National Immunization Technical Advisory Groups. Other grey literature such as conference abstracts, poster presentations and presentations on multi-model comparisons were not included, as methods and results were not sufficiently reported. The study settings were in Europe (N = 4)^{Footnote 4Footnote 5Footnote 8Footnote 10}, USA (N = 5)^{Footnote 7Footnote 9Footnote 11Footnote 12Footnote 13Footnote 14}, and Canada (N = 2) — one reflective of the Canadian Arctic region (Nunavik)^{Footnote 6}, and one reflective of the Canadian south^{Footnote 15}. All studies were published between 2013 to 2023.

All studies used a health system perspective, while three studies had additional analyses using a societal perspective — namely through the inclusion of productivity loss of parents from paid employment to care for a child with RSV and/or to receive an RSV intervention^{Footnote 4Footnote 9Footnote 15}. In addition to productivity loss in the societal perspective, Shoukat et al. also included the monetary loss of life due to infant mortality^{Footnote 15}, Regnier included out-of-pocket costs for travel, meals, and lodging^{Footnote 9}, and Getaneh et al. included loss of leisure time^{Footnote 4}. In terms of study quality, all studies met more than 50% of the Joanna Briggs Institute (JBI) Critical Appraisal Checklist criteria^{Footnote 16}. All studies reported incremental cost-effectiveness ratios (ICERs) with the exception of Kieffer et al., which reported medical costs saved due to reductions in healthcare use from RSV prophylaxis^{Footnote 7}. Two studies conducted sequential analyses, where authors compared three or more interventions in one analysis, unlike in traditional cost-effectiveness analyses where there are only two interventions compared (pair-wise)^{Footnote 4Footnote 5}. Six studies conducted threshold analyses for product prices, where authors determined at what price an intervention became cost-effective under specific cost-effectiveness thresholds^{Footnote 4Footnote 5Footnote 8Footnote 9Footnote 10Footnote 15}. Two studies reported industry funding^{Footnote 7Footnote 9}, and one study reported private and public funding with no involvement from the funders^{Footnote 8}.

Model-specific appraisal

Three studies modelled RSV transmission, allowing for indirect effects such as community immunity to be captured^{Footnote 6Footnote 8Footnote 10}. Given the uncertain causal relationship between RSV and asthma or wheezing, most models excluded these sequelae with the exception of Regnier (odds ratio of asthma or wheezing = 3.84 [95% CI: 3.23 to 4.58] until 10 years of age) and Shoukat et al. (probability of wheezing post-hospitalization = 0.31; duration = 5.2 to 9.8 days)^{Footnote 9Footnote 15}. Only one study included product wastage (5%)^{Footnote 6}. Several studies did not include RSV-related mortality^{Footnote 4Footnote 6}. Those that did took different approaches: per-infection probability of death (range: 0.0008197 to 0.0054%)^{Footnote 7Footnote 8Footnote 9Footnote 10}, and post-hospitalization probability of death (range: 0.02 to 3.3%)^{Footnote 11Footnote 12Footnote 13Footnote 14Footnote 15}.

For the included studies in the systematic reviews, the pregnancy vaccines assessed were not all specific to RSVpreF, with some studies evaluating theoretical maternal vaccines. The vaccine efficacies used ranged from 24.7 to 70%. Several studies used the World Health Organization's Preferred Product Characteristics (i.e., 70% efficacy lasting at least 4 months). In contrast, most studies assessed nirsevimab specifically (e.g., using MELODY clinical trial data) as opposed to a generic long-acting monoclonal antibody.

Several studies reported threshold analyses of product prices as their main results; hence they varied prices over a large range, with lower bounds likely beyond the range of plausible discounted prices, at least in the Canadian context. Of note, the study on the Canadian south assessed prices between $50 to $1,000 for both immunization products^{Footnote 15}. The England and Wales studies to support JCVI deliberations assessed prices from approximately $2 to $7,800 (£1 to £4,600) for nirsevimab^{Footnote 8}, and from approximately $0 to $340 (£0 to £200) for a pregnancy vaccine^{Footnote 10}. Among studies that did not conduct threshold analyses as their main results (i.e., studies that assumed one product price in the base case analysis), notable long-acting monoclonal antibody prices include: $1,065 to $2,048 per dose in the Canadian Arctic region^{Footnote 6}, and approximately $690 (500 USD) per dose in the United States^{Footnote 12}. Notable pregnancy vaccine prices include: $1,560 per dose in the Canadian Arctic region^{Footnote 6}, and approximately $408 (295 USD) per dose in the United States^{Footnote 13}.

Summary of results

Summaries of each peer-reviewed study from the systematic reviews can be found in the original reports^{Footnote 1Footnote 2}. Note that the included studies used a range of model inputs and assumptions (e.g., vaccine efficacies), took place in different settings (e.g., Canadian Arctic or South, Europe, USA), and modelled different implementation strategies (e.g., seasonal versus year-round). As most studies used the health system perspective, the ICERs reported below are from this perspective unless otherwise stated.

1. Pregnancy vaccines versus no intervention (N = 4 studies using pairwise or sequential analyses):
   • ICERs ranged widely: In Finland and in the Nunavik setting during moderate and severe RSV seasons (i.e., more than 50% of households infected with RSV), the estimated ICERs were dominant (i.e., less costly, more effective)^{Footnote 4Footnote 6}. In the Netherlands, Norway, and in the Nunavik setting during mild RSV seasons, ICERs were over $200,000 per quality-adjusted life-year (QALY)^{Footnote 4Footnote 5Footnote 6}.
2. Nirsevimab versus no intervention (N = 1 study using pairwise or sequential analyses):
   • ICERs ranged within the same Nunavik setting, depending on severity of the RSV season: During moderate and severe RSV seasons, nirsevimab in high-risk infants was dominant (i.e., less costly, more effective) compared to no intervention. High-risk infants were defined as preterm infants and chronically ill infants under 1 year of age (i.e., underlying comorbidities, such as chronic lung disease and hemodynamically significant heart disease). During a mild season, the ICER was over $200,000 per QALY^{Footnote 6}.
3. Nirsevimab versus palivizumab (N = 1 study using pairwise or sequential analyses):
   • In Nunavik, replacing palivizumab with nirsevimab among high-risk infants (i.e., preterm or chronically ill infants under 1 year of age) was dominant (i.e., less costly, more effective)^{Footnote 6}. Expanding nirsevimab to healthy infants aged 0 to 2 months in addition to high-risk infants had ICERs ranging from dominant during a severe RSV season to $39,414 per QALY during a mild season when compared to palivizumab^{Footnote 6}.
4. Pregnancy vaccines versus nirsevimab (N = 2 studies using pairwise or sequential analyses):
   • Pregnancy vaccines were consistently dominated (i.e., more costly, less effective) by seasonal programs of nirsevimab with or without a catch-up – regardless of setting (Denmark, England, Finland, Italy [Venato], The Netherlands, Scotland, Norway)^{Footnote 4Footnote 5}.
5. Combined products versus palivizumab (N = 1 study using pairwise or sequential analyses):
   • In Nunavik, a pregnancy vaccine program combined with nirsevimab use in preterm or chronically ill infants aged 3 to 11 months was dominant (i.e., less costly, more effective) compared to palivizumab in healthy infants aged 0 to 2 months^{Footnote 6}.

Below is a high-level summary of the additional studies included in the grey literature review:

1. The economic evaluation of nirsevimab by Hutton et al. in the US setting found a base case ICER of approximately $215,645 per QALY (or 157,537 USD per QALY) when comparing an all-infant program to "natural history" (which was a strategy that included the cost of palivizumab for high-risk infants)^{Footnote 11Footnote 13}. The product price plus administration was approximately $690 (500 USD) per dose, efficacy was taken from the MELODY trial data, and coverage was 50%. Cost-effectiveness results were robust when varying efficacy in months 6 to 10 (from 0% to 50%) and when varying seasonality of program (October to February, March or April). ICERs hovered around approximately $191,540 per QALY (or 140,000 USD per QALY) using an optimistic 50% efficacy assumption across different seasonal programs. The ICERs reported are from a societal perspective.
2. The economic evaluation of RSVpreF by Hutton et al. in the US setting found a base case ICER of approximately $547,555 per QALY (or 400,304 USD per QALY) when comparing year-round vaccination with no intervention^{Footnote 12Footnote 14}. The product price plus administration was approximately $408 (295 USD) per dose, and coverage was 50%. Cost-effectiveness results were robust when varying coverage. ICERs remained high when varying vaccine efficacy assumptions: approximately $500,300 per QALY (or 365,669 USD per QALY) using a flat efficacy of 57.1% against medically-attended lower respiratory tract infections and 56.8% against RSV-associated hospitalizations up until 6 months. When using more optimistic efficacy assumptions (higher and longer protection), the ICERs reduced slightly to approximately $391,480 per QALY (or 286,179 USD per QALY). In scenario analyses where seasonal pregnancy programs were explored, cost-effectiveness results were sensitive to months of administration. The lowest ICERs were observed for programs vaccinating from September to January and September to December (approximately $228,830 and $194,030 per QALY [or 167,280 USD and 141,806 USD per QALY] respectively). The probability of prematurity was a very influential factor that could drive the ICERs up to $1.3 million USD per QALY. The ICERs reported are from a societal perspective.
3. The combined products economic evaluation by Hutton et al. in the US setting assessed administering RSVpreF to all pregnant women people and nirsevimab to all infants (e.g., administered at time of birth when born October to March; administered as catch-up dose in October or November when born April to September) as the base case^{Footnote 13Footnote 14}. When compared to "natural history" (which was a strategy that included the cost of palivizumab for high-risk infants), the ICER was approximately $915,490 per QALY (or 668,735 USD per QALY). In an analysis of administering RSVpreF to all pregnant women and nirsevimab only to babies born out of the RSV season (i.e., born April to September; administered as a catch-up dose in October or November), the ICER was $666,150 per QALY (or 486,882 USD per QALY). The ICERs reported are from a societal perspective.
4. Shoukat et al. assessed the use of nirsevimab, RSVpreF vaccine, and both products in combination in the Canadian South^{Footnote 15}. Seasonal nirsevimab programs with catch-up targeting various populations were assessed: (1) preterm infants 32 weeks of gestational age (wGA) or less and infants with chronic lung disease (CLD) or congenital heart disease (CHD); (2) preterm infants 36 wGA or less and infants with CLD or CHD condition; (3) preterm infants 36 wGA or less, infants with CLD or CHD, and term infants born during RSV season; and (4) all infants. The comparator was palivizumab use in high-risk infants. The pregnancy program assessed was year-round. The combined products program was year-round vaccination of pregnant women followed by administration of nirsevimab to infants at high-risk of severe RSV disease (i.e., preterm infants 32 wGA or less and infants with CLD or CHD condition) during the RSV season. In the base case analysis, all programs had 100% coverage. The main findings were presented as threshold analyses on price, assessing the maximum product price in order for programs to be considered cost-effective under a threshold of $50,000 per QALY. Shoukat et al. varied the price of both products from $50 to $1,000 per dose and used an administration cost of $15. The following maximum prices were noted for the corresponding nirsevimab programs above: (1) $615; (2) $375; (3) $300; and (4) $215. The maximum price for a RSVpreF vaccine was $160 in a standalone year-round program. In a combined products program, the maximum price for RSVpreF would be $140 if the price for nirsevimab was $615 per dose; and $155 if nirsevimab price was reduced to $215 per dose. Under a societal perspective, the maximum product prices were all higher, driven by the inclusion of productivity loss of parents.
5. Hodgson et al. (2023) directly compared nirsevimab to RSVpreF in the England and Wales setting^{Footnote 10}. The nirsevimab programs assessed were: (1) seasonal program administered between September and February; (2) seasonal program administered between September and February with a catch-up dose in September for infants born out of the RSV season; and (3) year-round program. Coverage was 90%. The pregnancy programs assessed were: (1) seasonal program administered between July and December for women who are 24 to 36 weeks pregnant; and (2) year-round program. Coverage was 60%. The main findings were threshold analyses on maximum product prices (including administration costs) in order for programs to be considered cost-effective under a threshold of approximately $51,100 per QALY (or £30,000 per QALY). Hodgson et al. found that if nirsevimab were priced above approximately $143 (or £84), then a seasonal pregnancy program would be optimal between approximately $61 to $136 (or £36 to 80), and a year-round pregnancy program would be optimal up to $60 (or £35). Cost-effectiveness results were robust to varying coverage assumptions.

Discussion

In many settings, programs using nirsevimab alone, RSVpreF alone, or in combination generated ICERs that generally exceeded commonly used cost-effectiveness thresholds. Dominant results (i.e., programs being less costly and more effective) were seen under very specific conditions. For instance, in the Nunavik setting during mild RSV seasons (i.e., 30 to 50% of households had individuals infected with RSV), the pregnancy vaccine had an ICER above $200,000 per QALY^{Footnote 6}. During moderate or severe RSV seasons (i.e., more than 50% of households had individuals infected with RSV), a pregnancy vaccine program (not specific to RSVpreF) was dominant (i.e., less costly and more effective) compared to no intervention.

Nirsevimab programs for infants at high-risk, with or without a pregnancy vaccine program were dominant compared to no intervention, regardless of the severity of the RSV season^{Footnote 6}. In studies that conducted pricing threshold analyses, the product prices needed to be low in order for programs to be cost-effective. For instance, the study on the Canadian South estimated that RSVpreF needed to be below $160 per dose, and nirsevimab needed to be $215 per dose for an all-infant program, and between $300 to $615 for various high-risk infant programs^{Footnote 15}. The study on England and Wales assessed nirsevimab prices of approximately $143 per dose (or £84), and if priced any higher, pregnancy vaccine programs would be more cost-effective^{Footnote 10}. The maximum prices estimated by these studies differ from the prices used in the USA in support of Advisory Committee on Immunization Practices (ACIP) recommendations – approximately $690 (500 USD) per dose for an all-infant program in the United States. Note that the ACIP has recommended the use of nirsevimab for all infants aged less than 8 months born during or entering their first RSV season, and for infants and children aged 8 to 19 months who are at increased risk of severe RSV disease entering their second RSV season^{Footnote 17}. ACIP has also recommended the use of RSVpreF for persons 32 to 36 weeks pregnant using seasonal administration (meaning September to January in most of the United States)^{Footnote 18}. Similarly, JCVI recommended an RSV immunization program that is cost-effective should be developed for infants. Both products were recommended, and no preference was placed for a particular product^{Footnote 19}.

Overall, the variation across study findings is due to the wide variation in model inputs. For instance, many of the peer-reviewed studies were conducted when product prices and clinical trial data for RSVpreF were not yet available, and different assumptions were used. Further, the settings varied, and there may be underlying differences between modelled countries in terms of 1) their RSV burden, and 2) their health care system organization. Only two studies were directly generalizable to the Canadian context^{Footnote 6Footnote 15}. The implementation of the programs (i.e., offered seasonally versus year-round; offered with a nirsevimab catch-up dose versus none; offered to all versus subpopulations) also impacted cost-effectiveness. Influential parameters affecting cost-effectiveness results included: effectiveness and duration of protection assumptions, QALY decrement assumptions, severity of RSV season, and product prices.

Note that inclusion criteria were of cost-effectiveness studies, and the literature searches did not search for budget impact. Provinces and territories may benefit from conducting budget impact analyses to examine the financial impact of relevant immunization strategies within their own budgets.

List of abbreviations

ACIP

Advisory Committee on Immunization Practices

CHD

Congenital heart disease

CLD

Chronic lung disease

ICER

Incremental cost-effectiveness ratio

JBI

Joanna Briggs Institute

JCVI

Joint Committee on Vaccination and Immunisation

mAb

Monoclonal antibody

NACI

National Advisory Committee on Immunization

PHAC

Public Health Agency of Canada

QALY

Quality-adjusted life year

RSV

Respiratory syncytial virus

wGA

Weeks of gestational age