Full title: Update on the cost-effectiveness of routine childhood vaccination against hepatitis A

Authors: Valcárcel Nazco C, Guirado Fuentes C, Cazaña Pérez V, Herrera Ramos E, Burgos Simón C, Villanueva Micó R

Contact person: Cristina Valcárcel Nazco (cristina.valcarcelnazco@sescs.es)

SUMMARY

Introduction

Hepatitis A (HA) is a liver disease caused by the hepatitis A virus (HAV), which is transmitted mainly via the fecal–oral route, through the ingestion of contaminated food or water or through direct contact with an infected person. Although it does not cause chronic liver disease and its mortality is low, it can present with debilitating symptoms and, in some cases, progress to fulminant hepatitis.

Worldwide, it is estimated that more than 100 million HAV infections and around 15,000 deaths occur each year, mainly in high-endemicity countries with low levels of development. In countries with better sanitary conditions, transmission is low, but the age at infection tends to shift towards later stages of life, which may increase the severity of cases.

Spain is considered a low-endemicity country, with limited circulation of HAV and a high proportion of susceptible adults. According to the second national seroprevalence survey, 88.9% of the population aged 2–19 years and 71.5% of those aged 20–49 years lack antibodies against HAV. Cases are concentrated in risk groups such as people who inject drugs, men who have sex with men, and travellers to high-endemicity areas.

Currently, systematic childhood vaccination against HAV is not included in the common immunization schedule of the Spanish National Health System (SNS), although Ceuta, Melilla and Catalonia have incorporated it into their regional programmes. In the rest of the country, a selective strategy targeting risk groups is maintained.

The Health Services Evaluation Unit of the Canary Islands Health Service (SESCS) published two Health Technology Assessment (HTA) reports in 2018 and 2020 on universal childhood vaccination against HA, concluding that it was not a cost-effective strategy in the Spanish context.

The Ministry of Health has requested an update (2025) to incorporate new scientific evidence, recent seroprevalence and epidemiological data, as well as changes in costs, duration of immunity and vaccination coverage, in order to re-evaluate the efficiency, in cost-effectiveness terms, of this strategy.

Objective

The main objective of this report is to assess the cost-effectiveness of universal childhood vaccination against HA with one or two doses in Spain, from the perspective of the SNS.

Methodology

Systematic review of cost-effectiveness

A systematic review (SR) of economic evaluations (EE) of childhood vaccination against HA was conducted, following PRISMA guidelines and Cochrane Collaboration methodology. Full economic evaluations (conducted alongside primary studies or model-based) and systematic reviews of EE were sought if they reported any of the following outcomes: incremental cost-effectiveness ratio (ICER), costs expressed in monetary units, and benefits expressed as quality-adjusted life years (QALYs), life-years gained (LYG) and/or other monetary measures.

Studies were included if they involved infant populations under 24 months of age, in low- or very-low-endemicity countries, and evaluated universal vaccination strategies against HA compared with no vaccination. Partial economic evaluations, stand-alone budget impact analyses, studies in specific risk groups or in medium- or high-endemicity countries were excluded. The methodological quality of full EE was assessed using the Drummond checklist, and that of SR of EE using the ISPOR CiCERO instrument. Data extraction was performed with double checking, and a narrative synthesis with tabulation of results was carried out.

Economic analysis

In addition, a de novo full economic evaluation was conducted as an update of the dynamic model developed in the 2020 SESCS report. Three strategies were compared: no vaccination, universal childhood vaccination with a single dose at 12 months, and universal childhood vaccination with two doses (at 12 months and before 24 months).

A deterministic dynamic transmission model of the SEIRV type (Susceptible–Exposed–Infectious–Recovered–Vaccinated) was used, with weekly cycles and a lifetime horizon, calibrated to recent incidence data (RENAVE) and seroprevalence data (2020 National Seroprevalence Study). The analysis took the perspective of the SNS, including only direct healthcare costs (outpatient cases, hospitalizations, fulminant hepatitis, liver transplantation and vaccination). Costs were expressed in 2025 euros. Health outcomes were measured in QALYs.

An annual discount rate of 3% was applied to both costs and effects. The cost-effectiveness measure used was the ICER, comparing results with willingness-to-pay (WTP) values for Spain between €22,000–€25,000/QALY and more recent estimates placing WTP in an approximate range of €27,000–€34,000/QALY. A base-case analysis was performed and deterministic scenario-based sensitivity analyses were carried out, varying key parameters (vaccine price, duration of protection, effectiveness, disutilities) and considering a simulated-incidence scenario.

Budget impact analysis

Based on the base-case cost-effectiveness analysis, a 5-year (2025–2030) budget impact analysis (BIA) was performed from the perspective of the SNS. The aim was to estimate the cost of implementing a universal childhood vaccination programme against HA in Spain, considering separately the one-dose and two-dose strategies.

The BIA included the number of children in the target vaccination age group, assumed vaccination coverage (96.7% for one dose and 94.7% for two doses), the cost of doses, as well as costs avoided due to a reduction in outpatient and hospitalized cases. Unlike the cost-effectiveness analysis, no discounting was applied in the BIA and QALYs were not considered; only total and incremental annual costs associated with programme implementation were estimated.

Results

Systematic review of cost-effectiveness

The SR did not identify any new Spanish EE that met the inclusion criteria, but it did identify two relevant international references: a SR of EE and a full EE conducted in the USA.

The review by Gurav et al. identified 43 EE of vaccination against HA across different endemicity levels, 28 of which corresponded to high-income countries, used as a proxy for low-endemicity settings. Within this subgroup, results were heterogeneous: some EE in low-endemicity settings found that universal childhood vaccination could be cost-effective, while others did not. Studies conducted in Europe (including that by Arnal et al. in Spain) tended to conclude that universal vaccination was not cost-effective in low-incidence contexts, whereas several US studies supported universal vaccination in their setting. The methodological quality of the SR, assessed using CiCERO, was high, with limitations mainly related to the absence of a systematic search of grey literature and the lack of monetary standardization of costs and ICERs across studies.

The US study by Ghildayal evaluated, using a dynamic model, universal childhood vaccination with two doses compared with no vaccination in a low-endemicity setting. From a societal perspective, the estimated ICER was 55,778 $/QALY. Approximate conversion to 2025 euros places this value above the thresholds commonly used in Spain, although transferability to the Spanish context is limited by differences in cost structures, health system organization and incidence patterns.

Results of the economic evaluation

The dynamic transmission model shows that universal childhood vaccination against HA substantially reduces the number of disease cases over time, including outpatient cases, hospitalisations, and episodes of fulminant hepatitis. This effect is notable with the one-dose strategy and greater with the two-dose strategy. However, in a low-endemicity setting such as the current situation in Spain, the absolute magnitude of the health benefits is limited.

In the base-case cost-effectiveness analysis, none of the vaccination strategies was dominant. The one-dose vaccination strategy yielded an incremental cost-effectiveness ratio (ICER) of approximately €178,000 per QALY gained compared with no vaccination, while the two-dose strategy resulted in an ICER of around €206,000 per QALY. The incremental comparison between the two-dose and one-dose strategies also showed a high ICER (approximately €241,000 per QALY). In all cases, the ICERs were well above the reference value of €34,000 per QALY, used as an approximation of the opportunity cost per QALY within the National Health System.

The deterministic sensitivity analysis indicates that the results are robust to plausible changes in model parameters. Vaccine price and duration of protection were the parameters with the greatest influence on cost-effectiveness outcomes. In scenarios characterised by a reduced vaccine price (€5.6 per dose), both vaccination strategies would be cost-effective compared with no vaccination; however, the two-dose schedule would not be cost-effective when compared with the one-dose strategy. Similarly, assuming a prolonged duration of vaccine-induced protection, the one-dose strategy could achieve cost-effectiveness levels compatible with the reference threshold, whereas the two-dose strategy would continue to show high ICERs. Specifically, when a maximum duration of protection of 28 years was assumed for one dose, the ICER was €33,650.62/QALY compared with no vaccination, below the reference value of €34,000/QALY. In a more favourable scenario, with a duration of protection of 30 years for one dose, the ICER fell to €30,332.44/QALY.

However, when a longer duration of protection was also considered for the two-dose strategy, for example 50 years, this strategy continued to show high ICERs, above the reference value considered. In the extreme scenario of lifelong protection, the ICER of the one-dose strategy decreased to €2,098.05/QALY.

Results of the budget impact analysis

From a budgetary perspective, the budget impact analysis shows that the implementation of universal childhood vaccination would lead to a net increase in healthcare expenditure in the short to medium term. Over the 2026–2030 period, the cumulative net budget impact is estimated at approximately €10.6 million for the one-dose strategy and €28.7 million for the two-dose strategy, partially offset by savings derived from the reduction in disease cases, particularly in the later years of the time horizon.

Conclusions

Based on the systematic review of cost-effectiveness evidence, the economic evaluation, and the budget impact analysis conducted for the present health technology assessment report, the following conclusions can be drawn:

• The available evidence on the cost-effectiveness of universal childhood vaccination against hepatitis A in low-endemicity settings remains limited. The most recent systematic review confirms that, in high-income countries—used as a proxy for low-transmission contexts—universal childhood vaccination does not consistently demonstrate cost-effective results. Low incidence rates and limited viral circulation are the main factors attenuating the potential benefits of the intervention.
• The single economic evaluation included in the present review reinforces this conclusion. Although universal childhood vaccination was found to be cost-effective in the United States context, the approximate conversion of the ICER to euros in Spain (€39,713.93 per QALY) exceeds the threshold commonly considered cost-effective in this country.
• The updated dynamic model is consistent with these findings, showing that under current epidemiological conditions and assuming a vaccine price of €11 per dose, universal childhood vaccination yields unfavourable cost-effectiveness results. The estimated ICERs were €177,632.41 per QALY and €206,031.02 per QALY when comparing one-dose and two-dose universal vaccination strategies, respectively, with no vaccination. The sensitivity analysis shows that the vaccine acquisition price and the duration of the protective effect are the parameters with the greatest influence on the results. In vaccine price reduction scenarios, the one-dose strategy would reach cost-effectiveness values at prices of €6 per dose or lower. Likewise, when a longer duration of protection was assumed, the one-dose strategy could also become cost-effective: with a maximum duration of protection of 28 years, the ICER was €33,650.62/QALY compared with no vaccination, below the reference value of €34,000/QALY; and with a duration of 30 years, it decreased to €30,332.44/QALY. By contrast, the two-dose strategy continued to show high ICERs in scenarios assuming longer duration of protection.
• The budget impact analysis indicates that the introduction of a universal vaccination programme would entail a substantial increase in healthcare expenditure, which would not be offset by the savings associated with avoided cases, given the current low circulation of the virus. The analysis estimates that the implementation of universal hepatitis A vaccination strategies with one and two doses would result in a cumulative five-year budget impact at the national level of €10,627,492.15 (€2,125,498.43 annually) and €28,701,711.43 (€5,740,342.29 annually), respectively.
• Overall, the reviewed evidence and the results of the updated economic model suggest that, under current conditions, universal childhood vaccination against hepatitis A would not achieve cost-effectiveness in Spain. This conclusion could change if substantial modifications were to occur in the epidemiological context (for example, a sustained increase in incidence) or in the price of the vaccine.

Keywords: Hepatitis A; Childhood vaccination; Systematic review; Economic evaluation.

 

DOCUMENTS:

1. Full report: