A hypothetical cohort framework (deterministic) and a Markov-type process were used to depict clinical outcomes and costs related to RSV infections in newborn infants from birth to 1 year of age (Fig. 1).

Schematic of the health-economic model. LYs life years, QALYs quality-adjusted life years, RSV respiratory syncytial virus

The model population was initially characterized based on gestational age at birth (weeks of gestational age; wGA). Infants were assumed to be protected against RSV due to maternal vaccination (which occurred before model entry) or were assumed to have received no intervention. Infants born to vaccinated and unvaccinated mothers fell into one of the following health states: uninfected or infected, based on RSV infection rates and vaccine effectiveness if the mother had been vaccinated. RSV cases requiring medical care were stratified by care setting (hospital, emergency department or primary care). Hospitalized patients had a certain probability of dying from the disease.

Expected outcomes were evaluated at the end of each monthly cycle through the 1-year modeling horizon, based on age, wGA at birth, disease/fatality rates (which may vary by age, wGA at birth, and calendar month), and mother’s vaccination status. The model compared the reduction in RSV-medically attended cases (hospitalizations, emergency room visits and primary care visits) and RSV-related deaths versus no intervention, the corresponding life years (LYs), quality-adjusted life years (QALYs) gained, and cost savings. An incremental cost-effectiveness ratio (ICER) was calculated, and a €25,000/QALY willingness-to-pay (WTP) threshold was set to evaluate the cost-effectiveness of maternal vaccination versus no intervention [10].

The base-case analysis reflected the NHS perspective following Spanish cost-effectiveness recommendations and included only direct medical costs (€2023). All costs and outcomes were calculated for an entire RSV season, except for QALY loss due to premature RSV-related death, which was calculated over the lifetime of the cohort and discounted at 3% per year, according to the local recommendations for economic evaluation of health technologies [11, 12]. All data inputs were validated by a panel including three Spanish pediatrician experts in RSV management.

The model was based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

The model population included liveborn infants (n = 360,633) born to 355,250 women during a 1-year period. Data were taken from the Spanish Statistics National Institute for the year 2019 [13]. Specifically, data for 2019 were used to avoid the COVID-19 pandemic influencing the epidemiology estimate, since the number of cases and the seasonality of RSV were modified during this period [14].

Liveborn infants were characterized by term status and were distributed as follows: 92.9% were born at ≥ 37 wGA (full term), 6.0% were born at 32–36 wGA (late preterm), 0.8% were born at 28–31 wGA (early preterm) and 0.3% were born at ≤ 27 wGA (extreme preterm). Births were also distributed by calendar month according to Spanish data for 2019 [14].

Annual incidence rates of RSV by month of age and by care setting (i.e., hospital, emergency department, and primary care) were obtained from the retrospective observational study BARI (Burden of Acute Respiratory Infections) conducted in Spain (Table 1) [15]. The authors of the BARI study estimated RSV incidence considering both RSV-specific ICD-10 codes and unspecified ALRI cases, based on evidence that this broader definition improves sensitivity without sacrificing specificity [15].

Age-specific relative rates of RSV by term status were applied based on the study by Rha 2020., which reported cases by gestational age at birth and chronologic age at infection (Supplementary Material Table S1) [16]. Rates of RSV were allocated across calendar months using data from ISCIII (Carlos III Health Institute; Supplementary Material Table S2) [17].

Maternal immunization was implemented as a year-round program, in line with the strategy in the MATISSE trial. The vaccination coverage was estimated to be 70%, calculated as an intermediate value between the coverage observed in 2022 in pregnant women against Tdap (86%) and the coverage in pregnant women for influenza (53%), according to the Spanish Vaccination Information System of the Ministry of Health [18].

The distribution of RSVpreF administration by fetal wGA was based on a US observational study on maternal Tdap [19] and adjusted according to approved indication (administration between weeks 24 and 36 of gestation) [8] (Table 2).

Setting-specific vaccine effectiveness (VE) estimates were derived using the cumulative efficacy data (at 90, 120, 150, and 180 days) for the co-primary endpoints from MATISSE [9]. Efficacy against severe RSV-positive medically attended ALRI was used as a proxy for VE against RSV cases requiring hospitalization, and efficacy against RSV-positive medically attended ALRI was used as a proxy for VE against RSV cases treated in the emergency department or primary care setting. For full-term infants, VE by single month of age was derived by fitting a line to the cumulative efficacy datapoints from MATISSE and deriving marginal monthly estimates through age 5 to < 6 months. VE was then assumed to wane linearly to 0% by age 9 to < 10 months (Fig. 2).

Vaccine effectiveness against a RSV-LRTI requiring hospitalization for infants born ≥ 2 weeks after administration of maternal vaccine; b RSV-LRTI treated in ED or PC for infants born ≥ 2 weeks after administration of maternal vaccine. ED emergency department, PC primary care, RSV respiratory syncytial virus

MATISSE was not powered to provide estimates of efficacy among preterm infants; therefore, VE for late preterm infants was assumed to be 83.3% of corresponding values for full-term infants based on an ongoing observational seroepidemiology study of naturally acquired RSV antibody transplacental transfer [20]. In this study (n = 300 mother-infants), the transplacental transfer neutralizing antibody titer ratio (GMT CMR) was evaluated for RSV A/B. GMR was reported to be 1.2 among full-term infants and 1.0 among infants born at 32 to < 37 wGA (1.0/1.2 = 83.3%). VE among early and extreme preterm infants was assumed to be 0% (Fig. 2). For infants born < 2 weeks after maternal administration of RSVpreF, irrespective of term status, VE was conservatively assumed to be 0%, as early delivery was associated with low transfer [8].

Lacking robust estimates of healthy infant utility values, utility was assumed to be 1 for infants without RSV. For infants who experience RSV, utility value during the period of illness (14 days, irrespective of care setting) was 0.59 for infants treated in hospital and 0.84 for infants treated in outpatient settings based on Roy 2013 [21]. QALY loss was thus estimated to be 0.0157 for infants who are hospitalized and 0.0061 for outpatient cases [21]. QALY losses were assumed to be invariant by term status.

Utility values for persons aged ≥ 1 year (i.e., for use in quantifying the lifetime impact of RSV) were based on the reference population norms of the Spanish population obtained using the EQ-5D-5L instrument [22]. For children aged 1–15 years, utility values were estimated by linearly interpolating between values for children aged < 1 year and > 15 years.

Both infant mortality due to general causes and mortality due to RSV were considered to calculate the mortality of the population included in the model. The infant mortality rate in the general population was obtained from the data published by the Spanish Statistics National Institute for deaths in children under 1 year of age for 2019 [13] (Supplementary Material Table S3). These rates were then adjusted by applying a relative risk (RR) of age-specific infant mortality by subgroup of wGA at birth: RR of 6.3 for late preterm, 42.0 for early preterm, and 144.0 for extreme preterm infants [23].

The RSV-associated mortality was based on the mean in-hospital case-fatality rate of 0.14% observed in the BARI study [1]. This rate was adjusted by applying a RR of 12.9 for preterm infants (irrespective of wGA subgroup) [1]. Due to the absence of data, infants with RSV treated in the outpatient setting were conservatively assumed not to be at risk of disease-related death.

In the base-case analysis from the NHS perspective, only the direct medical costs of vaccination and disease events were considered (Table 3). The cost of an episode requiring hospitalization was extracted from an observational study employing Spanish Minimum Basic Data Set (MBDS) [5], while the cost for both emergency department and primary care events were extracted from the BARI study [15], which does not distinguish by wGA at birth, so the same cost for each subgroup was assumed.

For the vaccine, the list price was obtained from the Spanish Official College of Pharmacists database and discounted by a 7.5% according to the RDL 8/2010 national law decree [24]. A 6€ cost of administration was considered per injection [25]. All costs were adjusted to 2023 prices [26].

To assess the robustness of the results, two sensitivity analyses were performed: a one-way deterministic sensitivity analysis (DSA) to determine which variable had the greatest impact on cost-effectiveness results individually, and a probabilistic sensitivity analysis (PSA), which assessed the level of uncertainty of the variables in combination within the model. DSA was performed by varying disease incidence, vaccine effectiveness, mortality, utilities, and costs by ± 25%. Finally, results were compared to the base-case in a tornado diagram. The PSA was performed using Monte Carlo simulation with 1000 iterations, each selecting the input parameter values from a specified probability distribution. Supplementary Material Table S4 reports the variables included in the PSA, the form of distribution used for sampling and the parameters of the distribution.

The base-case analysis was modified to evaluate the impact of reduced vaccine coverage to account for the variability in vaccination uptake across the different Spanish regions, considering a reduced vaccine coverage of 50%. Moreover, we performed an alternative scenario assuming vaccine effectiveness to wane linearly to 0% by age 12 months, to test the assumption of no vaccine effect beyond 10 months.

Additionally, alternative scenarios with different cost assumptions and from the societal perspective were performed. Given that vaccine administration may occur during a routine pre-natal obstetric appointment or be co-administered with another vaccine at the same visit, an alternative scenario with a lower cost of administration (€1.43) was considered. A scenario with an alternative vaccine price was also conducted to assess the variability in costs between different regions, decreasing the vaccine price in the base-case by 5%. In addition, a €21,000/QALY WTP threshold was set as an alternative scenario.

To build the alternative scenario from the societal perspective, the non-healthcare indirect cost of caregiver productivity loss due to an RSV-hospitalization event was estimated, assuming that infants with an RSV infection would receive care throughout the duration of illness from one parent. The cost was calculated considering the mean cost of a lost day of work (€185.76 [27]) together with the probability that both parents are working and one needs to take time off (59% × 59% = 35%) [28, 29]; and assuming conservatively that the number of workdays lost due to RSV was the same as the average hospitalization length of stay per RSV event considering people work 5 days a week on average (i.e., work loss was estimated by multiplying episode length by 5/7). Considering that in Spain the length of maternity leave is 16 weeks, caregiver work loss days were considered only for infants ≥ 5 months, estimated as 1.9 in children 3 to < 6 months and 3.4 in children 6 to < 12 months.