Cost-utility analysis of pre-exposure prophylaxis rabies vaccine in 5-year-old children in Thailand

Abstract

Introduction

Rabies remains a life-threatening disease affecting children in endemic regions including Thailand. The cost-effectiveness of pre-exposure prophylaxis (PrEP) rabies vaccination in the Thai context is unclear. This study analysed the cost-utility of adding PrEP rabies vaccination to post-exposure prophylaxis (PEP) rabies vaccination compared with PEP alone in 5-year-old children.

Methods

A decision tree model compared eight strategies (four PEP alone and four PrEP+PEP), classified by route of administration (intradermal (ID) or intramuscular (IM)) and vaccine product (purified chick embryo cell vaccine (PCEC) or chromatographically purified Vero cell vaccine (CPRV)/purified Vero cell rabies vaccine (PVRV)). Costs and outcomes were derived from published literature and discounted at 3% annually. The analysis was conducted from a societal perspective over a 20-year horizon. Incremental cost-effectiveness ratios (ICERs) were evaluated against Thailand’s willingness-to-pay threshold of THB 160 000 per quality-adjusted life year (QALY).

Results

PrEP+PEP ID using PCEC was cost-effective, with an ICER of THB 40 977 (US$1160.8) per QALY versus PEP alone ID using PCEC; the remaining strategies were dominated. The one-way sensitivity analysis identified annual bite incidence as the most influential parameter, with the ICER ranging from cost-saving to not cost-effective (THB 454 265 (US$12 868.7) per QALY). The results were robust to variation in all other parameters.

Conclusion

PrEP+PEP ID using PCEC is cost-effective for children in Thailand, reducing reliance on equine rabies immunoglobulin and disease-related QALY losses. These findings support integrating PrEP into Thailand’s National Immunization Program for children in high-risk areas, prioritising early vaccination in high-risk populations to advance the goal of eliminating rabies by 2030.

WHAT IS ALREADY KNOWN ON THIS TOPIC.

• Pre-exposure prophylaxis (PrEP) rabies vaccine is not included in the Thailand National Immunization Program, and there is no economic evaluation of the PrEP rabies vaccine in children in Thailand.

WHAT THIS STUDY ADDS

• The study found that the PrEP with post-exposure prophylaxis (PEP) rabies vaccine administered intradermally using purified chick embryo cell vaccine is cost-effective under Thailand’s willingness-to-pay threshold of THB 160 000 per quality-adjusted life years in Thailand.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• This study supports the inclusion of PrEP rabies vaccine in the Thailand National Immunization Program, aligning with the WHO’s global strategy to zero human deaths from dog-mediated rabies by 2030.

Introduction

Rabies, also known as hydrophobia, is a fatal disease caused by infection with the rabies virus (Lyssavirus) in the family Rhabdoviridae.¹ The infection occurs through bites or scratches from rabid animals, particularly transmitting the virus through their saliva. Even though rabies is fatal, it is preventable by rabies biologics. However, once patients are infected with the rabies virus, it replicates and spreads through the central nervous system, leading to neurological symptoms. The incubation period for the virus is typically 2–3 months but can vary among individuals from 5 days up to several years.² The symptoms of rabies include fever, headache, influenza-like symptoms and neurological symptoms such as abnormal brain function, agitation, confusion and hydrophobia.³ After rabies-infected patients develop symptoms, the patients will have an almost 100% chance of death occurring within 10 days of symptom onset.⁴ Therefore, in 2015, the WHO called for collaboration among Southeast Asian countries to reduce the incidence of rabies and achieve rabies-free status by 2030.^{4 5}

In 2017, approximately 59 000 deaths worldwide were attributed to rabies.^{2 6} Despite efforts to control the disease, rabies remains prevalent, particularly in low- to middle-income countries in Asia and Africa, where access to treatment and widespread vaccination of domestic dogs are lacking.⁶ On the other hand, several countries have declared rabies-free for domestic animals, but cases of rabies still occur due to wildlife and imported animals.⁷ Thailand is among the countries where rabies is endemic, with both animal and human rabies cases, and is classified as a country with a high risk of rabies by the WHO.⁸ Although nationwide rabies exposure data are limited, a surveillance study in Eastern Thailand reported an adjusted suspected rabies exposure rate of 204.2 per 100 000 population in 2015, indicating an ongoing burden of rabies exposure.⁹ Rabies has been a notifiable disease in Thailand since 1980, with 370 cases of human rabies reported that year.¹⁰ Reported human rabies cases in Thailand have markedly decreased over the past decades, declining from 185 cases in 1990 to 50 in 2000, and to 15 in 2010. A comparable reduction was observed in animal rabies cases during the same period, with reported cases decreasing from 2939 in 1995 to 1181 in 2000, and further to 249 cases in 2010. Despite this substantial decline, animal rabies cases began to increase again after 2013, reaching 1105 cases in 2018, which caused 18 human rabies deaths in 2018, the highest number in a decade.⁷ Consistently, the recent report from the Department of Disease Control, Ministry of Public Health showed seven human rabies deaths in 2025.¹¹ Moreover, the recent systematic review in 2025 reported that the pooled prevalence of rabies in tested animals in Thailand is 21.8% (95% CI 15.5% to 28.0%).¹² This has intensified efforts to prevent and control rabies, resulting in significantly reduced rabies-related deaths in subsequent years.¹³

Rabies prevention relies on the effective use of pre-exposure prophylaxis (PrEP) rabies vaccine, post-exposure prophylaxis (PEP) rabies vaccine and rabies immunoglobulin (RIG).¹⁴ The PrEP rabies vaccines involve administering a series of vaccines before exposure to rabies, offering immunological memory response and significantly reducing the complexity and cost of PEP following exposure.^15–17 The PEP rabies vaccines, administered after a suspected rabies exposure, are effective in preventing disease onset if initiated promptly and completed as recommended.⁴ For severe wounds classified as category III exposure by WHO, RIG is provided alongside PEP rabies vaccines to deliver immediate passive immunity by neutralising the virus at the wound site before the vaccine-induced immune response develops.^{4 14} These interventions ensure a robust defence against rabies, especially in high-risk populations, highlighting the critical role of vaccines and timely treatment in rabies control programmes.^{2 4 14}

Rabies is also a significant issue in children. According to data from the WHO, 40% of those infected with rabies are children under 15 years old.² This aligns with data in Thailand, where the majority of rabies-infected individuals are children under 15 years old.^{9 16} Children are at high risk of rabies infection because they are often bitten on the head and face with serious wounds, resulting in shorter incubation periods and higher infection rates than other areas. Although vaccination and RIG treatment are effective in children, there have been reports of treatment failure due to inappropriate administration of immunoglobulin in children.¹⁸ Therefore, children are considered a priority population for rabies PrEP because of their increased risk of animal bites and rabies exposure. The WHO recommends PrEP in endemic settings where exposure risk is elevated and access to timely and appropriate PEP may be limited, with implementation guided by local epidemiology, such as dog-bite incidence.^{2 4 14} Although nationwide annual bite incidence data in Thailand are unavailable and may be lower than the >5% threshold for universal PrEP recommendations,^{2 14} rabies cases remain highly concentrated in specific areas of the country and not uniformly distributed across the country.¹⁹ A Bayesian spatial analysis of rabies cases from 2012 to 2017 identified marked geographical variation in rabies risk across Thailand.²⁰ In addition, an epidemiological study conducted in eastern Thailand reported low adherence to complete PEP rabies vaccination, with only 15.8% adherence among individuals receiving intramuscular regimens and 46.5% adherence among those receiving intradermal regimens.⁹ Therefore, the Thai Red Cross Society supports PrEP rabies vaccination for people at high risk of rabies exposure, for example, children living in areas with abundant stray dogs and cats.⁴

Currently, rabies vaccines have not yet been included in the Thailand National Immunization Program (NIP) for children. As a result, PrEP rabies vaccination is primarily limited to high-risk groups or individuals able to afford out-of-pocket payment. According to the clinical practice guidelines issued by the Department of Disease Control and the Thai Red Cross Society,^{4 21} the estimated vaccine cost per course ranged from THB 126–631 (US$3.6–17.9) for PrEP and THB 253–1578 (US$7.2–44.7) for PEP, depending on vaccine type and route of administration. In category III exposure, additional administration of RIG may further increase treatment costs, reaching approximately THB 5600 (US$158.6) for a 10 mL course. Moreover, the inappropriate use of RIG in category III exposure is also a key concern. A retrospective descriptive study of children in Türkiye reported that only 14.6% received RIG appropriately, which could lead to failure in rabies prevention.²² These suggest that broader PrEP implementation may potentially reduce the burden of rabies in Thailand.

To consider the inclusion of PrEP rabies vaccine in Thailand’s NIP, an economic evaluation study of the PrEP rabies vaccine to demonstrate value for money invested is required to support policymakers’ decision-making. Nevertheless, there are currently no economic evaluation studies of the PrEP rabies vaccine in children conducted in the context of Thailand. Therefore, this study aimed to evaluate the cost-utility of adding PrEP rabies vaccination to PEP compared with PEP rabies vaccination alone in 5-year-old Thai children and estimate the budget impact when including PrEP rabies vaccines in Thailand NIP for children. We expected that the results of this study can support policymakers’ decision-making of vaccine selection to be listed in Thailand NIP and help estimate a budget impact if the vaccines are to be listed in Thailand NIP.

Methods

We conducted a cost-utility analysis of the PrEP rabies vaccines in combination with PEP rabies vaccines compared with the PEP rabies vaccine alone among 5-year-old children in Thailand. The health outcome was measured as quality-adjusted life years (QALY). The analysis was performed from a societal perspective. Additionally, the willingness-to-pay (WTP) threshold in Thailand was THB 160 000 (US$4532.6) per QALY. A detailed health economic analysis plan was developed before data analysis. The plan, provided in the online supplemental material, was followed throughout the analysis to ensure methodological transparency and reduce analytic bias. Moreover, we reported this economic evaluation following the Consolidated Health Economic Evaluation Reporting Standards 2022 statement.²³

Model structure

The decision tree model was applied to move the cohort to each health state. We adopted a decision tree model of children at risk of rabies exposure from studies by Quiambao et al and Royal et al.^{24 25} The model presents two policy choices: (1) giving the PrEP rabies vaccines for the children at risk of rabies exposure followed by PEP rabies vaccines (PrEP+PEP) or (2) no PrEP rabies vaccine with only PEP rabies vaccines administered (PEP alone). Subsequently, if patients were bitten or exposed to rabies, they received treatment according to the clinical practice guideline for rabies issued by the Department of Disease Control, Ministry of Public Health of Thailand and Thai Red Cross Society’s guidelines following the WHO recommendations.^{4 14 21} Patients with prior pre-exposure rabies prophylaxis were assumed to require only two booster doses of PEP rabies vaccine without RIG, regardless of exposure severity. In contrast, individuals without pre-exposure rabies prophylaxis would receive a full course of PEP, four doses for intradermal administration and five doses for intramuscular administration, along with RIG for category III exposures. The decision tree model was reviewed by clinicians and is presented in figure 1.

Figure 1.

Decision tree model. PEP, post-exposure prophylaxis; PrEP, pre-exposure prophylaxis; RIG, rabies immunoglobulin.

A cohort of Thai children was assigned to the model with a 20-year time horizon because a published study demonstrated that subjects previously vaccinated with PrEP rabies vaccines for up to 20 years had rabies-neutralising antibodies above the WHO 0.5 IU/mL protective threshold after receiving PEP booster doses.¹⁷ The starting age of the Thai children cohort is 5 years old because children between 5 and 14 years old are frequent victims according to the WHO and previous economic evaluation in the Philippines.^{25 26} It is also consistent with the starting age reported in the previously published study on the economic evaluation of PrEP rabies vaccines in children in the Philippines.²⁵ In this study, the cycle length was 1 year. All rabies-free children from the previous year were re-entered into the model until they were infected or until the 20-year time horizon ended.

Vaccine and RIG schedule

We compared eight strategies based on the clinical practice guideline for rabies issued by the Department of Disease Control, Ministry of Public Health of Thailand and Thai Red Cross Society’s guidelines following the WHO recommendations.^{4 14 21} These strategies defined by the combination of three factors: (1) receipt of PrEP rabies vaccine (PrEP+PEP vs PEP alone); (2) route of administration (intradermal (ID) vs intramuscular (IM)); and (3) vaccine product, which determines vial size (purified chick embryo cell vaccine (PCEC), 1 mL/vial; or chromatographically purified Vero cell vaccine (CPRV) and purified Vero cell rabies vaccine (PVRV), 0.5 mL/vial). These factors led to four strategies of PEP alone regimen (strategy 1–4) and four strategies of PrEP+PEP regimen (strategy 5–8). All strategies are summarised in table 1.

Table 1.

Vaccine schedule for all strategies

Strategy	Receipt of PrEP	Route of administration	Vaccine product	PrEP regimen	PEP regimen
1	PEP alone	ID	PCEC (1 mL/vial)	–	0.1 mL×2 sites, Day 0, 3, 7, 28 or 30 (TRC-ID, 2–2-2-0-2)
2	PEP alone	ID	CPRV/PVRV (0.5 mL/vial)	–	0.1 mL×2 sites Day 0, 3, 7, 28 or 30 (TRC-ID, 2-2-2-0-2)
3	PEP alone	IM	CPRV/PVRV (0.5 mL/vial)	–	0.5 mL Day 0, 3, 7, 14, 28 or 30 (ESSEN, 1-1-1-1-1)
4	PEP alone	IM	PCEC (1 mL/vial)	–	1 mL Day 0, 3, 7, 14, 28 or 30 (ESSEN, 1-1-1-1-1)
5	PrEP+PEP	ID	PCEC (1 mL/vial)	0.1 mL×2 sites Day 0 and 7, or Day 0 and 21, or Day 0 and 28	0.1 mL×1 site Day 0 and 3
6	PrEP+PEP	ID	CPRV/PVRV (0.5 mL/vial)	0.1 mL×2 sites Day 0 and 7, or Day 0 and 21, or Day 0 and 28	0.1 mL×1 site Day 0 and 3
7	PrEP+PEP	IM	CPRV/PVRV (0.5 mL/vial)	0.5 mL Day 0 and 7	0.5 mL Day 0 and 3
8	PrEP+PEP	IM	PCEC (1 mL/vial)	1 mL Day 0 and 7	1 mL Day 0 and 3

CPRV, chromatographically purified Vero cell vaccine; ESSEN, standard intramuscular regimen; ID, intradermal; IM, intramuscular; PCEC, purified chick embryo cell vaccine; PEP, post-exposure prophylaxis; PrEP, pre-exposure prophylaxis; PVRV, purified Vero cell rabies vaccine; TRC-ID, modified Thai Red Cross-Intradermal.

Additionally, the management for individuals with rabies exposure at the WHO Category III level involved RIG administering as soon as possible on the first day along with the PEP rabies vaccine, but not after day 7 of the initial vaccine dose. RIG should be injected specifically at and around the wound(s) without exceeding the recommended dosage based on the patient’s weight (40 IU/kg for highly purified equine rabies immunoglobulin (eRIG)). The dosing of the intervention and the comparators were based on the current treatment guidelines for rabies from the Department of Disease Control, Ministry of Public Health of Thailand and Thai Red Cross Society’s guidelines.^{4 21}

Model inputs

The input parameters included epidemiological data, access to PEP treatment after rabies exposure, the probability of developing rabies and compliance, which were obtained through a literature review. In cases where certain input parameters could not be identified through literature review, the expert opinions were used to derive these parameters. The input parameters are demonstrated in online supplemental table 1.

Annual bite incidence

The annual incidence of animal bites among children was 1790 per 100 000 population in the base-case analysis derived from a Thai cross-sectional study in which 23.6% of children aged 1–15 years reported at least one previous mammalian bite.²⁷ Due to the absence of annual bite incidence data in Thailand, this represented the most relevant estimate available for the target population. For sensitivity analyses, a lower bound for annual bite incidence of 189.7 per 100 000 population among patients aged 0–15 years was obtained from a voluntary, hospital-based rabies exposure and PEP surveillance system in Eastern Thailand in 2015. Because this estimate is restricted to healthcare-seeking cases and may underestimate the true incidence in the community, it was treated as a lower bound in this study.⁹ An upper bound for annual bite incidence of 14 600 per 100 000 population was obtained from a prospective study of children in a rural, rabies-endemic setting in Cambodia, which represents the bite incidence in rural communities like those in Thailand.²⁸ While not directly representative of the Thai population, this estimate was considered a plausible upper bound because community-based active follow-up is more likely to capture bite events that may be missed by routine healthcare-based surveillance, which could reflect uncertainty surrounding the true incidence of animal bites when Thai community-based incidence data were absent.

Probability that the exposure is from a rabid animal

Since no Thai data directly reported the probability of exposure from a rabid animal, we derived this parameter from laboratory surveillance records of the national animal rabies surveillance system from Thai Rabies Net, Department of Livestock Development. Annual laboratory-confirmed positivity rates over ten years yielded a base-case value of 4.92% in 2025 (data from 1 January 2025 through 2 July 2025), with a lower bound of 3.3% in 2020 and an upper bound of 15.4% in 2018.^{7 29}

Distribution of categories of exposure

The distribution of bite exposures across WHO categories was derived from a Thai retrospective cohort study conducted at the QSMI animal bite clinic from 1 January 2000 to 30 April 2002, in which 3.6% of bites were classified as category 1, 17.5% as category 2 and 78.9% as category 3.³⁰

Vaccine efficacy and probability of developing rabies after exposure

For the rabies vaccine efficacy, WHO defines a rabies virus neutralising antibody (RVNA) titre of ≥0.5 IU/mL as the threshold for an adequate immune response.¹⁴ Modern cell culture rabies vaccines achieve this threshold when administered via either the intradermal or intramuscular route according to the recommended regimens.^{14 31} In this study, the probability of developing rabies depended on the exposure category, rabies status of the animal and adherence to PEP. For all bites caused by non-rabid healthy animals, the probability of developing rabies is zero. Consistently, category I exposure from rabid animals was classified as no exposure. Therefore, the probability of developing rabies in category I exposure from rabid animals was set to be zero in this study.^{14 32} For category II and III exposures from rabid animals, PEP-compliant individuals were assumed to have zero probability of developing.³³ Similarly, individuals previously immunised with PrEP who fully adhered to the recommended PEP booster regimen were assumed to have no risk of developing rabies.² In contrast, for category II and III exposures from rabid animals in which PEP was not received or incompletely received, the probability of developing rabies was 19% according to published literature.³⁴

Seeking for PEP after exposure

The probability of seeking PEP following a probable rabid-animal exposure was set at 75%, derived from contact tracing in the Serengeti and Ngorongoro districts of Tanzania, where 25% of probable rabies-exposed persons (418 of 1655) did not seek care.³⁵ Therefore, the probability of seeking PEP after exposure in this study is 75%. This parameter was varied between 55% and 95% (±20 percentage points) in one-way sensitivity analysis.

PEP compliance

PEP compliance was defined as completion of the full rabies vaccination course according to the schedules recommended by the Department of Disease Control, Ministry of Public Health of Thailand and Thai Red Cross Society’s guidelines following the WHO recommendations.^{4 14 21} Route-specific compliance estimates for bite victims without prior PrEP were derived from an epidemiological study in Eastern Thailand,⁹ which reported complete on-schedule PEP compliance in 46.5% of individuals receiving intradermal PEP and in 15.8% of those receiving intramuscular PEP. Individuals in the PEP alone arm who failed to complete PEP on schedule were assumed to receive no more than the first two doses of the PEP regimen. This assumption was based on immunogenicity studies demonstrating that RVNA titres exceeding the WHO protective threshold of 0.5 IU/mL are generally achieved by day 14 only after completion of vaccine doses administered on days 0, 3 and 7 using standard ID or IM regimens.^36–40 In the PrEP+PEP arm, individuals who failed to complete the recommended booster regimen after exposure were assumed to have received only one booster dose, whereas compliant individuals completed the recommended two-dose booster regimen. This assumption was supported by evidence showing that two-dose booster regimens in previously vaccinated individuals produce more consistent neutralising antibody responses than single-dose boosters.⁴¹

Model assumptions

It was assumed that patients experiencing category III rabies exposures would have 100% access to eRIG. Additionally, for the PrEP group, compliance with the PEP booster regimen was assumed to be 90% according to the study in the Philippines.⁴²

Costs

Costs included direct medical costs and direct non-medical costs. Direct medical costs included vaccine costs, RIG costs, medical service costs, outpatient treatment costs and hospitalisation costs for patients exhibiting symptoms of rabies. Direct non-medical costs included patient and family travel and food expenses to the hospital. For direct medical costs, the vaccine cost was obtained from the Drug and Medical Supply Information Center (DMSIC).⁴³ Other direct medical costs and direct non-medical costs were derived from the standard cost lists for health economic evaluation in Thailand.⁴⁴ All costs were adjusted to 2024 value by the consumer price index and reported in US dollars based on Thailand’s official exchange rate of THB 35.3 per US$1, according to the World Bank Group.⁴⁵ Moreover, the costs were discounted at 3% annually, according to the Guideline for Health Technology Assessment in Thailand.⁴⁶ All costs are demonstrated in online supplemental table 2.

Quality-adjusted life year

We applied the QALY calculation from Quiambao et al.²⁵ The loss of QALYs during the symptomatic phase of rabies infection was excluded from the analysis due to the brief duration of this stage. Instead, QALY losses were estimated based on premature death, calculated as the difference between the health-adjusted life expectancy at birth, as reported by the WHO, and the age at which patients were infected with rabies. The QALYs as a health outcome were discounted at 3% annually, according to the Guideline for Health Technology Assessment in Thailand.⁴⁶

Base-case analysis

All strategies were assessed using a fully incremental analysis for the base-case analysis. The results were reported in an incremental cost-effectiveness ratio (ICER), defined as the cost per QALY saved.

Sensitivity analyses

One-way sensitivity analysis was used to analyse variables affecting changes in ICER values, presented in a Tornado diagram. Probabilistic sensitivity analysis was also conducted to assess uncertainty by simultaneously varying all relevant variables 10 000 times and calculating the average ICER. Results were presented using incremental cost-effectiveness scatterplots and cost-effectiveness acceptability curves (CEAC).

Budget impact analysis

A cohort-based budget impact analysis (BIA) was conducted from the payer perspective over a 5-year time horizon to estimate the direct medical costs of each rabies vaccination strategy for children residing in high-risk communities in Thai provinces that report animal rabies cases through national surveillance systems. An open-cohort approach was adopted, whereby a new cohort of eligible 5-year-old children entered the programme each year. The annual number of eligible children was derived from the registered population of 5 year olds in Thailand’s Official statistics registration systems.⁴⁷ The eligible provinces were defined as those reporting the five highest proportions of rabies-positive animal samples in the national surveillance report in 2025, including Kamphaeng Phet, Rayong, Loei, Nakhon Si Thammarat, Chachoengsao, Samut Prakan, Nakhon Ratchasima and Chonburi.¹⁹ The size of each annual cohort was assumed to remain constant throughout the 5-year analytic horizon. Access to PrEP rabies vaccination was assumed to increase from 20% in year 1 to 100% in year 5. The BIA was based on the same decision-analytic model used in the cost-utility analysis and therefore incorporated the same epidemiological parameters, clinical pathways and mortality assumptions. Annual costs were estimated from rabies vaccine, RIG and administration costs, the cost of treating symptomatic rabies, and other direct medical costs. Budget impact was reported as the annual and 5-year cumulative direct medical costs of each strategy.

Scenario analysis

A scenario analysis was conducted to quantify how variation in compliance influences the cost-effectiveness of PrEP and PEP rabies vaccination strategies. Three compliance-related parameters were varied: compliance with the PEP booster regimen in the PrEP+PEP arm (80–100%), compliance with PEP alone administered intradermally (36.5–56.5%) and compliance with PEP alone administered intramuscularly (5.8–25.8%). Two scenarios were analysed: a poor-compliance scenario, applying the lower bound of each parameter, and a good-compliance scenario, applying the upper bound.

Patient and public involvement

Patients or the public were not involved in the design, or conduct, or reporting or dissemination plans of our research.

Ethical statement

The ethical approval is not required for this study.

Results

Base-case analysis

In the base-case analysis, strategy 1 (PEP alone ID using PCEC) remained the least costly option, with a total cost of THB 656 (US$18.6) per child, and it was used as a reference for the fully incremental analysis. Strategy 2–4 were found to be dominated by strategy 1 because they cost higher without additional health outcome benefits. Strategy 5 (PrEP+PEP ID using PCEC) was associated with a total cost of THB 2033 (US$57.6) per child. Strategy 5 reduced QALY loss from 0.1012 to 0.0676 when compared with strategy 1, resulting in an incremental QALY of 0.0336. The incremental cost of strategy 5 was THB 1377 (US$39.0), leading to an ICER of THB 40 977 (US$1160.8) per QALY. This ICER was below the WTP threshold of THB 160 000 per QALY in Thailand, indicating that strategy 5 was cost-effective. On the other hand, strategy 6–8 were dominated by strategy 5. The results of the base-case analysis are outlined in table 2.

Table 2.

Base-case results

Strategy	Cost in THB (US$)	Life-years (LY)	QALYs loss	Incremental cost in THB (US$)	Incremental LY	Incremental QALY loss	ICER per LY in THB (US$)	ICER per QALY saved in THB (US$)
1 (PEP ID using PCEC)	656 (18.6)	15.77	0.1012	Reference
2 (PEP ID using CPRV/PVRV)	688 (19.5)	15.77	0.1012	Dominated
3 (PEP IM using CPRV/PVRV)	746 (21.1)	15.77	0.1370	Dominated
4 (PEP IM using PCEC)	758 (21.5)	15.77	0.1370	Dominated
5 (PrEP+PEP ID using PCEC)	2033 (57.6)	15.78	0.0676	1377 (39.0)	0.0082	0.0336	167 638 (4748.9)	40 977 (1160.8)
6 (PrEP+PEP ID using CPRV/PVRV)	2151 (60.9)	15.78	0.0676	Dominated
7 (PrEP+PEP IM using CPRV/PVRV)	2595 (73.5)	15.78	0.0676	Dominated
8 (PrEP+PEP IM using PCEC)	2648 (75.0)	15.78	0.0676	Dominated

CPRV, chromatographically purified Vero cell vaccine; ID, intradermal; IM, intramuscular; LY, life year; PCEC, purified chick embryo cell vaccine; PEP, Post exposure prophylaxis; PrEP, pre-exposure prophylaxis; PVRV, purified Vero cell rabies vaccine; QALY, quality-adjusted life year; THB, Thai Baht; US$, United States dollar.

Sensitivity analyses

The one-way sensitivity analysis, shown in figure 2, revealed that annual bite incidence was the most influential factor affecting the ICER. With variations of annual bite incidence from 0.19% to 14.6%, the ICER ranged from cost-saving to not cost-effective (THB 454 265 (US$12 868.7) per QALY). In contrast, other input parameters can cause variation in ICER values, but the ICER values remain cost-effective across all parameters. These findings highlight the critical importance of accurately estimating annual bite incidence in Thailand to ensure robust economic evaluations of rabies prevention strategies and identify specific areas with high rates of rabies exposure in Thailand.

Figure 2.

Tornado diagram. eRIG, equine rabies immunoglobulin; PEP, post-exposure prophylaxis; PrEP, pre-exposure prophylaxis.

The probabilistic sensitivity analysis indicated that at the WTP threshold of 160 000 Thai Baht per QALY, the strategy 5 (PrEP+PEP ID using PCEC) is 17.7% likely to be cost-effective. The results of the probabilistic sensitivity analysis were shown in incremental cost-effectiveness scatterplot and CEAC in online supplemental figure 1 and online supplemental figure 2, respectively.

Budget impact analysis

The total population of 5-year-old children across all included high-risk provinces was 89 710. The PrEP+PEP rabies vaccination increased the budget impact compared with PEP alone. The 5-year cumulative direct medical costs of PEP-alone strategies (Strategies 1–4) ranged from THB 40.1–51.1 million (US$1.14–1.45 million), while PrEP+PEP strategies (Strategies 5–8) cost THB 312.4–458.6 million (US$8.85–12.99 million). Within each group, the ID route was less costly than the IM route, and PCEC was less costly than CPRV/PVRV. The lowest-cost PrEP+PEP option was strategy 5 (PrEP+PEP ID using PCEC) at THB 312.4 million (US$8.85 million) over 5 years. The budget impact for the base-case analysis is presented in table 3.

Table 3.

Budget impact analysis of direct medical costs in the base-case analysis, presented in million THB (million US$ in parentheses)

Strategy	Year 1	Year 2	Year 3	Year 4	Year 5	5-year cumulative
1 (PEP ID using PCEC)	2.7 (0.08)	5.3 (0.15)	8.0 (0.23)	10.7 (0.30)	13.4 (0.38)	40.1 (1.14)
2 (PEP ID using CPRV/PVRV)	2.9 (0.08)	5.7 (0.16)	8.6 (0.24)	11.4 (0.32)	14.3 (0.40)	42.9 (1.21)
3 (PEP IM using CPRV/PVRV)	3.3 (0.09)	6.7 (0.19)	10.0 (0.28)	13.4 (0.38)	16.7 (0.47)	50.2 (1.42)
4 (PEP IM using PCEC)	3.4 (0.10)	6.8 (0.19)	10.2 (0.29)	13.6 (0.39)	17.0 (0.48)	51.1 (1.45)
5 (PrEP+PEP ID using PCEC)	21.1 (0.60)	42.1 (1.19)	62.7 (1.78)	83.1 (2.36)	103.3 (2.93)	312.4 (8.85)
6 (PrEP+PEP ID using CPRV/PVRV)	23.3 (0.66)	46.3 (1.31)	69.0 (1.95)	91.5 (2.59)	113.7 (3.22)	343.7 (9.72)
7 (PrEP+PEP IM using CPRV/PVRV)	30.1 (0.85)	59.9 (1.70)	89.5 (2.53)	118.8 (3.36)	147.9 (4.19)	446.2 (12.63)
8 (PrEP+PEP IM using PCEC)	30.9 (0.88)	61.6 (1.74)	92.0 (2.61)	122.1 (3.46)	152.0 (4.31)	458.6 (12.99)

CPRV, chromatographically purified Vero cell vaccine; ID, intradermal; IM, intramuscular; PCEC, purified chick embryo cell vaccine; PEP, post-exposure prophylaxis; PrEP, pre-exposure prophylaxis; PVRV, purified Vero cell rabies vaccine; THB, Thai Baht; US$, United States dollar.

Scenario analysis

In the scenario analysis, strategy 5 (PrEP+PEP ID using PCEC) remained cost-effective compared with strategy 1 (PEP alone ID using PCEC) in both poor- and good-compliance scenarios. Under poor compliance, the ICER of strategy 5 was THB 47 033 (US$1332.4) per QALY, with an incremental QALY of 0.0296 over strategy 1. Under good compliance, the ICER fell to THB 36 195 (US$1025.4) per QALY, with an incremental QALY of 0.0375. Both ICERs were below the WTP threshold of THB 160 000 per QALY in Thailand. Strategies 2–4 and 6–8 were dominated in both scenarios, which was consistent with the results in the base case. Compared with poor compliance, good compliance reduced the QALY loss in strategy 5 from 0.0832 to 0.0520, indicating that the health gains of PrEP rabies vaccination increase with high compliance. The results of the scenario analysis are outlined in online supplemental table 3.

Discussion

Rabies is a severe and life-threatening viral disease that remains a significant public health concern in endemic regions such as Thailand, where children are especially vulnerable due to their higher risk of exposure and the severity of bites they often sustain.^{4 5} Therefore, determining the most cost-effective preventive strategy is essential to protect this high-risk population.⁴⁶ This cost-utility analysis showed that intradermally administering PrEP+PEP rabies vaccines using PCEC in children is cost-effective compared with PEP alone at a WTP threshold of THB 160 000 in Thailand. Specifically, administering the vaccine with the intradermal route costs less than the intramuscular route due to a lower amount of vaccine required.^{4 14} This study also highlighted that the pre-exposure rabies prophylaxis substantially decreases reliance on eRIG, as it is unnecessary for PrEP-vaccinated individuals after exposure. This reduction resulted in significant cost savings in eRIG-related administration. Furthermore, the pre-exposure rabies prophylaxis approach enhanced compliance with PEP regimens due to the reduced vaccine doses required following exposure.^{4 14}

The results from this study were consistent with results from previous economic evaluation studies conducted in the Philippines and India. All three studies demonstrated that the PrEP rabies vaccine was cost-effective compared with PEP rabies vaccine alone in children.^{24 25} As these three countries are endemic areas of rabies,⁵ all studies emphasise the potential of the PrEP rabies vaccine to prevent rabies and rabies-related mortality and reduce healthcare burdens in children in regions with high incidence of rabies.

According to the results of this study, the PrEP rabies vaccine has demonstrated its potential to be listed in Thailand NIP as it is cost-effective in children in Thailand due to decreased reliance on eRIG for vaccinated individuals and reduced complexity of PEP rabies vaccine administration. Moreover, the intradermal route for vaccination is recommended as it offers economic advantages due to its reduced vaccine volume requirement compared with the intramuscular route. Ultimately, to align with the WHO global strategic plan to eliminate human rabies by 2030,⁴⁸ a multidisciplinary approach is essential for effectively and sustainably addressing rabies prevention. Although this study focused on human PrEP rabies vaccination, mass dog vaccination and appropriate PEP remain the cornerstone to eliminate dog-mediated rabies infection because it addresses the source of transmission and reduces the risk of exposure across entire communities.² Therefore, PrEP rabies vaccination for high-risk children should be considered a complementary strategy to canine rabies control programmes. Consistent with the One Health approach advocated by the WHO, effective and sustainable rabies prevention requires coordinated action across the human health, animal health, and environmental sectors.⁴⁸ Collaboration among healthcare professionals, veterinarians, policymakers, and community stakeholders is essential to integrate rabies prevention into the national strategic plan.

This study faced a few limitations. First, the annual bite incidence is the most sensitive parameter in this model. However, we lack a valid annual bite incidence in Thailand. Further investigations using local data were encouraged to strengthen evidence-informed decision-making. In particular, additional real-world evidence should be collected to obtain actual data on annual bite incidence and rabies exposure patterns in the Thai context. Second, the probability that exposure was from a rabid animal was derived from the national animal rabies surveillance system, which could overestimate the rabies positivity. Third, due to the absence of a number of children living in informal settlements or other high-risk communities in Thailand, the target population was defined using the total population of 5-year-old children residing in provinces reporting the five highest proportions of rabies-positive animal samples. However, because rabies vaccination programmes may ultimately be implemented in more geographically targeted high-risk communities rather than province-wide populations, the budget impact estimates may overestimate the financial resources required for implementation.

A stepwise implementation of PrEP rabies vaccines should begin in areas with a high incidence of rabies, such as densely populated communities where contact with stray mammals is common, as results indicated that an annual bite incidence of up to 14.6% leads to cost savings for PrEP rabies vaccines. Consistently, Deray et al showed that implementing PrEP rabies vaccine in higher-incidence areas results in cost savings due to fewer PEP rabies doses and non-reliance on RIG.⁴⁹ Starting in the highest-risk areas also helps reduce uncertainty from the missing annual bite incidence data in Thailand. The delivery of PrEP rabies vaccination can be integrated into existing health infrastructure, including school-based immunisation programmes, to enhance accessibility among children in high-risk settings.^{50 51} School-based programmes can also facilitate the active surveillance of rabies data collection to bridge the gap of scarce data, as implemented in the Philippines.⁴⁹

Conclusion

The PrEP+PEP ID using PCEC is a cost-effective strategy for rabies prevention in Thailand, with an ICER of THB 40 977 (US$1160.8) per QALY versus PEP alone ID using PCEC. The intradermal route reduced costs, minimised reliance on RIG, and improved compliance, supporting the PrEP rabies vaccine’s inclusion in Thailand NIP to achieve rabies elimination by 2030.

Data availability statement

Data are available in a public, open access repository. https://stat.bora.dopa.go.th/stat/statnew/statMenu/newStat/home.php.

Ethics statements

Patient consent for publication

Not applicable.

Ethics approval

Not applicable.