FormalPara Key Summary Points

Why carry out this study?

Respiratory syncytial virus (RSV) is a major cause of respiratory infection among infants and medical resource usage upon worsening increases public spending.

In 2024, RSV prefusion F protein-based (RSVpreF) vaccine was approved for the prevention of RSV infection in infants by active immunization of pregnant women in Japan.

The cost-effectiveness of RSVpreF vaccine was assessed through economic modelling by considering the use of palivizumab, a licensed product for passive immunization for infants.

What was learned from the study?

In comparison with the current prophylaxis option (palivizumab only) in Japan, combined prophylaxis with year-round RSVpreF vaccination of expecting mothers and palivizumab prescription for infants was cost-effective when the price of RSVpreF vaccine was equal to or less than ¥23,948 (US $182).

Cost of interventions and effectiveness of the RSVpreF vaccine were the factors that most impacted on incremental cost-effectiveness ratios.

This study suggests that combination prophylaxis becomes more cost-effective if the palivizumab usage declines over time as a consequence of RSVpreF vaccination, raising the importance of active surveillance of RSV after initiation of RSVpreF vaccination.

Introduction

Respiratory syncytial virus (RSV) is a common cause of respiratory infections in infants and the leading cause of viral bronchiolitis and pneumonia [1]. Globally, there are 1.4 million RSV-associated hospitalizations each year in infants aged up to 6 months, with infants in their first 3 months of life accounting for approximately 60% of the total [2]. Infants aged up to 6 months account for approximately half of RSV-associated in-hospital deaths in children < 5 years [2]. The percentages of infants infected by RSV by 1 and 2 years of age are 68% and 97%, respectively [3]. Though prematurity and other chronic diseases increase the risk of RSV-associated hospitalization, the majority (79%) of infants < 2 years hospitalized for RSV are healthy, full-term infants with no underlying medical conditions [4, 5].

In Japan, RSV infection is a category V infectious disease; it is monitored under the National Epidemiological Surveillance of Infectious Diseases (NESID) Program’s pediatric sentinel surveillance system, and reporting requires laboratory diagnosis [6]. According to the data from this program, among RSV infections reported in all age groups in 2017–2020, 32–37% were infants aged less than 1 year [6]. A Japanese claims database analysis showed the annual incidence of medically attended RSV among infants aged 0–2 months, 3–5 months, and 6–11 months to be 63.4, 109.0, and 100.0 per 1000 person-years, respectively. Furthermore, approximately one-fourth of medically attended patients with RSV (< 2 years of age) identified in the medical claims database needed hospitalization [7]. Approximately 40% of RSV hospitalizations for children under 2 years of age occurred in the first 6 months of life, and hospitalizations for children under 3 months accounted for about 20% of all hospitalizations. The number of RSV hospitalizations by age peaked at 1–2 months of age, indicating a high burden of disease in the immediate postnatal period [7, 8].

Palivizumab, a humanized monoclonal antibody that targets an RSV protein, was the only product licensed for passive immunization and prevention of severe RSV infections as of February 2024 in Japan. Palivizumab reduces hospitalization due to RSV infection by 56% according to a systematic review [9]. The RSV-related hospitalization rate in patients who received palivizumab ranged from 0 to 3.0% in Japan [10]. Japanese guidelines recommended the use of palivizumab for infants who are eligible for its prescription and palivizumab is highly utilized among this population [11,12,13]. However, palivizumab requires multiple doses (once a month throughout the RSV season) and is associated with high cost [14]. A Japanese claims database analysis showed that the mean cumulative prescription number and drug costs of palivizumab by 11 months of age were 5.9 times and ¥890,259 (US $6770), resulting in an estimated cost to the Japanese healthcare system of ¥22.9 billion (US $174.1 million) per year for at least between 2016 and 2020 [15]. The Japanese government and local governments shoulder high financial burden because they provide financial support to medical care services for infants and children as part of a public welfare program [16]. Furthermore, palivizumab is not approved for usage in healthy, full-term infants even though this population accounts for 90% of the hospitalized cases of RSV [7, 14]. A protective measure that is applicable to all susceptible infants is necessary to reduce the overall disease burden of RSV in Japan.

Maternal vaccination protects all infants immediately after birth through transplacental transfer of increased levels of maternal antibodies [17]. In the USA, the bivalent RSV prefusion F protein-based (RSVpreF) vaccine (ABRYSVO™) was approved for the prevention of RSV infection in infants by active immunization of pregnant individuals and its use was recommended by the Advisory Committee on Immunization Practices (ACIP) in 2023 [18]. Furthermore, the RSVpreF vaccine was approved in other countries including Japan [19]. As RSVpreF maternal vaccination is a completely new concept to control RSV disease burden among infants, designing possible administration strategies and predicting their potential implications for epidemiology and healthcare costs shall be informative for developing a better RSV prophylaxis strategy in Japan. In this study, we investigated the cost-effectiveness of RSVpreF vaccine if it replaces palivizumab in some pediatric populations.

Methods

Model Structure

The model employs a cohort framework and Markov-type process to depict clinical outcomes and economic costs of RSV-positive respiratory tract illness (RTI) from birth to age 11 months, lifetime consequences of premature RSV-related death, and the expected impact of maternal vaccination with RSVpreF vaccine on the aforementioned outcomes among infants (Fig. 1). The model was adapted from a model presented at the ACIP meeting in September 2023 [20] and was calibrated to reflect Japanese healthcare settings.

Fig. 1
figure 1

Decision tree structure for cost-effectiveness analysis. In the cost-effectiveness analysis, a new combination RSV prophylaxis was compared with the current prophylaxis by epidemiology, costs, and cost-effectiveness. Neonates were divided into subgroups by their mothers’ vaccination status and subsequent usage of prophylaxis. RSV incidence, usage of medical resources, and subsequent mortality and productivity losses were calculated for each of the subgroups. RSV respiratory syncytial virus

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Clinical outcomes included RSV cases, RSV-related deaths, life years, and quality-adjusted life years (QALYs) for each healthcare setting including hospitalization, outpatient visits, and emergency department (ED) visits. Economic outcomes included intervention costs (costs for RSVpreF vaccine and palivizumab), medication costs for infants, and productivity losses. The model cohort was a monthly rolling cohort of infants aged less than 1 year. The analysis included 12-monthly cohorts; for each cohort, RSV cases, deaths, and costs are tallied only during the first year of life. The gestational age of infants was considered and divided into four age categories: full-term (≥ 37 weeks gestational age, wGA), and preterm (≤ 27 wGA, 28–31 wGA, and 32–36 wGA) [21]. In order to maintain internal consistency between international resources we used the definition of World Health Organization (WHO) for term pregnancy rather than the US definition [22, 23]. In the simulation, the number of cases was estimated for each healthcare setting on the basis of the epidemiologic inputs. Subsequent RSV-related deaths were calculated by multiplying the estimated number of cases in each care setting by case fatality rates. Life years were computed by aggregating life years for the first year of life and full life expectancies for the remaining alive population from all birth categories. Deaths of infants aged < 1 year were counted as 0.5 year. Along with the clinical and economic outcomes, incremental costs, incremental QALY, and incremental cost-effectiveness ratios (ICERs) per QALY gained were estimated from a payer perspective and a societal perspective, assuming a cost-effectiveness threshold of ¥5 million (US $38,052) per QALY gained. Model was adapted with a lifetime time horizon and an annual discount rate of 2.0% [24].

Intervention Strategies

As of February 2024, Japanese clinical guidelines for RSV prophylaxis did not yet include the addition of RSVpreF vaccination to the existing prophylaxis, palivizumab [9]. We assumed that RSVpreF vaccine and palivizumab will be used together in the clinical practice as a comprehensive prophylaxis program to improve protection against infants from RSV infection. At present, palivizumab is approved and highly used for premature who were born  ≤ 35 wGA and infants with risks of RSV disease, such as infants with bronchopulmonary dysplasia (BPD), congenital heart disease (CHD), Down’s syndrome, or a compromised immune system in Japan [11, 12, 14, 25]. In contrast, we assumed that RSVpreF vaccination is effective for full-term (≥ 37 wGA) and preterm born at 32–36 wGA, and some proportion of infants that could be protected from maternal immunization could be exempted from palivizumab prescription. In this study, two cases, scenario 1 (base case scenario) and scenario 2 were developed by changing the target population for palivizumab prescription in the combination prophylaxis (Table 1).

Table 1 Current and combination prophylaxis strategies of RSV infection
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For both cases, all women were eligible for year-round RSVpreF vaccination. In scenario 1, premature (≤ 31 wGA) without risk and all infants with risk were eligible to receive palivizumab. In this setting, premature (32–36 wGA) without risk was assumed not to receive palivizumab if their mother received RSVpreF vaccine. However, if their mothers were unvaccinated or infants born within 2 weeks after maternal vaccination, we assumed that the people were not sufficiently protected by transferred maternal antibodies and received palivizumab. In scenario 2, premature (≤ 31 wGA) regardless risk in infants were eligible to receive palivizumab. These combination prophylaxes were compared with the current prophylaxis (palivizumab alone) in the analysis (Table 1).

Model Input Parameters

The input parameters for the basic analysis are listed in Table S1.

Population Inputs

Values for birth-related parameters such as number of infants born during the 12-month period were extracted from the Vital Statistics Survey of Japan in 2021 and further calibrated to fit into the model [26]. The percentage of infants with high risk was assumed to be 2.58% based on the analysis of a Japanese claims database [15].

Epidemiological Inputs

The annual rates of RSV cases were extracted from the Japanese claims database analysis of 2021 and adjusted to mimic the condition where palivizumab was not yet utilized in Japan (Table S2) [7]. The proportion of RSV with lower respiratory tract illnesses (LRTI) in hospitalized cases was 91.6% [27]. Relative risk of RSV encounters was estimated from data obtained in the USA because of unavailability of relevant data in Japan [28]. The probabilities of being infected by RSV in each month were estimated from an average of the distributions of RSV encounters between 2017 and 2019 because the peak season of RSV was different in each year [29].

Mortality Inputs

Among mortality inputs, infant mortality rate and relative risk of infant mortality were based on the Vital Statistics Survey of Japan in 2021 [26]. Case fatality rate was calculated from the cases reported in 2020 [30]. As a result of lack of Japanese data, relative risk of death due to RSV was based on data from the literature and statistics from the Centers for Disease Control and Prevention [2, 31].

Intervention-Related Inputs

Maternal Vaccine

RSVpreF vaccination rate was set as 80% in scenario 1 based on the maternal vaccination rate against COVID-19 in Japan [32]. Vaccine effectiveness (VE) was estimated using the cumulative efficacy data of the pivotal phase 3 clinical trial (ClinicalTrials.gov Identifier NCT04424316) [33]. After 180 days, the VE was assumed to decrease linearly in the next 3 months until effectiveness rate reaches 0%. The VE values of RSV-positive LRTI requiring hospitalization and RSV-RTI (which includes RSV-LRTI and RSV-upper respiratory tract illnesses) for ED and outpatient settings were used for model input (Table 1). The aforementioned study was not powered to provide estimates of VE among preterm infants; therefore, the VE for preterm (32–36 wGA) was assumed to be 83.3% of the corresponding values for full-term infants (≥ 37 wGA) based on an ongoing observational sero-epidemiology study of naturally acquired RSV antibody transplacental transfer [34]. In the study, geometric mean transplacental transfer cord/maternal neutralizing antibody titer ratio for RSV A/B was reported to be 1.2 among full-term infants (≥ 37 wGA) and 1.0 among infants born at 32–36 wGA (1.0/1.2 = 83.3%). The VE values among other preterm (≤ 31 wGA) infants with risk and infants born < 2 weeks after maternal administration of RSVpreF vaccine irrespective of term status were assumed as 0% as a result of lack of evidence.

Palivizumab

Prescription rate of palivizumab among preterm infants was assumed to be 0% for 36 wGA and 90% for ≤ 35 wGA based on the literature and pediatric expert opinion [11, 12]. Thus, the weighted average 46.2% was applied for prescription rate among the preterm population (≤ 36 wGA). For the high-risk population, 95% was applied as a high prescription rate among this population was previously reported [11, 12, 25]. Palivizumab was administered six times during the peak season of RSV on the basis of the analysis of Japanese claims database [15]. Effectiveness of palivizumab was set as 56% based on systematic review [9].

Cost Inputs

Direct Costs

Direct costs included the costs of intervention (vaccine/drug costs with administration costs) and medical care. Administration costs were based on the national medical service fee points set by the Ministry of Health, Labour and Welfare [35]. As the unit cost of RSVpreF vaccine was not yet determined in Japan, a range of vaccine prices were explored from ¥5000 to ¥50,000 (US $38 to US $380). Drug prices of palivizumab per dose were obtained by dividing the mean cumulative drug costs of palivizumab by the number of admissions [15]. Medical care costs per episode in three different medical care settings were obtained through Japanese claims database analysis in 2022 [15].

Productivity Loss

Three potential sources of productivity losses were considered in the analysis: (1) the caregivers’ absence from work due to providing care to infected infants, (2) lost labor opportunities that might have been gained after maturity of the children who died of RSV infection, and (3) absence from work of pregnant women receiving maternal vaccination at a hospital visit and caregivers taking children to hospital for palivizumab administration. These productivity losses were calculated by multiplying the average daily wage and the number of working days missed. We assumed that all caregivers were in full-time employment and productivity losses due to caregiving tasks were incurred by all infants on the basis of input from a health economics expert. The number of days of parental care in ED and outpatient settings were determined on the basis of pediatric expert opinion. For hospitalized population, we added 3 days of home care in addition to average hospitalization period of 7 days [36]. For future productivity loss we assumed that a fully matured adult will be in the workforce between 18 and 64 years old and receive the average daily wage. The number of workdays lost as a result of maternal vaccination or taking infants to receive palivizumab administration was assumed 0.5 days per dose, based on input from health economics expert. As a result of lack of reference data, we assumed that productivity loss will arise in 50% of the aforementioned applicable population as no additional productivity losses shall be incurred if maternal vaccination or palivizumab administration were part of regular checkups on the basis of the discussion with an expert in health economics.

All costs were converted to US dollars using the exchange rate for 2022 provided by the Organisation for Economic Co-operation and Development (OECD; US $1 = ¥131.4) [37].

Health Utility Inputs

Baseline utility without RSV infection was set as 1.0 among infants aged 0–11 months. QALY loss due to RSV infection in each medical setting was extracted from a previous study [38]. The general population utility was set as 1.0 for 1–17-year-olds on the basis of input from a health economics expert. Utility for 18–99-year-olds was calculated on the basis of the population data of 2021 using the EuroQol 5-dimension 5-level (EQ-5D-5L) scores [39, 40]. These inputs were used to calculate future lost QALYs due to premature RSV-related mortality.

Analysis

Basic analysis for two cases was performed to analyze the impact of varying vaccine prices on ICER. One-way deterministic sensitivity analysis was performed to assess the impact of each parameter and identify key drivers for ICER other than vaccine price. The model parameters were examined at a lower and upper bound of ± 25%. For other scenarios of the sensitivity analyses, the input conditions are summarized in Table S3.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Results

ICER in Scenario 1 (Base Case Scenario) and Scenario 2

Figure 2 shows the estimated ICER with various vaccine prices (range ¥5000–50,000/US $38–380) in scenario 1 and scenario 2. From a payer perspective, the ICER remained below ¥5 million/QALY (the threshold value for Japan) when the RSVpreF vaccine price was equal to or less than ¥23,948 (US $182) in scenario 1. The combination prophylaxis (RSVpreF + palivizumab) was more effective than the current prophylaxis (palivizumab only) for preventing RSV infections, with a gain of 428.4 QALYs per population (Table 2). Incremental costs were ¥2.1 billion (US $16.3 million) and ICER was ¥4,998,847/QALY (US $38,043/QALY). From a societal perspective, incremental costs were ¥2.0 billion (US $15.1 million) and ICER was ¥4,638,509/QALY (US $35,301/QALY). On the other hand, in scenario 2, the ICER was more effective and less costly (i.e., dominant) from both payer and societal perspective at a RSVpreF vaccine price of ¥23,948 (US $182) (Table 2). In total, ¥11.0 billion (US $84.1 million) was saved from a payer perspective. The ICER continued to be below ¥5 million/QALY at a maximum RSVpreF unit cost of ¥43,881 (US $334) from a payer perspective, respectively (Table S7).

Fig. 2
figure 2

Incremental cost-effectiveness ratio with various RSVpreF vaccine price. Dynamics of ICERs for two combination prophylaxis strategies (blue, scenario 1; orange, scenario 2) upon changing the RSVpreF vaccine price were explored from a (A) payer perspective and (B) societal perspective. Exchange rate was US $1 = ¥131.4. ICER incremental cost-effectiveness ratio, RSV respiratory syncytial virus, RSVpreF vaccine RSV prefusion F protein-based vaccine, QALY quality-adjusted life year

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Table 2 Cost-effectiveness outcomes of scenario 1 and scenario 2
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Detailed Base Case Results

The detailed clinical and economic outcomes in scenario 1 are summarized in Table 3. Among the target population of 802,963 pregnant women and 813,857 newborns (preterm, 5.8%; high risk, 2.6%), 646,510 pregnant women received RSVpreF vaccine in the combination prophylaxis and 153,617 and 236,168 doses of palivizumab were prescribed to infants in the combination and current prophylaxes, respectively. The combination prophylaxis prevented 14,382 medically attended cases of RSV (hospitalization, 7490 cases; ED, 2239 cases; outpatient, 4653 cases) and 7 deaths compared with the current prophylaxis. The combination prophylaxis required additional vaccine costs of ¥17.4 billion (US $132.4 million) while reducing palivizumab costs (¥12.2 billion/US $92.6 million) and medication costs (¥3.1 billion/US $23.5 million). From a societal perspective, the combination prophylaxis resulted in a net reduction of productivity loss by ¥154.3 million/US $1.2 million (¥2.4 billion/US $18.5 million of caregiver’s productivity loss + ¥332.3 million/US $2.5 million of productivity loss due to visiting hospital for palivizumab prescription – ¥2.6 billion/US $19.8 million of productivity loss due to visiting hospital for vaccination).

Table 3 Clinical and economic outcomes of scenario 1 and scenario 2
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One-Way Sensitivity Analysis

The ICER values in one-way sensitivity analysis for scenario 1 were presented as a tornado diagram (Fig. 3). The parameters that had the greatest impact on ICER were cost of RSVpreF vaccine, cost of palivizumab, effectiveness of RSVpreF vaccine, incidence of RSV-related hospitalization, and cost of RSV-related hospitalization for both healthcare and societal perspective. Details are in Table S8.

Fig. 3
figure 3

One-way deterministic sensitivity analysis for scenario 1 from a societal perspective. Tornado diagram for the outcomes of DSA. Upon changing the value ranges of the parameter, ± 25% of each parameter was used as upper (red) and lower (blue) bounds. Input parameters are listed on the left. The analysis was conducted from a societal perspective in Japanese yen (US $1 = ¥131.4). RSVpreF vaccine price was ¥23,948 (US $182). DSA deterministic sensitivity analysis, ED emergency department, ICER incremental cost-effectiveness ratio, OC outpatient, RSV respiratory syncytial virus, RSVH RSV hospitalization, QALY quality-adjusted life year

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Other Sensitivity Analyses

Detailed other sensitivity analyses results are presented in Table 4. The weeks of pregnancy at vaccination (scenario 7), the prescription time of palivizumab per year (scenario 9), the use of palivizumab in the combination prophylaxis (scenario 10), RSV incidence (scenario 11), and productivity loss for visiting hospital for vaccination or palivizumab prescription (scenario 16) were impactful scenarios on ICER.

Table 4 Results of sensitivity analysis
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Discussion

With recent approval of RSVpreF vaccine for pregnant women in Japan [19], we undertook a new economic evaluation to examine the potential cost-effectiveness of a combination prophylaxis of RSVpreF vaccination and palivizumab prescription as a comprehensive prophylaxis program for pediatric RSV infection. Our findings suggested that the combination prophylaxis would further reduce RSV cases and deaths in comparison with the current prophylaxis using palivizumab alone. Furthermore, when the price of RSVpreF vaccine was equal to or less than ¥23,948 (US $182), we found that the combination prophylaxis would be cost-effective (scenario 1) or dominant (more effective and less costly; scenario 2). In scenario 2, a total of ¥11.0 billion (US $84.1 million) was saved from a payer perspective. This study is useful to understand the potential value of this novel vaccine and support future policy discussion to reduce the disease burden of RSV in Japan. However, our sensitivity analysis results showed that applying conditions that adequately reflect the local settings is important to make an estimate useful for policy makers to develop effective prophylaxis programs. For example, indication of RSVpreF vaccine is applicable for pregnant women at 24–36 weeks of pregnancy in Japan, but 32–36 weeks is recommended in the USA [18, 41]. However, resembling the vaccination schedule of the USA was less cost-effective in Japan (scenario 7 in sensitivity analysis). The vaccination schedule impacted the ICER as narrowing the vaccine eligibility increased unprotected cases and the incremental QALY was also reduced from 428.4 QALY to 408.1 QALY in the simulation. Analysis in the USA showed that vaccination prior/during seasonal circulation of RSV maximizes the cost-effectiveness of the maternal vaccine program [18]. We gained similar outcomes when the vaccination period was fitted to RSV seasonality (data not shown). However, seasonality of RSV changes every year in Japan [10, 29] and considering the negative impact of the mismatch of vaccination period and epidemic due to prediction failure, we consider that year-round immunization which is the condition of our base case scenarios is a safer option to stably control RSV in Japan.

As of this analysis, the Japanese guideline on the combined usage of palivizumab and RSVpreF vaccine for RSV prophylaxis has not yet been released. Thus, the conditions for combination prophylaxis used for scenario 1 are based on available clinical data. Although one-way sensitivity analysis showed that the effectiveness of the RSVpreF vaccine has a high impact on the cost-effectiveness of the combination prophylaxis, there are still uncaptured aspects of this vaccine usage. As of February 2024, there is no evidence of VE for infants with risk. Conservatively, we set the VE for infants with risk as 0% and assumed that palivizumab would be used for them even if their mothers received RSVpreF vaccine during pregnancy in scenario 1. However, the presence of risk in the infant might not impact the maternal antibody transfer from mothers to offspring whereas prematurity is one of the key factors [42, 43]. Therefore, we designed scenario 2 by assuming that palivizumab is not used for the premature born ≥ 32 wGA with/without risk if their mother received the RSVpreF vaccine. After accumulation of real-world evidence of VE, scenario 2 might be acceptable in the future. In addition to VE in the high-risk population, the evidence of VE among premature infants is also limited. Although sero-epidemiological research has revealed a certain amount of maternal antibody transferred to infants born at  ≤ 31 wGA [34], the VE for premature with ≤ 31 wGA was assumed to be 0% in this analysis. Furthermore, the VE for preterm (32–36 wGA) was assumed to be 83.3% of corresponding values for full-term (≥ 37 wGA) in this study; however, additional analysis of the phase 3 trial showed that the transferred neutralizing antibody levels of preterm infants (the majority was late preterm) were similar to those of full-term infants [44]. Potential effects of RSVpreF vaccine on pregnant women and herd effects were also not considered in this model because of lack of evidence. These ancillary features of vaccination may be worth considering in future analyses to assess the effectiveness of RSVpreF vaccine more comprehensively. The impact of combination prophylaxis such as additive synergic protection and impact on RSV cases in other populations (i.e., elderly population) due to reduced incidence among the infant population should be also monitored in future surveillance.

This study showed that RSV-related medical spending will decrease if usage of palivizumab declines, as a consequence of RSVpreF introduction. In addition to reducing costs, scenarios with fewer injections of palivizumab yield lower humanistic burden on infants and their caregivers. However, if palivizumab usage remains as the same level with the current practice, the combination prophylaxis shall simply increase costs and humanistic burden (scenario 10). Active collection of field evidence on combination prophylaxis is necessary after revising the best practice of RSV prophylaxis in Japan. In our model, RSV incidence rate is an important factor that impacts ICER, as increasing the incidence up to 1.5 times higher than scenario 1 improved the ICER in the sensitivity analysis (scenario 11). Clinically confirmed diagnosis is required for respiratory infectious diseases that have a curative medication such as seasonal influenza and COVID-19 in order to prescribe medications in Japan [45, 46]. It should be noted that RSV that lacks specific treatment is outside the scope of this clinical practice, raising the possibility of undetected RSV cases leading to underestimation of the current RSV incidence rate used as an input in this analysis.

This study has some other limitations. First, RSV infections are thought to be associated with the development of bronchial asthma and other conditions; however, reductions of bronchial asthma and other complications by RSVpreF vaccine and palivizumab were not considered as outcome measures. Secondly, adverse events of RSVpreF vaccine and palivizumab were not considered in the analysis. The impact of these limitations on the epidemiological and economic outcomes should be assessed in future cost-effectiveness analyses. Thirdly, epidemiological input values obtained before the COVID-19 pandemic (Supplemental Table 1) were used to minimize the impact of COVID-19 pandemic in this study. However, we cannot deny that these values may not accurately reflect the latest epidemiological situation. Lastly, as a result of lack of supporting evidence gained in Japan, we used data obtained in other countries for several parameters (e.g., relative risk of death due to RSV). Conducting a probabilistic sensitivity analysis (PSA) may be a potential solution to mitigate the uncertainties regarding parameters. However, given the circumstance that RSVPreF vaccine is not yet utilized in Japan and our model relies heavily on assumptions with many unknown factors, we did not conduct PSA. When real-world evidence is accumulated, reanalysis and PSA with most updated data reported from Japan shall be ideal, especially for parameters identified as critical in one-way sensitivity analysis. In addition, comparison with nirsevimab, a novel monoclonal antibody against RSV which is undergoing drug registration in Japan (as of February 2024), might be necessary upon future cost-effectiveness analysis, similar to the study conducted in Canada [47].

Conclusion

Compared with palivizumab only, a combined prophylaxis of year-round RSVpreF vaccination of pregnant women and palivizumab prescription for infants was cost-effective at the threshold value of ¥5 million/QALY when the price of RSVpreF vaccine was equal to or less than ¥23,948 (US $182). The findings in this study will be informative for future policy discussions about the inclusion of RSVpreF vaccine in clinical practice. Active surveillance of RSV is necessary to accurately capture the effect of combination prophylaxis once it is formally introduced. Further optimization of the target population for prophylaxis with palivizumab help improve the cost-effectiveness of the combined prophylaxis in the future.