A critical literature review of health economic evaluations in pertussis booster vaccination

Abstract

A review of worldwide economic evaluations of pertussis booster vaccination for adolescents and adults was conducted. Thirteen cost–effectiveness, cost–utility and economic impact models were identified. The most frequently studied strategies were adolescent booster, one-time adult booster, adult decennial boosters and cocoon strategy. All studies evaluating adolescent booster suggested this was a cost-effective or cost-saving strategy compared with no booster vaccination. Conclusions concerning adult vaccination, alone or in combination with adolescent vaccination, vary between studies. Studies were often strongly affected by assumptions regarding the amount of unreported cases and lack of reliable input data on real incidence, other epidemiological inputs, costs associated with mild disease and herd immunity effects. Reviewed studies were generally in favor of pertussis booster vaccination, but did not identify any optimal vaccination strategy. Future economic evaluations should explore a wider range of strategies, taking into account country-specific considerations.

Keywords::

• adolescent
• adults
• cost–effectiveness
• economic evaluation
• pertussis booster vaccination

Figure 1. Four types of models used in reviewed economic evaluations.

(A) Generic decision tree used for calculation of the cost–effectiveness of potential pertussis immunization strategies. (B) Structure of the Markov model. (C) Schematic representation of the possible pathways within the pertussis discrete event simulation model. (D) Diagram of the immunological and infectious states and transitions between states in the age-specific pertussis model.

V: Vaccine status; VC: Vaccination coverage; WN: Waning of natural immunity; WV: Vaccine waning.

(A) Adapted with permission from [21]; (B) Adapted with permission from [22]; (C) Adapted with permission from [13]; (D) Adapted with permission from [16].

Pertussis disease is a frequent cause of chronic cough in children, adolescents and adults [1]. While symptoms may be less severe for adults, it is an important public health threat worldwide: estimates from WHO in 2008 suggested that approximately 16 million cases of pertussis occurred worldwide, 95% of which were in developing countries, and that approximately 195,000 children died from this disease [2]. The disease is still a significant cause of morbidity and mortality in infants younger than 2 years of age, and is the leading cause of death in infants younger than 2 months of age in high-income countries [3].

The childhood formulation DTaP (also known as DTPa or TDaP) combines vaccines against diphtheria, tetanus and pertussis, in which the pertussis component is acellular. In 1991, the US FDA licensed the DTaP vaccine for infants and children. A complete pertussis vaccination schedule includes at least three doses received during the first year of life. A fourth dose of DTaP is sometimes given between 15 and 18 months, and a fifth dose at age 4–6 years.

Where primary and preschool pertussis vaccination has been implemented, there has been a significant reduction in pertussis morbidity and mortality in infants and children [4–6]. However, the disease persists in infants who are too young to be vaccinated, and amongst adolescents and adults who have lost the protection acquired through the disease or the vaccine [7]. Several countries have noted an epidemiological shift in the average age of the onset of pertussis infection, reporting a rising number of cases in adolescents and adults, inducing infection in infants [4,8,9]. For example, the incidence of pertussis notifications in children aged 10–14 years in British Columbia increased from below 50 per 100,000 person-years to approximately 240 per 100,000 between the outbreaks of 1996 and 2000 [8]. Moreover, the burden of pertussis disease is likely to be underestimated, due to underconsulting, under-recognition or misdiagnosis, and under-reporting of the disease [4].

The re-emergence of pertussis disease could potentially be limited by a booster vaccination for adolescents and adults. Many countries (e.g., France, Germany, the USA and Canada) have already integrated a booster for adolescents and/or adults into their current schedule. The Global Pertussis Initiative, set up in 2001 by Sanofi Pasteur, brought together experts from 17 countries that reached consensus on the primary and secondary objectives of various immunization strategies [10]. The universal adult and/or adolescent booster strategies aim at reducing morbidity in vaccinated populations and developing herd immunity, whereas the cocoon booster strategy for selected individuals (parents and childcarers) aims at reducing transmission to infants. The Global Pertussis Initiative recommended universal adolescent immunization and implementation of the cocoon strategy where economically feasible. Universal adult immunization was presented as a “logical goal for the ultimate elimination of pertussis disease”. According to the WHO position paper, decisions concerning the addition of booster doses for adolescents and adults should be based on incidence and cost–effectiveness data [11]. In the USA, the Advisory Committee on Immunization Practices recommends a single booster dose (tetanus–diphtheria–acellular pertussis [Tdap]) for persons aged 11–18 years who have completed the recommended childhood DTP/DTaP vaccination series and for adults aged 19–64 years [12]. The Tdap formulation has a reduced dose of diphtheria and pertussis components, substituting the previous Td booster vaccine that combined vaccines against diphtheria and tetanus.

The cost–effectiveness of pertussis booster vaccination has been evaluated in several studies worldwide; however, no review focusing on evaluations of booster vaccination for adolescents and adults has been published to date. The objectives of this article are first to provide a critical literature review of economic evaluations on pertussis booster vaccination, to investigate the disparity of the results among strategies and the reasons for such difference, and to identify those booster vaccination strategies that are likely to be most cost effective. In the context of rising interest in pertussis booster vaccination, it is expected that several economic evaluations will be conducted in the next few years. This review will attempt to provide guidance and suggestions for improvement, as such setting the scene for future economic evaluations.

Search methodology

A systematic literature review was conducted in order to identify all relevant economic evaluations worldwide on pertussis booster vaccination published before November 2010. We used the following search strategy in Medline: ((“whooping cough”[mesh] or “diphtheria-tetanus-pertussis vaccine”[mesh] or “diphtheria-tetanus-acellular pertussis vaccines”[mesh] or “bordetella pertussis”[mesh] or “pertussis vaccine”[mesh] AND cost-benefit[mesh])) OR (pertussis[ti] and (cost–effectiveness[ti] or economic evaluation[ti])). The search identified 63 publications. Of these, 40 were not economic evaluations, and 23 were preselected based on abstracts. Publications that did not provide cost–effectiveness results (eight), reviews (one) and letters (one) were excluded. Finally, 13 publications were selected in this review.

Screening of references and extraction of data were performed by two reviewers independently. A full list of the extracted data is provided in Supplementary Table 1.

Overview of studies

Table 1 describes all included economic evaluations. Of the 13 studies reviewed, four covered Europe (two The Netherlands, one England and Wales, and one Germany), eight covered North America (six USA and two Canada), and one covered Australia. Six were sponsored by the pharmaceutical industry (three GlaxoSmithKline and three Sanofi Pasteur) and seven were published by independent authors or government agencies, or did not report any industry funding. Twelve cost analyses, nine cost–effectiveness analyses and five cost–utility analyses (presenting cost per quality-adjusted life-year [QALY] and cost per disability-adjusted life-year [DALY] as outcomes) were conducted. Table 1 describes the 13 economic evaluations included in this review.

Nine studies considered adolescent booster vaccination. In The Netherlands approximately 20% of cases would be prevented, and the (incremental) cost per QALY would be between €4400 and €6400 according to De Vries et al.[13], compared with no booster vaccination, from a societal perspective. In the USA, this strategy was estimated to cost US$6253 per life-year gained according to Caro et al.[14], and US$20,000 per QALY gained according to Lee et al.[15] from a societal perspective. Coudeville et al. predicted that adolescent booster vaccination dominated no booster vaccination, with a reduction of 77% in disease incidence; however, adolescent booster vaccination was dominated by broader booster vaccination strategies, including adult vaccination [16]. In Quebec or in Ontario, the incremental cost of adolescent booster vaccination was less than CAD$600 per discounted pertussis case avoided, from the perspective of Ministry of Health, according to Iskedjian et al.[17,18]. Edmunds et al. found that from the perspective of the healthcare provider, approximately 35% of the simulations resulted in a cost per life-year gained of less than GBP£10,000 [19]. Level of herd immunity and mortality rate were identified as key cost–effectiveness drivers.

Six studies considered one-time adult booster vaccination. In Germany, Lee et al. presented incremental cost–effectiveness ratio (ICERs) of €5800 per QALY saved from a societal perspective, with 10–12% of cases prevented [20]. In the USA, Lee et al. estimated that only 1.4% of cases would be prevented and that this strategy would be dominated by absence of booster vaccination, since the detrimental impact of vaccine side effects on QALYs exceeded their benefits [15]. Coudeville et al. considered a strategy combining childhood vaccination, adolescent booster, cocoon strategy and one booster dose at 40 years of age in the USA [16]. Reduction in the overall incidence of symptomatic pertussis would be approximately 97% compared with childhood vaccination. A single booster dose at 40 years of age in addition to the cocoon strategy and adolescent booster was the dominant strategy compared with cocoon plus adolescent booster.

Six studies considered cocoon strategy (broadly defined as administering booster vaccines to household members of newborn infants). In The Netherlands, Westra et al. reported an ICER of €4600 per QALY from a third-party payer (TPP) perspective [21]; this strategy would be cost-saving from the societal perspective. In a study by Lee et al., postpartum vaccination was found to be more costly than adolescent vaccination and would provide fewer health benefits [15]. Coudeville et al. considered childhood vaccination combined with adolescent booster and cocoon strategy [16]. Reduction in the overall incidence of symptomatic pertussis was approximately 80% compared with childhood vaccination only. This strategy dominated childhood vaccination combined with adolescent booster alone, but was dominated by broader vaccination strategies. In Australia, Scuffham et al. reported an ICER of AUS$787,504 per DALY avoided versus no current schedule, from a TPP perspective [22]. This strategy could reduce pertussis cases, deaths and DALYs by 38.6, 38.2 and 38.3%, respectively. Nevertheless, it was not cost effective, and dominated by the at-birth vaccination strategy.

Four studies considered decennial adult booster vaccination. In Germany, Lee et al. reported an ICER of €7200 per QALY gained versus no booster vaccination, from a societal perspective [20]. Between 20 and 25% of cases would be prevented depending on incidence data. In the USA, Lee et al. predicted that 5% of cases would be prevented, and this strategy was found to be dominated (as was the one-time adult vaccination strategy, due to adverse events) [15]. Coudeville et al. considered a strategy combining childhood vaccination, adolescent booster and a routine decennial adult vaccination in the USA [16]. The overall incidence of symptomatic pertussis was predicted to decrease from 400 to 30 cases per 100,000 person-years, at a total cost per year of US$732,981 in a cohort of 1 million individuals from the societal perspective. The ICER of this strategy compared with ‘adolescent booster + cocoon + one dose at 40 years’ was very high (close to US$700,000 per QALY gained).

Other strategies were also considered. Maternal immunization, vaccination of specific populations (persons >18 years of age with chronic obstructive pulmonary disease, healthcare workers >20 years of age), and universal immunization appeared to be very cost effective. Immunization at birth was found not to be cost effective in base-case analysis because of the assumed limited vaccine effectiveness in infants, as stated by Westra et al.[21]. This finding was reinforced by the results presented by Scuffham et al.[22]. The authors also evaluated a strategy where infants would receive a vaccine dose at 1 month, the subsequent immunization schedule (2, 4 and 6 months) remaining unchanged. Table 2 presents final results for all studies and strategies considered. A detailed table providing all results (epidemiological, cost–effectiveness and economic impact) is provided in Supplementary Table 2.

Critical analysis

Models

There are substantial differences among models used by authors, both in methodology and in structure. Four major types of models are available: decision trees, Markov models, discrete events simulation (DES) and dynamic compartmental models, as described in Figure 1.

Model structures

Out of the 13 articles presenting results from a model, three did not describe the model structure [14,23,24] and there were six Markov models [15,17,18,20,22,25], one decision tree [21], one dynamic DES model [13], one dynamic compartmental model [24], and one only indirectly used results from a dynamic model [19].

Westra et al. used a decision tree with probabilities for individuals to be infected or not, for the infection to be symptomatic or not, and for the case to be reported or not [21]. As time is not explicitly defined, duration of infection is not modeled, and individuals could not be infected more than once. Also, the authors designed separate models for adults and infants; therefore, indirect protection was not included in the model.

Lee et al. used a Markov model (static cohort model) with 1-year cycles [15,20,25]. In such a model, patients may go from one health state to another according to transition probabilities that depend on the current state. Health outcomes and costs associated with these states were simulated for a cohort of people over their lifetime. Advantages of the Markov model versus decision tree is that patients are followed-up over time, taking into account variations of immunity level. Adolescents and adults with pertussis were classified as having mild or severe cough illness, or pneumonia. Infants who had pertussis developed either respiratory or neurologic complications or died as a result of the disease.

Scuffham et al. also used a Markov model, arguing that the differential timing of events could be modeled explicitly [22]. They used a time horizon of only 6 months, with 26 1-week cycles, and seven health states including susceptible, infected, immune, vaccinated (× three doses) and death.

De Vries et al. designed a stochastic DES model that represents a chronological sequence of events, where individuals are modeled rather than cohorts [13]. Stochastic models are generally recommended when there is concern about first-order uncertainty; for example, when a small number of infected cases in a population could lead to a large outbreak by chance. This is a situation encountered with pertussis. The model distinguished between three types of infections (primary, recurrent and asymptomatic infections), considered two scenarios of duration of immunity acquired by natural infection (8 and 15 years) and distinguished vaccine-induced immunity for infection (2 years) and for disease (an additional 6 and 13 years, respectively). The main disadvantage of this stochastic model is the running time, as authors could only run 20 iterations per scenario.

Coudeville et al. developed a transmission dynamic compartmental model [16]. This takes into account some specific features of pertussis transmission such as the progressive switch from naturally acquired immunity to vaccine-acquired immunity, and can capture herd immunity by modeling transmission mechanisms via computer simulations. Individuals are compartmentalized into three main pertussis states: fully susceptible, fully or partially immune, and infectious. They may be transferred from one to another according to a ‘who acquires infection from whom’ matrix.

Time horizon

The time horizon should be long enough for the analysis to capture the entire difference in costs and outcomes between alternative strategies. Out of the 13 articles, the time horizon was 6 months for one study [22], 8 years for one study [21], 10 years for four studies [17,18,23,24], 25 years for one study [13], four presented a lifetime analysis [14,15,20,25] and two dynamic models presented results at steady state, which corresponds to a period over which the full impact of the vaccination strategy has been reached [19,21]. The model used by Coudeville et al. reached steady state at approximately 80 years [16]. Edmunds et al. did not explicitly state the time horizon [19]. Scuffham et al. used a time horizon of 6 months, assuming it was adequate to capture the main effects of infection in infants [22]. The authors considered it to be a conservative approach, as potential additional benefits would not be taken into account. Only Iskedjian et al. conducted a sensitivity analysis on the time horizon and found that it can have an impact: decreasing the 10-year horizon to a 5-year horizon increased incremental costs per child per year by approximately twofold [17].

Epidemiological inputs

Incidence rates, under-reporting correction factors, other epidemiological inputs and their sources are presented in Table 3.

Incidence

When reported, incidence rates differed largely between studies (some did not present explicit incidence rates and some just mentioned that they were age specific). For several reasons pertussis disease is generally under-reported: most of the time only culture-positive cases or cases with highly typical symptoms are reported; and it is typically considered to be a childhood disease and passes unnoticed in other populations. Most studies used a correcting factor to estimate incidence, from 2.5 to 660 depending on the country. Data on hospitalizations and deaths were particularly influenced by the characteristics of the surveillance system in place, reflected by the large variation in the estimates observed. After correction, incidence rates of pertussis varied from 22 to 58.5 per 100,000 for infants, from 95 to 511 per 100,000 for adolescents and from 11 to 507 per 100,000 for adults. This parameter can strongly influence the results, and may inverse the sense of conclusions. Also, regarding the nonreported cases (although still symptomatic), some could argue that they are in general milder and hence cheaper; however, several studies showed that the burden associated with these cases was significant. Input values for healthcare resource use and mortality also varied considerably. In addition, the incidence has increased over recent years in several countries. For example, in 2007 Lee et al. used revised incidence in the second study performed in the USA, contributing to more favorable results towards vaccination [25].

Asymptomatic cases

These are unrecognized infections with mild or subclinical symptoms, which are not associated with significant costs or effects on quality of life. There is no need to account for such cases in static models, whereas their consideration is crucial in dynamic models as they may participate in pertussis infection transmission. The majority of infections in adults and adolescents are actually asymptomatic, ranging from 78 to 95%, according to recent studies [26,27]. It is also suggested that 16% of infections in infants are the result of transmission via asymptomatic cases [26]. Out of the three dynamic models, only two clearly considered asymptomatic cases [13,16]. For both analyses the duration of infectiousness was estimated to be 1 week with no productivity losses.

Herd immunity

Herd immunity refers to the indirect protection conferred by the vaccine: vaccination of some age groups, in particular adolescents, may considerably reduce the transmission of the disease in the nonvaccinated population, which will impact the cost–effectiveness of the vaccination strategy under consideration. Table 4 presents information relative to herd immunity considered in the included economic analyses.

Despite the different methodologies adopted, most authors tried to incorporate herd immunity in their model (or clearly stated that they did not incorporate its benefits as a conservative approach).

Sensitivity analyses on the percentage of herd immunity were often performed to examine the impact on model outcomes. Lee et al. found that herd immunity had a greater impact on cost–effectiveness when disease incidence was low, suggesting that a certain threshold of cases prevented is needed for the intervention to appear cost effective [25]. It seems then more appropriate to use a dynamic approach, especially to evaluate booster vaccination of adolescents. Indeed, herd immunity effects depend on the age groups considered, and potential positive and negative indirect effects can be associated with it. For instance, the age shift observed could be perceived as a positive effect since disease is less likely to be severe in adults. Nevertheless, it increases the risk of transmission from parents to infants. Unfortunately, no publication reported the size of indirect effects relative to direct effects.

Vaccine-related data

Efficacy

Several estimates of efficacy were used in the models: Edmunds et al. used an initial rate of 95%, with no information about waning values [19]. Lee et al. assumed that immunity waned each year for 15 years, from 100 to 0%, based on the basis of expert panel input and published data [15,20,25]. Depending on the authors assumptions, protective efficacy varied from 85% [17,18] to 89% [13]. Only Coudeville et al.[16] and Westra et al.[21] used dose-dependent efficacy data. Westra et al. assumed that the maximum level of efficacy was reached at the third dose, whereas Coudeville et al. considered an increase of the vaccine efficacy up to the fourth dose [16]. The impact of inputs related to protective efficacy was investigated with low and high vaccine efficacy scenarios, which were found to substantially change the results. For example, Coudeville et al. found that in the low vaccine efficacy scenario implementing routine decennial vaccination appeared to be a more cost-effective solution than the combination of a cocoon vaccination with a single booster dose at 40 years of age [16]. The situation was reversed for a high vaccine efficacy scenario: implementing only the adolescent or adolescent and cocoon seems to be sufficient and the cost–effectiveness ratio is higher than US$1,000,000 for the booster dose at 40 years of age. The impact of vaccine efficacy on ICERs was also established in Caro et al., where a duration of protection of 3 instead of 10 years considerably deteriorated the cost–effectiveness [14].

Adverse events

In most of the studies reviewed, side effects of vaccination were not considered. Five studies included side effects as part of a conservative approach: Lee et al. included local reaction, systemic reaction and anaphylaxis [15,20,25], Purdy et al. included local or systemic reactions [23] and Caro et al. considered adverse reactions of sufficient severity to warrant a physician visit [14]. In all studies, the impact was negligible, except for adult vaccination in Lee et al., which resulted in fewer QALYs compared with no vaccination, mostly due to adverse events [15].

Costs

Perspectives

Eight studies reported costs from both a TPP and societal perspective, one considered only TPP perspective and four only considered societal perspective. All studies adopted the perspective recommended in local health economic guidelines.

Table 5 lists all costs included in the economic analyses.

Vaccination cost

Vaccination cost is often presented as an incremental cost of Tdap booster versus Td. Values largely differ according to the geographical area: from an extra cost of GBP£5 in the UK to a vaccine price above €18 in The Netherlands, where the Td vaccine was not available. Administration costs were sometimes added to the vaccine cost when authors thought an additional medical visit would be needed. Westra et al found a moderate impact of administration cost assumption on ICERs in The Netherlands; conclusions were not affected [21].

Disease-related costs

All studies clearly described what types of costs were included in terms of direct medical, direct nonmedical and indirect costs.

Direct costs

Direct medical costs included clinical resources, such as hospitalizations, emergency room and physician visits, laboratory tests for diagnosis and medications. Direct nonmedical costs included additional childcare provision and travel expenses incurred for consultations. Both medical and nonmedical costs were mostly age specific. Direct costs are considered in the TPP perspective.

Indirect costs

Indirect costs included those associated with time diverted from normal activities and reduced work productivity. These costs were added to the direct costs when a societal perspective was considered.

Ratio of direct/indirect costs

Ratio of direct/indirect costs varied a lot between studies, countries and age groups: for Purdy et al., the indirect costs due to productivity losses comprise by far the largest part (∼80–90%) of the costs associated with pertussis diseases [23], whereas it accounts for less than half of total costs for Iskedjian et al.[17,18] and Coudeville et al.[16].

Health-state utilities

The QALYs combine survival and health-related quality of life (i.e., utility values) into a single health outcome. This is the preferred health outcome measure for several health technology assessments using economic evaluations to support decision making. There is only one available data source for utility values for pertussis disease [28]. In this study the authors conducted a survey using time trade-off (TTO) and contingent valuation methods to determine the utility of either short- or long-term health scenarios for adolescents and adult patients, referring to vaccination health states (local reaction or systemic reaction) and disease health states (mild cough, severe cough or pneumonia). For infants, they considered respiratory and neurologic complications.

Due to the specificity of the models used in economic evaluations, the authors had to make several assumptions. For example, Lee et al. assigned for moderate cases the value reported for mild cough, and assumed a higher utility for mild cases [15,20,25]. They also assumed a utility for anaphylaxis and for outpatient respiratory complications. De Vries et al. considered the reported value for mild cough as input value for unreported cases, and moderate cough as input for reported cases [13].

Utility input values had limited impact on results in Lee et al.[15,20,25] and Westra et al.[21], but significantly affected results in De Vries et al.[13].

Scuffham et al. used DALY, which is an index combining morbidity and mortality according to weights for each health state multiplied by the duration in that state [22]. DALYs are useful for broad cross-country comparisons, more than for comparing specific diseases and priority setting within a country. The authors used the DALY weights for pertussis infection and complications reported from the global burden of disease study [22,29–31], computed with the TTO method. Changes in the DALY weights for illness and hospitalization had insignificant impact on the ICERs.

Discount rate

Outcomes and costs were discounted at a rate of 3% in all studies, except for The Netherlands, where guidelines suggest using 4 and 1.5%. Costs were not discounted in Scuffham et al. since all costs incur within a short time horizon (less than a year) [22]. The impact of using discount rates was investigated by sensitivity analysis, showing generally a limited impact except for Edmunds et al.[19] and Caro et al.[14]. It is notable that for these two studies the outcome expressed as life-year gained was very sensitive to discount rate.

Expert commentary

Disparity of strategies

There were remarkable disparities in the definitions of strategies used by the authors. The cocoon strategy was defined as a “vaccination of both parents immediately after birth of the child” by Scuffham et al.[22] and Westra et al.[21], and as “targeted vaccination of parents of newborn” by Coudeville et al.[16]. Lee et al. considered it to be “vaccination of mothers after birth plus another adult caregiver after the firstborn child” [15], and Purdy et al. analyzed a subgroup of “adults ≥15 years of age who are the primary caretakers of infants <1 year of age” [23]. All have been considered as referring to the cocoon strategy in this review. Concerning the adolescent strategy, several ages were considered for vaccination.

There was also a disparity in the choice of strategies assessed, which can potentially be explained by the difference in vaccination schedules already in place in the studied countries as well as the type of market (e.g., public or private). For example, while the primary vaccination has been implemented in all countries, preschool vaccination is not recommended everywhere and implementation of a strategy such as ‘cocoon’ might be facilitated in a public market with tender process compared with a private market. Consequently, the authors had to evaluate different vaccination strategies depending on the local context. Moreover, some authors chose to evaluate vaccination strategies for different population groups separately (only adults, only adolescents and so on) whereas others used combinations of those groups [15,16].

Lack of data

Cost–effectiveness analyses are limited by the available data. First, the incidence and extent of under-reporting are not precisely known, and authors would benefit from more data about the true incidence of symptomatic cases in all age groups. Also, it is not clear whether the cost of the nonreported symptomatic cases is the same as the cost of those reported. Moreover, incidence data relative to asymptomatic cases is clearly not sufficient. Second, data about mortality is also rare. As assessed by Edmunds et al., the disease-related mortality rate can have a substantial impact on the cost–effectiveness results, and this is of importance in models considering protection of infants [19]. Third, there remain crucial questions regarding the efficacy of the vaccine. Currently, there is a lack of knowledge concerning the duration of immunity acquired by individuals after vaccination, which may vary between strategies. In addition, several facts were not known at the time of analysis: efficacy and tolerability when more than five doses are assessed; safety and efficacy in nonpediatric populations; maternal immunization efficacy; and efficacy of vaccination at birth. Fourth, only one study collected health-state utilities for pertussis disease, and utility values may not be suitable for use in infants. Decision makers in different countries recommend different instruments for measuring utilities. For example, in the UK, the NICE has a preference for the EQ-5D valued using the UK TTO value set. Such values are not available for pertussis disease. Health-state valuations are not exhaustive, and most of the studies used assumptions. Further evaluations would benefit from new data. Last, authors often have access to limited data about costs, which ideally should be country and age specific (especially relative to mild pertussis and indirect costs). Major obstacles to the accurate assessment of the costs of pertussis are the severity and cost consequences of unreported and undiagnosed cases.

Herd immunity

There is uncertainty regarding the degree of indirect protection provided by vaccination. The fact that booster vaccination may generate herd immunity seems to be well accepted, yet data about its extent are scarce. Level of infectiousness of different types of cases and mixing patterns are often assumed by authors. In dynamic models, many parameters are probably obtained from calibration, but it is not clearly reported whether all those calibrations are performed with appropriate and sufficient data. There are two possible ways to estimate herd immunity. One can analyze the impact of previously implemented programs, but the impact of herd immunity is largely dependent on local parameters, and is difficult to estimate because the changes in incidence following the implementation of a new vaccination program are generally not entirely attributable to this program. One can also develop and use transmission dynamic models, which require many input data but appear to be useful. Nowadays, the validity of transmission models could be assessed based on the impact of recent vaccination programs.

Although the current epidemiological situation for pertussis is not comparable with the prevaccine era, potential negative externalities of booster vaccination have to be appropriately evaluated. For example, implementation of adolescent vaccination is expected to reduce circulation of the virus among adolescents. Nonvaccinated individuals will therefore be less likely to be infected (symptomatically or asymptomatically) during adolescence, and may then not benefit from natural immunity when they become young adults, at an age when they are most likely to transmit infection to infants. In addition, the duration of immunity after vaccination may be shorter than the duration of natural immunity, and adolescents or young adults with low immunity levels may be less likely to benefit from natural boosting conferred by asymptomatic infections, due to lower prevalence of the disease around them if an adolescent booster strategy is implemented. These combined facts could result in a greater risk of infection among parents of young infants, leading to transmission of infection to the key risk group. Depending on the level of vaccination coverage and duration of immunity after vaccination, it is possible that the negative externalities associated with booster vaccination exceed indirect protection conferred to infants. This issue was not discussed in reviewed publications based on transmission dynamic models and would merit investigation. Also, it is important to report outcomes of vaccination policies by age group and evaluate the risk of negative externalities as a function of vaccination coverage and the duration of immunity conferred by vaccination, relative to natural immunity [32]. Both positive and negative externalities must be discussed, and considered accordingly to the large extent of vaccination benefit.

Sensitivity analyses & key drivers

As the lack of data is a major issue in evaluations of pertussis vaccination, it is necessary to conduct appropriate sensitivity analyses. The authors mostly used deterministic univariate sensitivity analysis. Probabilistic sensitivity analysis was reported in only one article [21]. Although the conclusions were generally quite robust to sensitivity analyses, disease incidence and the associated issue of under-reporting were reported as key cost–effectiveness drivers. Case fatality rates might be expected to have a strong influence on ICERs as one of the reasons for using booster vaccination is to prevent risk of fatal complications in infants [33]. However, only two studies found this parameter as a cost–effectiveness driver [19,22].

Methodological issues

One pecularity of pertussis vaccination is the multitude of strategies being compared by the authors, and some authors performed questionable comparisons.

For example, Lee et al. considered adolescent vaccination, adult routine vaccination, combined adolescent and adult routine vaccination and postpartum vaccination [15]. The latter strategy is said to be ‘dominated’, presumably because it is more expensive and less effective than adolescent vaccination. However, these strategies have different objectives: postpartum vaccination aims at protecting infants, and adolescent vaccination aims at protecting adolescents. More relevant comparisons would have been postpartum vaccination versus no booster vaccination, or combined postpartum vaccination and adolescent vaccination versus adolescent vaccination. Coudeville et al. evaluated the adolescent vaccination strategy, then combined with cocoon and then with both cocoon and one-time adult vaccination [16]. The one-time adult vaccination was not assessed separately and therefore this analysis does not address the issue of whether vaccinating adults only would be cost effective.

When more than two strategies are considered, strategies must be ranked from the least effective to the most effective, and ICERs must be calculated for each strategy versus the previous one after exclusion of dominated and weakly dominated strategies [34–36]. Unfortunately, this methodology was not used by most of the authors, leading to inappropriate conclusions.

Concerning models, the choice between static and dynamic approach is of utmost importance. A static approach may be considered as conservative, since a dynamic model will often (although not always) predict a more favorable outcome, due to a more rapid effect and because the effect of herd immunity accumulates over time [37]. Nevertheless, the choice between static and dynamic approach should mostly depend on the type of strategy considered. When the primary objective of the strategy is to reduce transmission to infants – that is, when herd immunity development is not the primary objective of the strategy (e.g., for cocoon strategy) – a static approach is likely to be sufficient. That approach was appropriately used by Westra et al., which only considered strategies aimed at directly protecting infants [21]. When adolescent or adult immunization strategies are considered (i.e., when the strategy implementation can potentially produce significant changes in the severity of infection), then a transmission dynamic model is necessary [37]. There are many issues associated with dynamic models, but estimates of indirect effects are required, and unless there is any other way to account for them, dynamic models should be preferred in order to determine an optimal strategy.

Outbreaks may be identified via a stochastic approach; nevertheless, a major drawback of the stochastic approach is that the model running time is long. For example, De Vries et al. ran multiple simulations, but as the computational time required was considerable, they could perform only a limited number of simulations [13].

The correct time horizon is also subject to discussion, and presenting analyses over very long time horizons only may not be very informative for decision-makers. Indeed, it is very unlikely that models are able to predict disease impact in 50 or 100 years, since the transmission dynamics of pertussis are not fully understood, and some external factors are unpredictable [37]. Many changes or events could happen in the long term, such as demographic changes or medical innovations, which would make the results in the very long term irrelevant. This raises concerns about the steady-state approach, as the time needed to achieve equilibrium is very long, approximately 80 years according to Coudeville et al.[16]. The choice of estimating ICERs at steady state might only seem insufficient for a decision maker, since they might be more interested in average costs and effects over a short- or medium-term time horizon, as well as in the long term.

Recommendations for future studies

Since this review was performed, an abstract has already been published [38], and we anticipate that a number of new models will be published within a few years.

Based on the review of published economic evaluations of pertussis booster vaccination, we would recommend the following for future studies:

• • To assess the predictive validity of existing models against recent data;

• • To use a timeframe over which disease incidence can realistically be predicted;

• • To compare each strategy versus the next best strategy, not versus no booster;

• • To consider the advantages and the feasibility of improving coverage rates in currently targeted age groups versus adding new age groups;

• • To consider research to get further insight on management of outbreaks.

As stated above, it is highly desirable to collect new data to improve the future evaluations of pertussis booster vaccination, especially costs of different types of pertussis cases, utility and transmission of pertussis, and incidence of symptomatic and asymptomatic cases for transmission dynamic models.

The rationale for the choice of strategies assessed is one of the key points that should be discussed in new studies. Indeed, it is very important to consider the possibility of combining strategies [24], and to consider relevant population subgroups (healthcare workers, or individuals with chronic obstructive pulmonary disease, as considered by Purdy et al.[23]). Also, it could be useful to use the model to search for the optimal age of vaccination. Nevertheless, the choice of age of vaccination is likely to be influenced or constrained by the country-specific context.

It may be valuable to explore the cost–effectiveness of other subgroups of population. Nevertheless, authors will face incomplete data or even lack of information; for example, efficacy of booster during pregnancy. Therefore, the evaluation of such strategies would require strong assumptions.

Comparisons between epidemiological data in countries with different vaccination programs could be useful, and may provide clues about the potential extent of herd immunity effects. However, the disparity in vaccination policies (in terms of number of doses or age groups) inevitably has an impact on epidemiology, making the comparison difficult to interpret.

The majority of reviewed publications reported cost–effectiveness analyses (i.e., they addressed the issues of the value for money of booster vaccination). Budget impact analyses would also provide valuable information for decision makers about the affordability of vaccination. Although several articles provided costs with and without vaccination at country level, no full budget impact analysis on pertussis booster vaccination was found in the literature.

Moreover, it is expected that existing models will be adapted for future evaluations in other countries. Nevertheless, predictive validity of existing models, in particular of transmission dynamic models, is still to be assessed [39] and should now be performed prior to conducting further adaptations. For example, it would be interesting to compare the disease incidence observed in the USA following implementation of booster vaccination to that predicted by Coudeville et al.[16]. However, this comparison may not be straightforward due to geographical variations in vaccination uptake.

Last, we noticed the need for a consistent terminology across studies to refer to the different age groups, to distinguish between ‘young adults’ and ‘adolescents’, or ‘young children’ and ‘infants’.

Summary

Despite the differences at several levels between the analyses, economic evaluations were generally favorable to pertussis booster vaccination, especially in adults and adolescents, with some divergences concerning the age groups to vaccinate and exact epidemiological conditions under which vaccination would be cost effective. The existence of such divergences is hardly surprising given the lack of information available, and the assumptions authors had to make about epidemiological, vaccine-specific, costs and utility inputs. Furthermore, the epidemiology of pertussis varies over time, between countries, and sometimes between regions within countries. There remains uncertainty concerning the optimal vaccination policy to adopt, and future cost–effectiveness studies should explore and compare a wider range of strategies.

Five-year view

National health authorities have to consider not only health benefits, but also economic aspects when deciding to recommend and fund new vaccination programs. In this framework, health technology assessment of vaccination programs is performed. The latter give a statement/advice to policy decision makers on whether these new vaccination programs should be included in the current national immunization program and funded. Health economic evaluation is often an essential component of this health technology assessment, being a key decision tool in a context of rising budget constraint. Changes in health policy are hardly predictable, making future requirements for economic evaluations of vaccines difficult to anticipate.

In this review, all included analyses used assumptions for several inputs. However, more data will become available, whether from further models or from real-life assessments (data from countries with new vaccination programs). These estimates should be incorporated into new models, so that comparison of different strategies is more precisely performed. The results of clinical trials evaluating the efficacy of maternal immunization should become available by the end of 2012 [101].

In the absence of pertussis booster vaccination, new disease outbreaks are likely to occur in the future, which may strengthen the economic case for vaccination in coming years.

Table 1. Description of economic evaluations included in this review.

Study (year)	Journal	Sponsor	Country	Type of analysis	Strategies^†	Authors’ conclusion(s)	Ref.
European studies
Edmunds et al. (2002)	Vaccine	Independent	UK and Wales	CEA	(0) no booster vaccination (1) booster vaccination at 4 years of age (2) booster vaccination at 15 years of age	Introduction of acellular boosters, particularly at 4 years of age, has the potential to be cost effective in the UK	[19]
Lee et al. (2008)	Vaccine	Independent	Germany	CEA + CUA + economic impact analysis	(0) no adult booster vaccination (1) one-time adult pertussis vaccination at 20–64 years of age, where TdaP is administered instead of Td (2) adult pertussis vaccination with decennial boosters	The one-time adult vaccination strategy resulted in CE ratios of €5800 per QALY saved, or €160 per pertussis case prevented. The decennial booster strategy cost €7200 per QALY saved, or €200 per case prevented	[20]
De Vries et al. (2010)	PLoS ONE	GlaxoSmithKline	The Netherlands	CUA + economic impact analysis	(0) no booster vaccination (1) vaccination at the age of 12 years, with duration of protection equal to 8 or 15 years	ICERs are below €10,000 per QALY saved, for both durations of protection considered. Adolescent pertussis vaccination is likely to be a cost-effective intervention for The Netherlands	[13]
Westra et al. (2010)	Clinical Therapeutics	GlaxoSmithKline	The Netherlands	CUA + economic impact analysis	(0) current Dutch vaccination schedule (five doses) using an acellular pertussis vaccine (1) immunization at birth (2) cocooning strategy (3) maternal immunization (4) combine (2) and (3)	Addition of cocooning or maternal immunization to the current Dutch national immunization program would likely be cost effective or even cost saving	[21]
North American studies
Purdy et al. (2004)	Clinical Infectious Diseases	GlaxoSmithKline	USA	Economic impact analysis^‡	(0) no booster vaccination (1) adolescents 10–19 years of age (2) adults >20 years of age (3) adults >50 years of age (4) individuals >18 years of age with COPD (5) adults >15 years of age who are the primary caretakers of infants <1 year of age (6) healthcare workers >20 years of age (7) all persons 10 years of age (i.e., universal immunization)	The most economical strategy would be to immunize adolescents 10–19 years of age	[23]
Iskedjian et al. (2004)	Vaccine	Sanofi-Pasteur	Canada	CEA + economic impact analysis	(0) no booster vaccination (1) combined vaccination program including tetanus, dTacp administered at age 12 years	Administering a booster dose of dTacp at 12 years of age to replace diphtheria and tetanus vaccination at 14 years of age may reduce the economic burden of pertussis treatment in the long term at a reasonable cost	[17]
Iskedjian et al. (2005)	Paediatric Drugs	Sanofi-Pasteur	Canada	CEA + economic impact analysis	(0) current practice (1) booster in adolescence at the age of 14 years	Administering a booster dose of dTacp at 14 years of age to replace diphtheria and tetanus vaccination will slightly increase the economic burden from MOH and societal perspectives; however, the number of pertussis cases and the number of hospital admissions will decrease	[18]
Caro et al. (2005)	The Pediatric Infectious Disease Journal	Independent	USA	CEA + economic impact analysis	(0) no booster vaccination (1) adolescent booster	Although there is considerable uncertainty surrounding key inputs, the results indicate that the conditions required for adolescent immunization to be economically warranted are realistic	[14]
Hay et al. (2005)	The Pediatric Infectious Disease Journal	Independent	USA	Economic impact analysis	(0) no booster vaccination (1) adults >10 years of age (2) adults >20 years of age (3) adults >50 years of age (4) adolescents 10–19 years of age (5) persons >18 years of age with COPD (6) adults >15 years of age who are the primary caretakers of infants <1 year of age (7) healthcare workers >20 years of age	Immunizing adolescents with a pertussis booster in the form of Tdap is the most economical and easiest-to-implement strategy and should provide significant health and economic benefits	[24]
Lee et al. (2005)	Pediatrics	Independent	USA	CEA + CUA + economic impact analysis	(0) no vaccination (or status quo, with children being vaccinated at 2, 4, 6 and 12–15 months and 4–6 years of age) (1) one-time adolescent vaccination at 11 years of age (2) one-time adult vaccination at 20 years of age (3) adult vaccination with 10-year boosters (4) adolescent and adult vaccination with 10-year boosters (5) postpartum vaccination (vaccinating mothers after birth plus another adult caregiver after the firstborn child)	Routine pertussis vaccination of adolescents results in net health benefits and may be relatively cost effective	[15]
Lee et al. (2007)	American Journal of Preventive Medicine	Independent	USA	CEA + CUA + economic impact analysis	(0) no adult pertussis vaccination (1) one-time adult pertussis vaccination at 20–64 years, where Tdap is administered instead of Td (2) adult pertussis vaccination with decennial boosters	Routine vaccination of adults aged 20–64 years with combined tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis is cost effective if pertussis incidence in this age group is greater than 120 per 100,000 population	[25]
Coudeville et al. (2010)	PLoS ONE	Sanofi-Pasteur	USA	CEA + economic impact analysis	(0) childhood vaccination (1) childhood + adolescent (2) childhood + adolescent + cocoon (3) childhood + adolescent + cocoon + one dose at 40 years of age (4) childhood + adolescent + routine adult	By providing a high level of disease control, the implementation of an adult vaccination program against pertussis appears to be highly cost effective and often cost saving	[16]
Oceanic studies
Scuffham et al. (2004)	Vaccine	Independent	Australia	CEA + economic impact analysis	(0) childhood vaccination (1) at-birth immunization (2) 1-month vaccination (3) parental vaccination at birth	The birth vaccination strategy appears to offer the greatest potential for one-child families, but the efficacy at birth needs to be established	[22]

^†Strategy ‘(0)’ is the current situation of the country, as stated in the publication.

^‡Purdy et al. presents its analysis as a cost–benefit analysis; nevertheless, there is no monetary valuation of health benefits. It is counted as an economic impact analysis in this review, as is Hay et al., as it is based on Purdy et al.

CE: Cost–effectiveness; CEA: Cost–effectiveness analysis; COPD: Chronic obstructive pulmonary disease; CUA: Cost–utility analysis; dTacp: Diphtheria and acellular pertussis; ICER: Incremental cost–effectiveness ratio; MOH: Ministry of health; QALY: Quality-adjusted life-year; Td: Tetanus–diphtheria; Tdap: Tetanus–diphtheria–acellular pertussis.

Table 2. Summary of cost–effectiveness results.

Study (year)	Country	Comparator	Vaccination strategy									Ref.
			Adolescent	One-time adult	Cocooning	Decennial adult	Immunization at birth	Immunization at 1 month	Maternal immunization	COPD^†	HCW^‡
European studies
Edmunds et al. (2002)	England and Wales	No booster vaccination	✓ At ages 4 and 15 years	–	–	–	–	–	–	–	–	[19]
Lee et al. (2008)	Germany	No adult booster vaccination	–	✓	–	✓	–	–	–	–	–	[20]
De Vries et al. (2010)	The Netherlands	No booster vaccination	✓ At age 12 years	–	–	–	–	–	–	–	–	[13]
Westra et al. (2010)	The Netherlands	Current Dutch vaccination schedule	–	–	✓	–	×	–	✓	–	–	[21]
North American studies
Purdy et al. (2004)	USA	No booster vaccination	?	?	?	–	–	–	–	?	?	[23]
Iskedjian et al. (2004)	Ontario, Canada	Current practice: no booster	? At age 14 years	–	–	–	–	–	–	–	–	[17]
Iskedjian et al. (2005)	Quebec, Canada	Current practice: no booster	? At age 12 years	–	–	–	–	–	–	–	–	[18]
Caro et al. (2005)	USA	No booster vaccination	✓ At age 11–18 years^§	–	–	–	–	–	–	–	–	[14]
Hay et al. (2005)	USA	No booster vaccination	?	?	?	–	–	–	–	?	?	[24]
Lee et al. (2005)	USA	No booster vaccination	✓ At age 11 years	×	×	× Alone ✓! + adolescent	–	–	–	–	–	[15]
Lee et al. (2007)	USA	No adult pertussis vaccination	–	✓ If incidence >120 per 100,000	–	✓ If incidence >120 per 100,000	–	–	–	–	–	[25]
Coudeville et al. (2009)	USA	Childhood vaccination	✓!	+ cocoon + adolescent ✓ at age 40 years	+ adolescent ✓!	+ adolescent ✓!	–	–	–	–	–	[16]
Oceanic studies
Schuffham et al. (2004)	Australia	Childhood vaccination	–	–	–	–	×	×	×	–	–	[22]

^†Persons ≥18 years of age with COPD (i.e., asthma, chronic bronchitis, emphysema and so on).

^‡Healthcare workers ≥20 years of age.

^§Cost per life-year gained below US$23,000.

✓ Cost-effective strategy vs comparator.

! Strategy not cost effective vs an alternative booster strategy.

× Strategy not cost effective.

? No base-case incremental cost–effectiveness ratio or uncertain cost–effectiveness results.

COPD: Chronic obstructive pulmonary disease; HCW: Healthcare worker.

Table 3. Epidemiology input parameters used in economic evaluations.

Study (year)	Incidence rate^†	Under-reporting correction factor	Other epidemiological inputs	Epidemiological source	Ref.
European studies
Edmunds et al. (2002)	Not reported	Adolescents: 2.5 for GP consultation	0–0.25 years/0.25–4 years/5–14 years/15–44 years/>45 years, per 100,000 population per year Consultation rate: 38.58/107.88/49.27/5.33/2.21 Consultations per episode: 1.70 Admission rate: 89.58/15.17/2.11/0.02/0.02 LOS per admission: 7.27/2.33/2.36/8.33/9.31 Percentage time in intensive care (%): 1.1/0.00/0.00/0.00/0.00 Death rate: 1.29/0.04/0.00/0.00/0.00	Royal College of General Practitioners Weekly Returns Service Hospital Episode Statistics Office of National Statistics population projections	[19]
Lee et al. (2008)	Adults: 165 per 100,000 Adolescents: 95 per 100,000 Infants: 22 per 100,000	Not reported	Adult and adolescent disease outcomes Mild cough illness: 1% Moderate cough illness: 72% Severe cough illness: 26% Pneumonia (hospitalized): 1% Infant disease outcomes Respiratory (outpatient): 38.8% Respiratory (inpatient): 59% Neurologic: 1.2% Death: 0.7%	Not reported	[20]
De Vries et al. (2010)	Age specific	Age specific (up to 660)	Not reported	Not reported	[13]
Westra et al. (2010)	Infants <1 year of age 0 months: 9.0 per 100,000 1 month: 27.7 per 100,000 2 months: 23.4 per 100,000 3 months: 14.4 per 100,000 4 months: 6.9 per 100,000 5 months: 3.5 per 100,000 6 months: 10.1 per 100,000 7 months: 5.5 per 100,000 8 months: 10.3 per 100,000 9 months: 7.1 per 100,000 10 months: 6.4 per 100,000 11 months: 4.9 per 100,000 Adults 25–34 years of age 17.9 per 100,000	Adults: 200 Children: 1	Number of hospital admissions in infants <1 year of age 0 months: 9.0 per 100,000 1 month: 27.7 per 100,000 2 months: 23.4 per 100,000 3 months: 14.4 per 100,000 4 months: 6.9 per 100,000 5 months: 3.5 per 100,000 6 months: 4.2 per 100,000 7 months: 2.3 per 100,000 8 months: 4.3 per 100,000 9 months: 2.9 per 100,000 10 months: 2.4 per 100,000 11 months: 2.0 per 100,000 Adults 25–34 years of age 0.035 per 100,000	Literature, national databases and expert opinions	[21]
North American studies
Purdy et al. (2004)	Adolescents: 450 per 100,000 person-years Adults: 507 per 100,000 person-years (ages 10–19 years: 41%; 20–29 years: 7%; 30–39 years: 17%; 40–49 years: 28%)	Children aged 0–9 years: 2 (50% of cases among the US children aged 0–9 years not reported)	–	US Census Bureau population projections for 2001–2010	[23]
Iskedjian et al. (2004)	Adolescents (aged 12–17 years): 511 per 100,000 Young adults (aged 18–21 years): 65 per 100,000	Adolescents: 9	Adolescents (aged 12–17 years)/young adults (aged 18–21 years) Overall pertussis-related hospitalization rate: 1.07%/1.8% Overall rate of pertussis cases managed at clinic: 89%/89% Overall rate of pertussis cases managed at emergency room: 11%/11% Duration of hospital stay (days): 4.3/8.5 Physician office visits per pertussis case: 2.3/2.5 Sinusitis: 11%/15% Pneumonia: 2%/5%	Not reported	[17]
Iskedjian et al. (2005)	Adolescents: (14–17 years) 511 per 100,000 Young adults: (18–24 years) 65 per 100,000	Adolescents: 9	Adolescents (14–17 years)/young adults (18–24 years) Overall pertussis-related hospitalization rate: 1.07%/1.8% Overall rate of pertussis cases managed at clinic: 89%/89% Overall rate of pertussis cases managed at emergency room: 11%/15% Physician office visit per case: 2.3/2.5	Not reported	[18]
Caro et al. (2005)	(per 100,000 person-years) 0.2–57 (age-specific rates used)	All: 8.6 (Unreported cases/reported case: 7.6 [estimated by GPI], unreported cases [mild] 68%)	Case fatality: infants 0.69%, children 0.05%, adolescents 0.00%, adults 0.03% Hospitalizations per case: infants 58.5%, children 7.0%, adolescents 2.1%, adults 3.5%	Average of estimates from the CDC from 1996 to 1999	[14]
Hay et al. (2005)	Not clear	Not reported	Not clear	US Census Bureau population projections for 2001–2010	[24]
Lee et al. (2005)	Adolescents: 155 per 100,000 Adults: 11 per 100,000 Infants: 58.5 per 100,000	Not reported	Disease outcomes Severe cough: adolescents 58%, adults 67% Pneumonia: adolescents 1%, adults 3% Respiratory disease (hospitalized), infants: 58.5% Neurologic disease, infants : 2% Death, infants : 0.7%	Review of the literature, recent vaccine clinical trial data and unpublished data provided by the CDC and the Massachusetts Department of Public Health	[15]
Lee et al. (2007)	Not reported	Not reported	Adult with symptomatic pertussis Mild cough illness: 38% Moderate cough illness: 21% Severe cough illness: 40% Pneumonia (hospitalized): 1% Infant disease outcomes Respiratory (outpatient): 38.8% Respiratory (inpatient): 58.5% Neurologic: 2% [1] Death: 0.7%	Not reported	[25]
Coudeville et al. (2009)	90 per 100,000 for adult cases requiring medical attention	All: age specific	% of cases resulting from exposure to household contacts 0–1 months 48.1%, 2–3 months 48.1%, 4–5 months 48.1%, 6–12 months 33.6% 13–18 months 39.2%, 19–24 months 41.7%, 2 years 38.2%, 3 years 41.5%, 4 years 40.5%, 5 years 23.6% Case fatality rates Typical cases: <1 year 0.69%, 1–9 years 0.05%, 10–17 years 0%, 18+ years 0.03% Mild cases: <1 year 0.0%, 1–9 years 0.0%, 10–17 years 0.0%, 18+ years 0.0% Rates of long-term sequelae Typical cases: <1 year 0.06%, 1-9 years 0.02%, 10-17 years 0.02%, 18+ years 0.02% Mild cases: <1 year 0.0%, 1–9 years 0.0%, 10–17 years 0.0%, 18+ years 0.0%	Based on incidence data reported in APERT for adolescents and adults For children, CDC surveillance data were adjusted for under-reporting using age-specific under-reporting estimates	[16]
Oceanic studies
Schuffham et al. (2004)	Notified cases per 100,000 infants per week: 5.171	–	No. of GP consultations per case: 2.0 Probability of infections from parents: 0.51 Case duration: 2.0 weeks Hospitalization rate for notified cases (age ≤9 weeks): 0.529 Hospitalization rate for notified cases (age >10 weeks): 0.386 Probability of complication in hospitalized cases: 0.17 Probability of death from complications: 0.125 All-cause mortality rate per 1000 infants ≤4 weeks: 3.91 All-cause mortality rate per 1000 infants aged 5–52 weeks: 1.95	Health Outcomes Information Statistical Toolkit of the New South Wales Department Australian Childhood Immunization register	[22]

^†In most cases, it seems that the numbers provided are the numbers after correction for under-reporting.

GP: General practitioner; GPI: Global Pertussis Initiative; LOS: Length of stay.

Table 4. Herd immunity consideration in economic evaluations.

Study (year)	Herd immunity consideration	Comments	Ref.
European studies
Edmunds et al. (2002)	Yes	Results are presented according to herd immunity percentage, from 20 to 100% Herd immunity was estimated from transmission dynamic model solved at equilibrium. It is only considered in younger children, and impact on other populations is not considered at all	[19]
Lee et al. (2008)	Yes	10% among adults from 20 to 29 years of age, 12% from 30 to 39 years of age and 14% from 40 to 64 years of age	[20]
De Vries et al. (2010)	Yes	Transmission dynamic discrete event simulation model. Authors do not report direct and indirect effects of vaccination separately	[13]
Westra et al. (2010)	No	NA	[21]
North American studies
Purdy et al. (2004)	No	NA	[23]
Iskedjian et al. (2004)	No	NA	[17]
Iskedjian et al. (2005)	No	NA	[18]
Caro et al. (2005)	Yes	Reduction in nontarget cases (herd immunity): 20% Duration of herd immunity: 10 years Distribution of herd immunity: infants 20%, children 30%, adolescents 25%, adults 25%	[14]
Hay et al. (2005)	No	NA	[24]
Lee et al. (2005)	Yes	(Sensitivity analysis) Potential to reduce infant transmission for each strategy: 17% for the one-time adolescent vaccination strategy 10% for the one-time adult vaccination strategy 17% for the adult vaccination with 10-year boosters 35% for adolescent and adult vaccination with 10-year boosters 40% for the postpartum vaccination strategy (in both baseline and alternative analyses)	[15]
Lee et al. (2007)	Yes	(Sensitivity analysis) Potential to reduce infant transmission for each strategy: 15% for the one-time adult vaccination strategy 0, 15, 30 and 45% for the adult vaccination with decennial boosters	[25]
Coudeville et al. (2009)	Yes	Transmission dynamic compartmental model	[16]
Oceanic studies
Schuffham et al. (2004)	No	NA	[22]

NA: Not applicable.

Table 5. Cost parameters in economic evaluations.

Study (year)	Perspective	Monetary unit	Direct costs	Indirect costs	Vaccination costs	Ref.
European studies
Edmunds et al. (2002)	TPP and societal	1999/2000 GBP£	(≤0.25 years/0.25–4 years/5–14 years/15–44 years/>45 years) GP consultation: 24/24/24/24/24 Cost per inpatient day: 297/297/297/222/222 Cost per intensive care day: 1065/0/0/0/0	(≤0.25 years/ 0.25–4 years/ 5–14 years/ 15–44 years/>45 years) Work days lost: 0/7/7/7/7 Average daily wage: 50/50/50/52/67	Vaccine price Incremental cost of booster (vs Td): 5 (Assuming 15% wastage, then the cost per course of vaccine becomes 5.75 in the base case)	[19]
Lee et al. (2008)	TPP and societal	2006 €	Medical costs for adults Mild cough illness: 10; moderate cough illness: 97; severe cough illness: 165; pneumonia: 2435 Nonmedical costs for adults Mild cough illness: 58; moderate cough illness: 442; severe cough illness: 442; pneumonia: 789 Medical costs for adolescents Mild cough illness: 7; moderate cough illness: 72; severe cough illness: 122; pneumonia: 1802 Nonmedical costs for adolescents Mild cough illness: 20; moderate cough illness: 155; severe cough illness: 155; pneumonia: 276 Medical costs for infants Respiratory (outpatient): 43; respiratory (inpatient): 4771; neurologic: 2539 (not specified if inpatient or not); death: 4771 Nonmedical costs for infants Respiratory (outpatient): 119; respiratory (inpatient): 1132; neurologic: 1115; death: 1132		Vaccine price Incremental Tdap vs Td: 12 Administration costs Vaccine visit: 0 Vaccine administration: 0 Vaccine AEs Local reaction: 1 Systemic reaction: 1 Anaphylaxis: 1162	[20]
De Vries et al. (2010)	Societal	2008 €	Diagnostic procedures Chest radiography: 48.49; C-reactive protein: 6.09 Blood concentration determination: 9.74; PCR: 99.13 Serology: 43.38; culture: 15.00 Treatment Azithromycine for adolescents and adults: 8.20 Azithromycine for infants <12 years of age: 2.44/kg Prescription fee (pharmacist): 6.10 Consultations Consult GP: 21.75 Consult medical specialist: 52.89	Standard day care: 387.75 Pediatric intensive day care: 1500 Pediatric intensive care admission costs (one-off): 5000	Vaccine price: 18.30 Administration costs: 6	[13]
Westra et al. (2010)	TPP and societal	2008 €	(Ambulatory cases treated in hospital/GP) Diagnostics: 221.83/52.48 Visits to general practitioner: 22.59/45.18 Visits to specialist: 158.67/0 Treatment: 9.40 infant; 17.24 adult/9.40 infant; 17.24 adult	(Ambulatory cases treated in hospital/GP) Infants: 508.00/508.00 Adult female, reported: 254.00/254.00 Adult male, reported: 403.00/403.00 Adult female, unreported: 127.00/127.00 Adult male, unreported: 202.00/202.00	Vaccine price: 18.30 Administration costs: 6	[21]
North American studies
Purdy et al. (2004)	Societal	2002 US$	(Children/adolescents/adults) Outpatient costs Office/emergency department visit: 127.76/105.52/67.50 Medication: 22.98/22.45/16.50 Procedure/test: 73.93/46.66/57.03 Inpatient costs Number of inpatient days: 7/3/1 Total per inpatient day: 1100/1100/1100 Base-case hospitalization: 7700/3300/1100 Additional, by illness Seizures: 4000/3000/2000 Pneumonia: 2000/1300/1000 Encephalopathy: 6000/5000/4000 Terminal: 20,000/17,000/12,000	(Children/adolescents/adults) Work, hours: 48/16/28 Other activities, hours: 96/16/28 Total, per hour of activity: 22/22/22 Overall (base-case estimate): 3168/704/1232 Societal costs Per case of encephalopathy: 20,000/20,000/20,000 Per case of PBD: 2400,000/2400,000/2400,000 Per death: 5,000,000/5,000,000/5,000,000	Not reported	[23]
Iskedjian et al. (2004)	MOH and societal	2001 CAD$	Cost of purchasing and administering the vaccine, physician fees, hospitalization, contact tracing and cost of medications	Productivity loss by parents of younger adolescents or by older adolescents Younger adolescent hospitalized (work time lost = 1 day): 139.52 Older adolescent hospitalized (work time lost = 5 days): 697.60 Younger adolescent hospitalized (leisure time lost = 1 day): 139.52 Older adolescent hospitalized (leisure time lost = 5 days): 697.60 Younger adolescent nonhospitalized (work time lost = 2 h): 34.88 Younger adolescent nonhospitalized (leisure time lost = 4 h): 69.76 Older adolescent nonhospitalized (work time lost = 1 day): 139.52 Older adolescent nonhospitalized (leisure time lost = 1 day): 139.52 dT administration (1 h for 50% of subjects): 8.72	Vaccine price DTacp vaccine 20.82 + dT vaccine 5.10 Administration costs Physician outpatient injection 8.40 + nurse outpatient injection 1.00 Immunization supplies: 1.17	[17]
Iskedjian et al. (2005)	MOH and societal	2003 CAD$	Treatment costs Consultation clinic: 31.40 + physician on duty Emergency room: 36.40 Investigations Nasopharyngeal aspirate: 40.05 Chest radiograph: 20.75 Sinus radiograph: 31.00 Contact tracing: 273.08 Comorbidities Pneumonia: 130.66 + sinusitis 64.46 Hospitalization: per day 402.95	Productivity loss by parents of younger adolescents or by older adolescents Younger adolescent hospitalized (work time lost = 1 day): 139.52 Older adolescent hospitalized (work time lost = 5 days): 697.60 Younger adolescent hospitalized (leisure time lost = 1 day): 139.52 Older adolescent hospitalized (leisure time lost = 5 days): 697.60 Younger adolescent nonhospitalized (work time lost = 2 h): 34.88 Younger adolescent nonhospitalized (leisure time lost = 4 h): 69.76 Older adolescent nonhospitalized (work time lost = 1 day): 139.52 Older adolescent nonhospitalized (leisure time lost = 1 day): 139.52 dT administration (1 h for 50% of subjects): 8.72	Vaccine price DTacp vaccine: 20.82 + dT vaccine: 5.10 Administration costs 2.17 (administration + supplies)	[18]
Caro et al. (2005)	TPP and societal	2002 US$	Costs per case Infants: 5925; children: 546; adolescents: 300; adults: 337 Cost of long-term disability Annual direct 43,680 if institutionalized	Costs per case Infants 330; children 330; adolescents 55; adults 632 Cost of long-term disability Annual indirect 23,064 (lost wages)	Not reported	[14]
Hay et al. (2005)	Societal	Not reported	(Adolescent/adult) Hospitalization: 18/70 Physician visits: 104 /117 Chest radiography: 19/27 Laboratory test: 32/29 Prescription drugs Antibiotics: 57/58 Cough medicine: 3/15 Inhalers: 8/11 Total direct cost per case: 242/326	(Adolescent/adult) Childcare: 4/4 Transportation: 20/21 Informal caregiver time (unpaid): 14/41 Time costs (for adults) Work missed: 94/360 Hospitalization: 0/2 Emergency department visit: 1/2 Doctor visit: 12/4 Over-the-counter drugs Cough medicine: 5/7 Other (e.g., pain relievers, herbal agents): 4/5 Total indirect cost per case: 155/447 Societal total cost per case: 397/773	Not reported	[24]
Lee et al. (2005)	TPP and societal	2004 US$	Medical cost for mild cough Adolescent: 201; adult: 243 Medical cost for severe cough Adolescent: 256; adult: 338 Medical cost for pneumonia Adolescent: 402; adult: 373 Medical cost for infants Respiratory disease: 98 Respiratory disease with hospitalization: 6496 Neurologic disease: 6238 Death: 13,559 Nonmedical costs attributable to pertussis Adolescent: 160; adult: 460 Nonmedical costs for infants Respiratory disease: 43 Respiratory disease with hospitalization: 449 Neurologic disease: 688 Death: 652	–	Vaccine price Vaccine incremental price (vs Td): 15 Administration costs Adolescent or adult booster: 0 Significant other in postpartum strategy: 10 Cost of vaccine visit Adolescent or adult booster: 0 Significant other in postpartum strategy: 20 Vaccine AEs Cost of local reaction: 1 Cost of systemic reaction: 1 Cost of anaphylaxis: 2066	[28]
Lee et al. (2007)	TPP and societal	2005 US$	Medical costs for adults Mild cough illness: 50; moderate cough illness: 246; severe cough illness: 342; pneumonia: 377 Medical cost for infants Respiratory illness (outpatient): 99; respiratory illness (hospitalization): 6577; neurologic illness: 6315; death: 14,197 Nonmedical costs for adults: 466 Nonmedical costs for infants Respiratory disease (outpatient): 42; respiratory disease (hospitalization): 437; neurologic disease: 669; death: 660	–	Vaccine price Incremental Tdap vs Td: 20 Vaccine administration: 0 Vaccine adverse events Local reaction: 1 Systemic reaction: 1 Anaphylaxis: 2091	[25]
Coudeville et al. (2009)	Societal assumed	2006 US$	(<1 year/1–9 years/10–17 years/>18 years) Typical cases Short-term direct costs: 7006/646/256/338 Medical disability costs per year: 51,648/51,648/51,648/51,648 Mild cases Short-term direct costs: 377/256/219/265	(<1 year/1–9 years/10–17 years/>18 years) Typical cases Short-term indirect costs: 390/390/174/501 Indirect costs due to disability or death per year: 25,036/25,036/25,036/25,036 Mild cases Short-term indirect costs: 390/390/174/501	Vaccine price: 14.13^† Administration costs No additional administration costs Cocoon strategy (additional visit for father of newborns): 30 AE: 0.74/dose administered	[16]
Oceanic studies
Schuffham et al. (2004)	TPP	2000 AUS$	GP consultation: 23.45 Hospital admission with complications (age <1 year): 15.830 Hospital admission no complications (age <1 year): 2.815 Hospitalization for IHPS from erythromycin: 2.646 Treatment medications: 10.00		Vaccine per dose: 25.00 Administration costs Administration of vaccine as per schedule: 12.00 Administration of vaccine at birth: 9.00 Administration of parental vaccine: 12.00	[22]

^†For the cost of the vaccine itself, the authors applied the price difference between a combined Td vaccine and the price of a combined TdaP vaccine in the public sector, available at [102].

AE: Adverse event; dT: Diphtheria–tetanus ; DTacp: Diphtheria–tetanus–acellular pertussis; GP: General practitioner; IHPS: Idiopathic hypertrophic pyloric stenosis; MOH: Ministry of health; PBD: Permanent brain damage; Td: Tetanus–diphtheria; Tdap: Tetanus–diphtheria–acellular pertussis; TPP: Third-party payer.

Key issues

• • The cost–effectiveness of pertussis booster vaccination has been evaluated in 13 studies so far. Despite differences in methodology, results converge towards the same conclusion – that the pertussis booster vaccination is economically valuable where used in an appropriate context. However, there remains uncertainty concerning the optimal vaccination policy to adopt considering current pediatric vaccination schedule and affordability.

• • Disease incidence and under-reporting level were identified key cost–effectiveness drivers in sensitivity analyses.

• • A steady-state approach is unlikely to be sufficient; time horizon should be long enough to capture all relevant outcomes, but not too long, so that realistic results are provided.

• • There is a substantial need for more accurate data concerning incidence, under-reporting, utility and costs associated with pertussis disease. Such data could be obtained from new epidemiological studies, but modeling studies, in particular transmission dynamic models, may also provide insight into the epidemiology of pertussis.

• • Reviewed economic analyses were generally in favor of booster vaccination; nevertheless, further studies are needed to appropriately evaluate the most cost-effective strategy, taking into account country-specific considerations.

• • Future studies will also need to consider the indirect effects of vaccination, and potential specific externalities of vaccination should be taken into consideration.

Acknowledgements

We would like to thank Professor MJ Postma, Dr L Coudeville, Dr TJ Westra and Dr F Alvarez for comments on previous versions of this manuscript.

Financial & competing interests disclosure

This article was funded by Sanofi-Pasteur MSD. S Quilici is an employee of Sanofi Pasteur MSD. A Millier and S Aballea are employees of Creativ-Ceutical, which received funding from Sanofi Pasteur MSD. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.