University of Groningen Cost-effectiveness of vaccination strategies to protect older adults Boer ,de, Pieter Taeke

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University of Groningen

Cost-effectiveness of vaccination strategies to protect older adults

Boer ,de, Pieter Taeke

DOI:

10.33612/diss.126806948

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Boer ,de, P. T. (2020). Cost-effectiveness of vaccination strategies to protect older adults: Focus on herpes zoster and influenza. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.126806948

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strategies to protect older adults:

focus on herpes zoster and influenza

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This thesis was financially supported by Sanofi Pasteur, AstraZeneca, and the World Health Organization

Financial support for the printing of this thesis was kindly provided by the University of Groningen, Research Institute SHARE, and the Graduate School of Science and Engineer-ing of the University of GronEngineer-ingen

ISBN: 978-94-034-2476-7 (printed version) ISBN: 978-94-034-2475-0 (electronic version)

Cover: Temps, Dietmar. Table Mountain with clouds, Cape Town, South Africa [Digital image]. Retrieved from www.shutterstock.com.

Print: Ridderprint | www.ridderprint.nl

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strategies to protect older adults:

focus on herpes zoster and influenza

Proefschrift

ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen

op gezag van de

rector magnificus prof. dr. C. Wijmenga en volgens besluit van het College voor Promoties.

De openbare verdediging zal plaatsvinden op vrijdag 19 juni 2020 om 11.00 uur

door

Pieter Taeke de Boer

geboren op 21 maart 1985

te Wonseradeel

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Promotores

Prof. dr. M.J. Postma Prof. dr. J.C. Wilschut

Beoordelingscommissie

Prof. dr. J. Wallinga Prof. dr. P. Beutels Prof. dr. E. Buskens

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Werner Bijlsma Christiaan Dolk

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Chapter 1

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10 Chapter 1

Overview

Older adults are at increased risk of complications and dying from infections [1]. Immune re-sponses decline with age (immunosenescence), and older adults have an increased likelihood of having chronic medical conditions [2]. In Europe, 24% of the total disease burden caused by infectious diseases occurs among older adults aged ≥65 years, with influenza acknowl-edged as the most important contributor [3]. Moreover, infections among older adults cause a considerable economic burden to the health care sector and society. In the Netherlands, for instance, the health care costs of pneumonia and influenza in 2011 among older adults aged ≥65 years was €388 million, which was 55% of the total health care costs of these diseases in the population [4]. Given that developed countries currently deal with aging populations, it is expected that infections among older adults will put an increasing burden on health care facilities and the health care budget in the next decades.

Prevention of infectious diseases among the elderly through vaccination is becoming an in-creasingly important strategy to ensure healthy aging and to alleviate the pressure on the health care system. Nonetheless, despite the availability of vaccines, various vaccine-pre-ventable diseases among older adults still pose a substantial burden; these include influ-enza, pneumococcal disease, herpes zoster and pertussis [5]. Vaccination recommendations for older adults differ between countries. In the Netherlands, for instance, only vaccination against influenza is currently offered free of charge to older adults, while in the UK, next to the flu shot, vaccination programmes against pneumococcal disease and herpes zoster have been implemented already for at least several years [6]. Next to direct protection by vaccination of older adults themselves, it is also relevant to consider the indirect protection of older adults as a result of routine childhood vaccination programmes due to herd immuni-ty. Most developed countries have implemented childhood vaccination programmes against pneumococcal disease and pertussis (including the Netherlands), and several countries also recommend vaccination of children against influenza (e.g. US, UK, Finland) and varicella (e.g. US, Germany, Finland) [7], with potential herd immunity effects in some of these cases. As the number of available vaccines on the market increases, governments have to make decisions on which vaccinations to include in public programmes in the context of scarce resources [8]. To make evidence-based decisions, ministries of health are usually advised by national immunization technical advisory groups (NITAGs). These NITAGs assess vaccina-tion policies according to frameworks that include criteria on the disease burden as well as the effectiveness, safety, acceptability, efficiency and priority of vaccination. In the context of efficiency and priority of vaccination programmes, cost-effectiveness analyses play an increasingly prominent role. These analyses provide insight into the balance between the costs of vaccination and the associated benefits as compared to other strategies to reduce or

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treat the relevant disease burden. Nowadays, most European countries routinely consider economic evidence as part of their recommendations [9].

Aim of the study presented in this thesis

This thesis provides evidence on the cost-effectiveness of vaccination strategies to protect older adults against two diseases that cause a significant disease burden in this specific age-group: herpes zoster (HZ) and influenza. HZ is commonly seen in older adults, and has low risk of mortality but significant impact on the quality of life. When vaccines against HZ be-came available in the Netherlands, the following research questions bebe-came relevant for pol-icy makers: “What is the cost-effectiveness of introducing HZ vaccination for older adults in the Netherlands?”, “How do the available HZ vaccines compare to each other?”, and “What would be the optimal age to vaccinate?”.

Influenza causes significant morbidity and mortality among older adults each winter season, despite existing vaccination programmes for this age group. Potential vaccination strategies to improve the protection of older adults against influenza include the use of an improved vaccine for older adults themselves and to reduce the transmission of the influenza virus through vaccination of children. The following questions became relevant for policy makers: “What is the cost-effectiveness of a new quadrivalent influenza vaccine that contains anti-gens of one additional virus as compared to the traditionally used trivalent influenza vaccine cost-effective for the current target groups?”, “What would be the cost-effectiveness of pae-diatric influenza vaccination when taking into account indirect protection?” and “Is paedi-atric influenza vaccination a better strategy to protect older adults against influenza than a switch from the trivalent to the quadrivalent influenza vaccine for older adults themselves?”. The following sections of this chapter provide background on cost-effectiveness analysis in general, infectious disease modelling, reaching a decision on implementation of a specific vaccination, and the diseases herpes zoster and influenza and their vaccination modalities.

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12 Chapter 1

Cost-effectiveness analysis

Cost-effectiveness analyses help policy makers to decide how to optimally allocate a limited health care budget in order to maximize health [10]. The main outcome of such analyses is the incremental cost-effectiveness ratio (ICER), which expresses the extra costs paid to gain a single unit of benefit. The most often used measure of benefit is the quality-adjusted life year (QALY) that combines both quantity gains (averted mortality) and quality gains (averted morbidity) from health care interventions and thus allows the comparison of health care in-terventions across different diseases. Cost components included in the analysis depend on the adopted perspective of the analysis. The health care payer’s perspective includes only costs that are incurred by the payer, such as costs of general practitioner consultations, prescribed drugs and hospital admissions. The societal perspective includes all costs borne by society, including also costs incurred by the patient or productivity losses due to missed work days.

Infectious disease modelling

The highest grade of economic evidence is obtained when cost-effectiveness analyses are conducted alongside clinical trials [11]. However, evidence from clinical trials can be mis-leading if the endpoints are not translated into measures that are valued by patients, health care providers, and the general public [12]. Clinical trials do not usually include all available comparator interventions, often exclude certain patient groups of interest, may be too small to monitor rare disease outcomes, define immunological rather than clinical endpoints, of-ten have a limited follow-up period, and may lack ability to analyse herd immunity effects. To overcome these limitations, mathematical modelling is used widely in health-economic evaluations. Models use evidence on health effects and costs from many different sources, including data from clinical trials, observational studies, insurance claim databases, case reg-istries, public-health statistics and preference surveys [12].

Different types of mathematic models can be used to model the burden of an infectious disease and the impact of vaccination. Generally, these models can be divided in two cate-gories: ‘static’ models and ‘dynamic’ models. Static models, such as decision trees or Mar-kov-models, are relatively simple models with a fixed force of infection irrespective of the proportion of the population that is infected and can transmit the infection [13]. Accordingly, static models are appropriate for infectious diseases that are non-transmissible between hu-mans (e.g. tetanus, or rabies), and may therefore be used for interventions that do not impact significantly on the transmission of infection (e.g. hepatitis A vaccination for travellers from low- to high-endemic countries), or interventions of which the effects are expected to be almost entirely direct (e.g. vaccination programmes against herpes zoster or influenza among older adults). However, static models are not appropriate when an intervention significantly

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limits the transmission of infection between humans (e.g. childhood vaccination programmes against varicella or influenza). If the transmission of the pathogen involved is reduced by a vaccination programme and coverage is sufficiently high, unvaccinated individuals are also indirectly protected against the disease. This indirect protection is referred to as herd immu-nity. However, reduced transmission can also result in negative indirect effects, such as an increased average age of infection that may be associated with more severe disease (vari-cella) [14], and an increased risk of congenital infections, for example, when the mother is ill during pregnancy (rubella) [15]. Only dynamic models are able to capture these indirect effects by assuming that the force of infection is dependent on the part of the population that is infected. As a consequence, dynamic models allow studying the transmission of infectious disease within and between different age-groups.

Model calibration and validation

In infectious disease models, specific parameter values may be uncertain because the param-eters are unobservable or have not been properly studied yet. Model calibration is a process of determining input parameter values so that model outputs best recapitulate the observed values of the same output parameters [16]. The calibration process can be used to estimate such unobserved parameters, or to identify the best fitting set (or most plausible sets) of input values, including observed and unobserved parameters. Next to model calibration, validation of the model is important since it provides policy makers with information on how accurately the model predicts the outcome of interest. Model validation is a process of subjecting the model to tests, such as comparing model results with events observed in reality [16]. The model can be validated internally by comparing its results with data used to develop the mod-el (is the modmod-el performing wmod-ell mathematically?) or externally by comparing its results to other data sets. Model validation efforts also encompass other components such as the overall quality of the model (model structure, assumptions and input parameters), cross-validation to results of other models, and a subjective assessment or face validity [17].

Reaching a decision on implementation of a specific

vac-cination

As mentioned before, cost-effectiveness is one of the aspects considered in decision making on implementation of a certain vaccination strategy. Table 1 shows the decision framework that is used by the Health Council of the Netherlands to assess vaccine candidates for the national immunization programme (or “Rijksvaccinatieprogramma”) [18]. Considerations include the seriousness and extent of the disease burden, effectiveness and safety of vacci-nation, its acceptability, its cost-effectiveness and the urgency of the urgent public-health issue. When vaccination does not serve a population-level benefit but prevents serious

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dis-14 Chapter 1

ease in specific sub-groups, the Health Council of the Netherlands could also recommend offering vaccination within a public programme to promote equal access to ‘essential health care’ [19]. Then, vaccination should meet criteria on the seriousness of the individual disease burden involved, the effectiveness and safety of vaccination, and its cost-effectiveness. For instance, vaccination of older adults against HZ and influenza, the two diseases studied in this thesis, would qualify for essential health care rather than a population-level benefit, because these interventions aim to prevent individual disease among vaccinated individuals and not transmission of the infection.

Table 1: Criteria for inclusion of vaccination in the national immunization programme (or “Rijksvacci-natieprogramma”) of the Netherlands [8].

Seriousness and extent of the disease burden

1. The infectious disease causes considerable disease burden within the population. • The infectious disease is serious for individuals.

• The infectious disease affects or has the potential to affect a large number of people.

Effectiveness and safety of the vaccination

2. Vaccination may be expected to considerably reduce the disease burden within the population. • The vaccine is effective for the prevention of disease or the reduction of symptoms.

• The necessary vaccination rate is attainable (if eradication/elimination or the creation of herd immunity is sought).

3. Any adverse effects associated with vaccination are not sufficient to substantially diminish the public health benefit.

Acceptability of the vaccination

4. The inconvenience or discomfort that an individual may be expected to experience in connection with his/her personal vaccination is not disproportionate in relation to the health benefit for the individual concerned and the population as a whole.

5. The inconvenience or discomfort that an individual may be expected to experience in connection with the vaccination programme as a whole is not disproportionate in relation to the health benefit for the individual con-cerned and the population as a whole.

Efficiency of the vaccination

6. The balance between the cost of vaccination and the associated health benefit compares favourably to that associated with other means of reducing the relevant disease burden.

Priority of the vaccination

7. Relative to other vaccinations that might also be selected for inclusion, provision of this vaccination serves an urgent public health need at reasonable individual and societal costs.

When used as a decision rule, the ICER of a cost-effectiveness analysis is often compared with an established willingness-to-pay threshold for the outcome of interest. For instance, the willingness-to-pay threshold adopted by the National Institute for Health and Care Ex-cellence (NICE) in the United Kingdom is £15,000 to £30,000 per QALY gained [20]. When the ICER lies above this threshold, the intervention is deemed too expensive and may not be funded. The Netherlands has no clear decision rule for the cost-effectiveness of public-health interventions, but for preventive measures such as vaccination the Health Council of the Netherlands considers an ICER below €20,000 per QALY gained as cost-effective [21]. For introducing therapeutic measures in the basic health care insurance package, the National

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Health Care Institute uses cost-effectiveness thresholds of €20,000, €50,000 and €80,000 per QALY gained for diseases with low, moderate and high severity, respectively [21]. In view of the severity of some infectious diseases, the consistent use of the threshold at €20,000 per QALY in the Netherlands can be considered conservative for vaccines, and a threshold of €50,000 per QALY gained has been suggested for pneumococcal vaccination of children [22].

Vaccination against herpes zoster

Clinical overview

HZ is characterized by a painful, unilateral dermatomal rash. The life-time risk of HZ has been estimated at 20-30%, and its most important risk factors are older age and a compro-mised immune system [25, 26]. The most common complication of HZ is post-herpetic neu-ralgia (PHN), a potentially long-lasting pain syndrome with significant impact on the quality of life. PHN occurs in 3-19% of HZ patients, and its risk and severity increase with age [26-28]. HZ-related mortality is rare [29].

Varicella zoster virus

HZ is caused by the varicella zoster virus (VZV), which is a double-stranded DNA virus be-longing to the family of alpha-herpesviruses. Its primary infection causes varicella, a disease that occurs mostly in childhood and is characterized by fever and rash [23]. After primary infection, the virus remains latently present in the dorsal root ganglia. Natural immunity to VZV can be maintained through either endogenous or exogenous boosting; the former in response to subclinical reactivation of VZV and the latter from exposure to VZV in the community [24]. Herpes zoster occurs when VZV-specific cell-mediated immunity fails to contain viral reactivation.

Live attenuated varicella vaccine

The first vaccine developed against VZV is a live attenuated varicella vaccine that was li-censed in 1995. The varicella vaccine contains the live attenuated OKA VZV strain and is administered subcutaneously. Vaccination boosts both humoral immunity (production of VZV-specific antibodies) as well as cell-mediated immunity (VZV-specific T-cells), of which the latter is believed to cause the protective effect against VZV reactivation [23]. Some coun-tries have implemented VZV vaccination in their childhood immunization programmes. A meta-analysis from studies worldwide showed a vaccine effectiveness of 81% (95% confi-dence interval [95%CI]: 78-84%) after one dose and 92% (95%CI: 88-95%) after two doses. Live-attenuated VZV can reactivate to cause HZ, but the incidence of HZ in vaccinated

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16 Chapter 1

children has shown to be significantly lower as compared to naturally infected children [30, 31]. Some countries have been hesitant to introduce varicella vaccination in the national immunization programme, as the reduction of wild-type VZV circulation reduces exogenous boosting, which may potentially increase the incidence of HZ in adults [32]. The Netherlands currently has no paediatric vaccination programme against varicella.

Live attenuated HZ vaccine

Since the increased risk of HZ with older age is due to waning of immunity against VZV, vac-cination with live attenuated VZV could also protect adults against HZ. In 2006, a live attenu-ated vaccine against HZ (Zoster vaccine live [ZVL]) was licensed. This ZVL vaccine in prin-ciple is the same as the varicella vaccine, but it contains a higher dose of the live attenuated vaccine against varicella [33]. ZVL is administered subcutaneously, and is only available for immunocompetent adults aged 50 years and older [34]; hence, the vaccine is contraindicated to immunocompromised patients. A large-scale clinical trial among immunocompetent older adults aged ≥60 years demonstrated that the overall efficacy against HZ was 51% (95%CI: 44-58%), and that the severity of disease among those affected was reduced [35]. However, the efficacy against HZ declined with increasing age, and the protection appeared to wane completely within 10 years [36]. ZVL causes no serious adverse events, although mild ad-verse events such as headache and local injection-site reactions have been reported [35].

Subunit HZ vaccine

In 2018, a new HZ vaccine was registered that is a non-live recombinant subunit vaccine con-taining an immunoadjuvant (HZ/su) [37]. The vaccine is administered intramuscularly and contains the recombinant VZV glycoprotein E combined with the AS01_B adjuvant system to enhance the immunological response [38]. HZ/su is licensed for all individuals aged 50 years and older; hence, the vaccine can also be given to immunocompromised patients [37]. The vaccine induces strong glycoprotein E-specific humoral and cell-mediated immunity sufficient to elicit protection against reactivation of VZV [24]. A second dose given after two months improves cell-mediated immunity substantially [39]. Therefore, the vaccine is devel-oped for administration in two doses, given 2-6 months apart. Two large-scale clinical trials among immunocompetent older adults demonstrated that the efficacy of two doses was 97% (95%CI: 94-99%) in patients aged ≥50 years and 91% (95%CI: 80-97%) in patients aged ≥70 years [40, 41]. The duration of protection is currently unknown, but trial data showed a relatively stable efficacy over the 4 years of follow-up. HZ/su did not cause serious adverse events, although most vaccinated people reported pain, redness and swelling at the injection site [41]. About 1 out of 6 people experienced adverse events that prevented them from con-ducting their daily activities, although these symptoms resolved within 2-3 days.

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Vaccination against influenza

Clinical overview

Influenza is a respiratory infection caused by the influenza virus. It is characterized by a sudden onset of symptoms, including fever, cough, muscle pain, joint pain and sore throat. Globally, 5-10% of the adults and 20-30% of the children are annually infected with influen-za [42]. Possible complications due to influeninfluen-za are a secondary bacterial infection including pneumonia and otitis media. Influenza infections may result in hospitalization or even death [43]. People at highest risk of severe complications are older adults, those with chronic un-derlying disease, pregnant women, and children below two years of age [44]. The annual number of influenza deaths worldwide has been estimated at 290,000-650,000, with most deaths in older adults aged ≥65 years [42]. In countries with temperate climates, influenza usually circulates in the winter season, while in countries with subtropical or tropical cli-mates year-round influenza activity is observed [45].

Influenza virus

The influenza virus is a single-stranded negative-sense RNA virus belonging to the family of Orthomyxoviruses. In humans, three types of influenza viruses are circulating, influenza A, B and C, of which only influenza type A and B viruses cause seasonal epidemics [46]. Influenza A is further subdivided into subtypes based on the hemagglutinin (HA) and neur-aminidase (NA) surface proteins. Over the last few decades, influenza A/H3N2 and A/H1N1 subtypes have been commonly circulating in humans. Influenza B viruses are broken down into two lineages. Current antigenically distinguishable influenza B lineages are B/Victoria and B/Yamagata. Influenza A subtypes and B lineages can be further broken down into dif-ferent strains. These strains exist due to continuous antigenic changes to escape the immune response of the host due to small changes during replication (antigenic drift), resulting in annual epidemics of seasonal influenza. When a new influenza A subtype emerges due to a major change in HA and/or NA proteins subtype (antigenic shift), a pandemic or severe glob-al epidemics of influenza occur, because most people do not have immunity [47]. Four major influenza pandemics have happened over the past century: the 1918 pandemic caused by the A/H1N1 virus (“Spanish flu”), the 1957-58 pandemic cause by the A/H2N2 virus (“Asian flu”), the 1967-68 pandemic cause by A/H3N2 (“Hong Kong flu”) and the 2009 pandemic caused by the A/H1N1pdm09 virus (“Swine flu” or “Mexican flu” ). The A/H1N1pdm09 vi-rus, which was very different from A/H1N1 viruses circulating at that time, has now become one of the seasonal influenza viruses circulating each winter. Viruses that have caused past pandemics typically originated from animal viruses, especially from those circulating among birds.

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18 Chapter 1

Influenza vaccination

Most western countries have long-standing vaccination programmes against influenza. Tra-ditionally, these vaccination programmes focus on those at highest risk of complications, i.e. older adults and patients with certain chronic medical conditions. The Netherlands currently offers influenza vaccination free of charge to all adults aged ≥60 years and patients below 60 years with certain chronic medical conditions. Some other countries, most notably UK and Finland, also have introduced influenza vaccination for children. Next to direct protection, vaccination of children is also thought to reduce influenza spread in the population, indirectly protecting those at highest risk of complications. In the United States, influenza vaccination is recommended for all age-groups.

Available influenza vaccines include inactivated influenza vaccines (IVs) and live attenuat-ed influenza vaccines (LAIVs) which will be discussattenuat-ed in more detail below. Traditionally, these vaccines were trivalent (TIVs), containing strains against two influenza A subtypes (A/ H1N1 and A/H3N2) and one B lineage (either B/Victoria or B/Yamagata lineage). Due to the antigenic drift of influenza viruses, the vaccine composition is updated annually according to the recommendations of the World Health Organization (WHO). Therefore, people need to be revaccinated every year before the start of the influenza season. Since 2012, the WHO also provides recommendations on the composition of quadrivalent influenza vaccines (QIVs). Quadrivalent vaccines contain one extra B-virus strain (one of each B/Victoria and B/Ya-magata) as compared to TIVs and are available in the US since the 2013/2014 season and in Europe since the 2014/2015 season.

Inactivated vaccine

Intramuscularly administered IVs are the most commonly used influenza vaccines and are licensed in Europe for individuals aged ≥6 months [48]. Its influenza antigen preparation varies between manufacturers containing either whole virus, split virus or subunit influen-za virus products. The main protective effect of IVs is based on the boosting of humoral immunity that is specific to the virus-strains included in the vaccine, but there is possibly also a cell-mediated immune response [49]. However, IVs do not generally induce cytotoxic T-lymphocytes, which are important in limiting disease severity and are cross-reactive to antigenically distinct influenza viruses. Therefore, repeated use of IVs in young children that that are immunologically naïve to influenza viruses should be considered with caution, as it could inhibit the build-up of a broad long-lasting immune response, leaving them more susceptible to pandemic strains.

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The efficacy of influenza vaccines varies per season, country, virus and age-group. A me-ta-analysis of clinical trials estimated the efficacy of trivalent inactivated influenza vaccine (TIV) against laboratory-confirmed influenza at 58% (relative risk [RR] 0.42; 95%CI: 0.27-0.66) in older adults aged ≥65 years [50]. However, as most clinical trials were conducted more than a decade ago, recent evidence on vaccine effectiveness derives from observational data of implemented influenza vaccination programmes. A recent meta-analysis of test-neg-ative design studies estimated the vaccine effectiveness against laboratory-confirmed influ-enza in older adults aged ≥60 years at 44% (95%CI: 23-60%) when the vaccine matched the circulating viruses and 20% (95%CI: 3-34%) when the vaccine did not match the circulating viruses [51]. Vaccine efficacy is higher in children as compared to older adults. A meta-anal-ysis of clinical trial data estimated the vaccine efficacy of TIV against laboratory-confirmed influenza at 64% [RR 0.36; 95%CI: 0.28-0.48) in children aged 2-16 years [52].

Live attenuated influenza vaccine

Live attenuated influenza vaccine (LAIV) is an intranasally administered influenza vaccine. In Europe, LAIV is registered for children aged 2-17 years and since 2014/2015 only the quadrivalent LAIV (Q-LAIV) is available [53]. LAIV contains a temperature-sensitive vari-ant of the influenza virus that replicates well in the nasopharynx but poorly in the lower respi-ratory tract [54]. LAIV induces a humoral response as well as a cellular response including cytotoxic T-lymphocytes and also induces a local antibody response in the mucosa of the upper respiratory tract [49]. Given that LAIVs induce a broader immune response that more closely resembles a natural infection, LAIV is the preferred vaccine candidate for children that are immunologically naïve to influenza viruses. However, LAIVs are less effective in adults, presumably because pre-existing humoral immunity against influenza blocks replica-tion of the attenuated vaccine virus. In clinical trials, LAIV showed higher efficacy against laboratory-confirmed influenza in children as compared to IV. A meta-analysis of trial data estimated the efficacy of LAIV at 78% (RR 0.22; 95%CI: 0.11-0.41) in children aged 2-16 years [52]. However, recent observational data do not confirm the superior efficacy of LAIV, as studies reported lower, similar or higher vaccine effectiveness estimates of LAIV as com-pared to IV [55].

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20 Chapter 1

Thesis outline

The thesis is structured in two parts. Part I focuses on the cost-effectiveness of vaccination strategies against HZ and part II on the cost-effectiveness of vaccination strategies against influenza.

Part I: Herpes zoster

After the results of a large clinical trial of ZVL were published in 2005, a variety of cost-ef-fectiveness analyses have been performed in different countries using different models and assumptions. In Chapter 2, we reviewed the international literature on the cos-effectiveness

of vaccination against HZ for older adults with ZVL. In Chapter 3, we present results of a

cost-effectiveness analysis of ZVL in older adults in the Netherlands. As the burden of HZ increases with age but the efficacy of ZVL decreases with age, we performed an age-strati-fied analysis to determine the optimum age of vaccination. When HZ/su became available in 2018, decision makers needed health-economic evidence on the cost-effectiveness of vacci-nation with HZ/su and how the vaccine compared with ZVL. The efficacy of HZ/su is higher, but vaccination is presumably also more expensive as double dosing is required. In Chapter 4, we compared the cost-effectiveness of HZ/su and ZVL for older adults in the Netherlands.

We determined for each vaccine, dosing strategy and age of vaccination, the maximum costs per vaccination course to equal the conventional Dutch willingness-to-pay thresholds. In

Chapter 5, we briefly discuss results of a cost-effectiveness analysis of varicella vaccination

in the Netherlands in order to illustrate that HZ vaccination may also have value to counter a potential increase in HZ incidence in older adults following the introduction of a varicella vaccination programme among children. Such an increase in HZ incidence in older adults may occur when the varicella vaccination programme eliminates exogenous immune boost-ing against VZV [32, 56].

Part II: Influenza

When QIVs came available in the period 2013-2015, decision makers were in need of evi-dence regarding whether a switch from traditionally used TIVs to QIVs would provide good value for money. In Chapter 6, we reviewed the international literature on cost-effectiveness

analyses comparing QIV with TIV. Chapter 7 presents a cost-effectiveness analysis

com-paring QIV with TIV for the current programme in the United States. As the United States recommends influenza vaccination for all ages and has high coverage in children, we used a dynamic model for this analysis. Besides high-income countries, low- and middle-income

countries are also dealing with the question as to whether influenza vaccination should be introduced, and if so, whether QIV or TIV provides best value for money. Chapter 8 shows

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communities in South Africa and Vietnam using an individual-based dynamic model, and these findings were contrasted to results from a high-income community in Australia. The

Annex to Chapter 8 contains additional results on what would happen if the additional

money spent on QIV was used to stimulate the uptake of TIV. Chapter 9 describes the

epi-demiological impact and cost-effectiveness of a paediatric influenza vaccination programme in the Netherlands using a dynamic transmission model. As children are acknowledged to be the driver of influenza transmission, such a programme is expected to not only protect the children themselves but to also reduce the disease burden among older adults via herd im-munity. In addition, the study contains results of modelling a switch from TIV to QIV for the current target groups. As model validation and transparency of cost-effectiveness analysis are deemed important for sound decision making, Chapter 10 describes a systematic review of

modelling studies on seasonal influenza (and one other selected oncological disease area for comparison) to investigate and evaluate which model validation efforts had been performed. Finally, in Chapter 11 the main findings of part I and part II are discussed.

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14. Brisson M, Edmunds WJ, Gay NJ, Law B, De Serres G. Modelling the impact of immunization on the epide-miology of varicella zoster virus. Epidemiol Infect 2000, 125(3):651-669.

15. Anderson RM, May RM. Vaccination against rubella and measles: quantitative investigations of different policies. J Hyg (Lond) 1983, 90(2):259-325.

16. Eddy DM, Hollingworth W, Caro JJ, Tsevat J, McDonald KM, Wong JB, Force I-SMGRPT. Model transpar-ency and validation: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force--7. Value Health 2012, 15(6):843-850.

17. Vemer P, Corro Ramos I, Van Voorn G, Al MJ, Feenstra TL. Advishe: a New Tool to Report Validation of Health-Economic Decision Models. Value Health 2014, 17(7):A556-557.

18. Health Council of the Netherlands. The future of the national immunization program: towards a program for all ages [In Dutch] 2007 https://www.gezondheidsraad.nl/documenten/adviezen/2007/03/07/de-toe-komst-van-het-rijksvaccinatieprogramma-naar-een-programma-voor-alle-leeftijden. Accessed at 1 June 2019. 19. Health Council of the Netherlands. The individual, collective and public relevance of vaccination 2013

https://www.healthcouncil.nl/documents/advisory-reports/2013/10/03/the-individual-collective-and-pub-lic-importance-of-vaccination. Accessed at 1 September 2019.

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22. Rozenbaum MH, Sanders EA, van Hoek AJ, Jansen AG, van der Ende A, van den Dobbelsteen G, Rodenburg GD, Hak E, Postma MJ. Cost effectiveness of pneumococcal vaccination among Dutch infants: economic analysis of the seven valent pneumococcal conjugated vaccine and forecast for the 10 valent and 13 valent vaccines. BMJ 2010, 340:c2509.

23. Arvin AM. Varicella-zoster virus. Clin Microbiol Rev 1996, 9(3):361-381.

24. Heineman TC, Cunningham A, Levin M. Understanding the immunology of Shingrix, a recombinant glyco-protein E adjuvanted herpes zoster vaccine. Curr Opin Immunol 2019, 59:42-48.

25. Johnson RW, Alvarez-Pasquin MJ, Bijl M, Franco E, Gaillat J, Clara JG, Labetoulle M, Michel JP, Naldi L, Sanmarti LS et al. Herpes zoster epidemiology, management, and disease and economic burden in Europe: a multidisciplinary perspective. Ther Adv Vaccines 2015, 3(4):109-120.

26. Cohen JI. Herpes zoster. N Engl J Med 2013, 369(18):1766-1767.

27. Opstelten W, Mauritz JW, de Wit NJ, van Wijck AJ, Stalman WA, van Essen GA. Herpes zoster and posth-erpetic neuralgia: incidence and risk indicators using a general practice research database. Fam Pract 2002, 19(5):471-475.

28. van Wijck AJM, Aerssens YR. Pain, Itch, Quality of Life, and Costs after Herpes Zoster. Pain Pract 2017, 17(6):738-746.

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31. Weinmann S, Chun C, Schmid DS, Roberts M, Vandermeer M, Riedlinger K, Bialek SR, Marin M. Incidence and clinical characteristics of herpes zoster among children in the varicella vaccine era, 2005-2009. J Infect Dis 2013, 208(11):1859-1868.

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33. Oxman MN, Levin MJ, Shingles Prevention Study G. Vaccination against Herpes Zoster and Postherpetic Neuralgia. J Infect Dis 2008, 197 Suppl 2:S228-236.

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Gershon AA, Davis LE et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005, 352(22):2271-2284.

36. Morrison VA, Johnson GR, Schmader KE, Levin MJ, Zhang JH, Looney DJ, Betts R, Gelb L, Guatelli JC, Harbecke R et al. Long-term persistence of zoster vaccine efficacy. Clin Infect Dis 2015, 60(6):900-909. 37. European Medicines Agency. Shingrix: EPAR - Product Information 2018

https://www.ema.europa.eu/docu-ments/product-information/shingrix-epar-product-information_en.pdf. Accessed at 1 October 2018. 38. Cunningham AL. The herpes zoster subunit vaccine. Expert Opin Biol Ther 2016, 16(2):265-271. 39. Chlibek R, Smetana J, Pauksens K, Rombo L, Van den Hoek JA, Richardus JH, Plassmann G, Schwarz TF,

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40. Cunningham AL, Lal H, Kovac M, Chlibek R, Hwang SJ, Diez-Domingo J, Godeaux O, Levin MJ, McEl-haney JE, Puig-Barbera J et al. Efficacy of the Herpes Zoster Subunit Vaccine in Adults 70 Years of Age or Older. N Engl J Med 2016, 375(11):1019-1032.

41. Lal H, Cunningham AL, Godeaux O, Chlibek R, Diez-Domingo J, Hwang SJ, Levin MJ, McElhaney JE, Poder A, Puig-Barbera J et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med 2015, 372(22):2087-2096.

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43. Centers for Disease Control and Prevention. Flu Symptoms & Complications 2019 https://www.cdc.gov/ flu/symptoms/symptoms.htm?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fflu%2Fconsum-er%2Fsymptoms.htm. Accessed at 1 April 2019.

44. World Health Organization. Vaccines against influenza WHO position paper - November 2012. Wkly Epide-miol Rec 2012, 87(47):461-476.

45. Cox N. Influenza seasonality: timing and formulation of vaccines. Bull World Health Organ 2014, 92(5):311. 46. Centers for Disease Control and Prevention. Types of Influenza Viruses 2019 https://www.cdc.gov/flu/about/

viruses/types.htm. Accessed at 1 April 2019.

47. Centers for Disease Control and Prevention. How the Flu Virus Can Change: “Drift” and “Shift” 2017 https://www.cdc.gov/flu/about/viruses/change.htm. Accessed at 1 April 2019.

48. European Centre for Disease Prevention and Control. Types of seasonal influenza vaccine 2017 https:// ecdc.europa.eu/en/seasonal-influenza/prevention-and-control/vaccines/types-of-seasonal-influenza-vaccine. Accessed at 1 August 2018.

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ated Influenza Vaccines. Vaccines (Basel) 2015, 3(2):373-389.

50. Demicheli V, Jefferson T, Di Pietrantonj C, Ferroni E, Thorning S, Thomas RE, Rivetti A. Vaccines for pre-venting influenza in the elderly. Cochrane Database Syst Rev 2018, 2:CD004876.

51. Darvishian M, van den Heuvel ER, Bissielo A, Castilla J, Cohen C, Englund H, Gefenaite G, Huang WT, la Bastide-van Gemert S, Martinez-Baz I et al. Effectiveness of seasonal influenza vaccination in communi-ty-dwelling elderly people: an individual participant data meta-analysis of test-negative design case-control studies. Lancet Respir Med 2017, 5(3):200-211.

52. Jefferson T, Rivetti A, Di Pietrantonj C, Demicheli V. Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev 2018, 2:CD004879.

53. European Medicines Agency. Fluenz Tetra: EPAR - Product information 2013 https://www.ema.europa.eu/ documents/product-information/fluenz-tetra-epar-product-information_en.pdf. Accessed at 21 Dec 2018. 54. World Health Organization. Influenza 2018 https://www.who.int/biologicals/vaccines/influenza/en/. Accessed

at 1 April 2019.

55. Chung JR, Flannery B, Ambrose CS, Begue RE, Caspard H, DeMarcus L, Fowlkes AL, Kersellius G, Steffens A, Fry AM et al. Live Attenuated and Inactivated Influenza Vaccine Effectiveness. Pediatrics 2019, 143(2).

56. Thomas SL, Wheeler JG, Hall AJ. Contacts with varicella or with children and protection against herpes zoster in adults: a case-control study. Lancet 2002, 360(9334):678-682.

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Part I

Cost-effectiveness of vaccination

against herpes zoster

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Chapter 2

Cost-effectiveness of vaccination

against herpes zoster

De Boer PT, Wilschut JC, Postma MJ.

Human Vaccines & Immunotherapeutics 2014;10(7):2048-61

(https://doi.org/10.4161/hv.28670)

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28 Chapter 2

Abstract

Herpes zoster (HZ) is a common disease among elderly, which may develop into a severe pain syndrome labeled postherpetic neuralgia (PHN). A live-attenuated varicella zoster virus vaccine has been shown to be effective in reducing the incidence and burden of illness of HZ and PHN, providing the opportunity to prevent significant health-related and financial conse-quences of HZ. In this review, we summarize the available literature on the cost-effectiveness of HZ vaccination and discuss critical parameters for cost-effectiveness results. A search in PubMed and EMBASE was performed to identify full cost-effectiveness studies published before April 2013. Fourteen cost-effectiveness studies were included, all performed in west-ern countries. All studies evaluated cost-effectiveness among elderly above 50 years and used costs per quality-adjusted life year (QALY) gained as primary outcome. The vast major-ity of studies showed that vaccination of 60- to 75-year-old individuals would be cost-effec-tive, when the duration of vaccine efficacy was longer than 10 years. The duration of vaccine efficacy, vaccine price, HZ incidence, HZ incidence and discount rates were influential to the incremental cost-effectiveness ratio (ICER). HZ vaccination may be a worthwhile interven-tion from a cost-effectiveness point of view. More extensive reporting on methodology and more detailed results of sensitivity analyses would be desirable to address uncertainty and to guarantee optimal comparability between studies, for example regarding model structure, discounting, vaccine characteristics and loss of quality of life due to HZ and PHN.

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1. Introduction

Varicella zoster virus (VZV) causes chickenpox (varicella) and shingles (herpes zoster [HZ]). Varicella commonly occurs during childhood and is regarded as a mild self-limiting disease [1]. After remission, however, the virus remains latent, residing in the sensory nerve ganglia of the dorsal root, and can be reactivated decades later in life [2]. This reactivation episode is labeled HZ and is characterized by a painful dermatomal skin rash [1]. The lifetime risk to encounter HZ has been estimated at 20–30% [3], and the probability to develop HZ as well as the severity of pain increase with age [4,5]. Besides age, other risk-factors to HZ are a com-promised or suppressed immune system and the female gender [6,7]. Although the rash heals within a month [8], complications might occur. The most serious complication is postherpetic neuralgia (PHN), defined as a neuropathic pain persisting longer than three months [9]. It has been estimated that approximately 8–33% of HZ patients develop PHN, and the risk increases with age [4,10-12]. Pain due to PHN may remain for months or even years [13,14], and available therapeutic options are only partially effective [15]. PHN has been shown to have a substantial impact on the patient’s quality of life and functional status. Often reported sequelae of PHN comprise sleeping problems, chronic fatigue, anorexia, weight loss and depression, resulting in substantial interference with social life and self-care [4,14,16,17]. In 2006, a VZV vaccine with the tradename Zostavax® (Sanofi-Pasteur/MSD) was approved by the US Food and Drug Administration (FDA) as well as by the European Medicines Agency (EMA) [18,19]. Zostavax® contains a live attenuated strain of VZV and is thought to induce primarily T-cell-mediated immunity against VZV. A large double-blind placebo-con-trolled clinical trial including 38,546 immunocompetent adults ≥60 y of age (Shingles Pre-vention Study [SPS]) has demonstrated that the vaccine reduces the incidence of HZ by 51%, the pain burden by 61%, and the incidence of PHN by 67% [20,21]. However, the vaccine-induced protection seems to decline with age, with an efficacy against HZ of 64% among individuals of 60 to 69 y of age and 38% in individuals aged 70 y or older [20,21]. A more recent trial additionally showed that efficacy against HZ was 70% among of 50 to 59 y of age [22]. Regarding safety of the vaccine, multiple studies have shown that Zostavax® is well-tolerated and that side reactions are generally mild [20,23-26]. However, as the mean follow-up time of the SPS was limited to 3.1 y [20,21], the duration of the vaccine protection is still unknown. A short-term persistence substudy (STPS) of the SPS recently showed that vaccine efficacy persists for at least 7 y, but also demonstrated that protection is waning in time [27]. The vaccine is contraindicated for immunocompromised patients, as it comprises a live attenuated virus [19].

Given all this evidence, vaccination against HZ might be an interesting option for introduc-tion into naintroduc-tional immunizaintroduc-tion programs. Besides reducing the disease burden itself,

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pre-30 Chapter 2

vention of HZ and PHN may yield a significant benefit in limiting the economic burden to the healthcare. For instance, in the US, healthcare costs per acute episode of HZ were estimated at $431 and in the UK, healthcare costs of HZ and PHN were estimated at £103 and £397 per episode, respectively [28,29].

After the results of the SPS were published, multiple cost-effectiveness analyses for different countries have been performed. The aim of this review is to summarize and synthesize the literature on cost-effectiveness of routine vaccination against HZ and to identify those input parameters that are crucial in determining cost-effectiveness outcomes.

2. Methods

2.1 Search strategy

A bibliographic search was performed in MEDLINE and EMBASE for relevant papers as-sessing the cost-effectiveness of HZ vaccination (April 10, 2013). The search was restricted to the English language and the search algorithm was as follows: (‘herpes zoster’ OR ‘shin-gles’ OR ‘postherpetic neuralgia’) AND (‘vaccination’ OR ‘vaccine’ OR ‘Zostavax’ OR ‘im-munization’) AND (‘cost-effectiveness’ OR ‘cost-utility’ OR ‘cost-benefit’ OR ‘economic evaluation’ OR ‘pharmacoeconomics’). The search was limited to articles with an abstract. Only cost-effectiveness studies of HZ vaccination were assessed and original full papers were considered; reviews, editorials and letters were excluded. We screened titles, abstracts and finally the full content of the articles identified and selected. Studies on varicella vacci-nation only were excluded. Studies combining varicella and HZ vaccivacci-nation were excluded in the main analysis, but briefly discussed in a separated section. A manual examination of reference sections of included papers was performed in order to identify further material of interest (snowballing).

2.2 Synthesis of results

We focused in particular on those variables exhibiting a large impact on the cost-effective-ness and we assessed these parameters critically. Obviously, our analysis plan comprised a review of the main characteristics of the studies, including type of analysis, perspective, targeted population, time horizon, discount rates and a short description of main results. Furthermore, results were stratified by vaccination age, as incidence of HZ, risk to PHN and vaccine efficacies are highly dependent on age. Finally, we analyzed per study which parameters influenced cost-effectiveness results significantly. To improve the comparability of the selected studies, costs were standardized to 2006 euros according to country-specific harmonized consumer price indices. If the costing year was not provided in the study, we assumed a costing year of ‘publication year – 3 y’. Studies were evaluated with regards to

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various aspects, including model type, perspective taken and quality according to previously defined criteria.

3. Results

3.1 Study selection

A total of 369 studies were found in MEDLINE and EMBASE. After evaluation of titles, abstracts or full contents, 18 studies were identified that assessed the cost-effectiveness of HZ vaccination. Two studies were excluded, because full texts were not available [30,31]. However, their main results will be briefly mentioned when cost-effectiveness results are discussed. Two studies were excluded from the main analysis, but described in a separated section, because they assessed the cost-effectiveness of HZ vaccination combined with var-icella vaccination [32,33]. Finally 14 cost-effectiveness studies of HZ vaccination remained and were systematically reviewed [34-47].

3.2 Main study characteristics

Table 1 summarizes the main characteristics of the included studies ordered by publication date. Several studies did not mention all the main features reported in Table 1, such as time horizon, costing year, sensitivity analysis and funding. In these cases, we estimated most plausible values and options and explicitly marked this in the table.

3.2.1. Country and funding

Of the 14 studies included, 9 were conducted in European countries (UK, Belgium, The Neth-erlands, Switzerland and France) [34, 40-47] and 5 in non-European countries (US and Can-ada) [35-39]. Six studies were funded by the pharmaceutical industry [36,38,41,42,44,46], five studies by public resources [34,37,39,40,43,45], and two studies were performed without external funding [35,47].

3.2.2. Type of analysis

All 104 studies used the incremental cost-effectiveness ratio (ICER) as primary outcome, in which costs are expressed as monetary units and effects as quality-adjusted life years (QALY) gained. Several studies also performed a cost-effectiveness analysis, presenting re-sults as costs per averted HZ case [36,41,42,44,46], per averted PHN case [36,41,42,44,46] or per life year gained [34].

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32 Chapter 2

Table 1: Main characteristics and results of the included studies Reference; country Type of analysis Model design

Perspec

-tive

Vaccination age in years (range) Time Horizon Currency year; Dis

-count rate

Sensitivity analysis

Cost-ef

fectiveness results, ICER (cost per QAL

Y

gained)

(Short description of the studies in

Appendix B)

Funding

Edmunds et al. (2000) [34]; England & W

ales CUA, CEA D A model HCP 65 (45-80) Lifetime a £ (1998); C: 3% E: 3% One-way , multi-way

£8684 for a 65 year old assuming 10 year protection and £3560 assuming lifelong protection (£80 per vaccine course).

Public Hornber ger et al. (2006) [35]; USA CUA D A model Society ≥60, median age 69 (60- 85) Lifetime US$ (1995); C: 3% E: 3% One-way , multi-way , PSA Cost-ef

fective ($50,000 threshold) if vaccine price is

$100 and duration of vaccine protection is at least 20 years. No funding

Pellissier et al. (2007) [36]; USA CUA, CEA D A model HCP and Society ≥ 60 (60- 85) Lifetime US$ (2006); C: 3% E: 3% One-way , PSA $18,439-27,609 from payer ’s perspective and

$16,229-25,379 from societal perspective depending on input data source and assuming lifelong vaccine efficacy (vaccine price: $168). Cost-ef

fective below threshold of $50,000

when vaccine duration of efficacy is at least 12 years.

Industry Rothber g et al. (2007) [37]; USA CUA D A model Society ≥60 (60-69, ≥70) Lifetime a US$ (2005); C: 3% E: 3% One-way , multi-way $44,000 for a 70-year

-old woman to $191,000 for a

80-year

-old man (10 year duration of vaccine efficacy

and vaccine price of $149). Cost-ef

fective below thresh

-old of $50,000 for all adults ≥60 if vaccine cost of $46.

Public

Brisson et al. (2008) [38]; Canada

CUA D A model HCP 65 (50- 80) Lifetime Can$ (2005); C: 5% E: 5% One-way , PSA

Can$1277 to Can$73,609, depending on age and vaccine cost, assuming lifelong vaccine efficacy

. V

accinating

between 60-75 years is likely cost-ef

fective below

Can$40,000 threshold if duration of vaccine efficacy is at least 22 years (vaccine cost Can$150)

Industry

Najafzadeh et al. (2009) [39]; Canada

CUA DES model TPP >60 (60-74; >75) Lifetime Can$ (2008); C: 5% E: 5% One-way , PSA

Can$41,709 for vaccinating age-group >60 years, assuming vaccine cost of Can$150 and a vaccine effi

-cacy half-life of 15 years.

When vaccine cost is higher

than Can$150, the ICER increases above threshold of Can$50,000.

Public

Van Hoek et al. (2009) [40]; England & W

ales CUA D A model HCP 60, 65, 70, 75 Lifetime a £ (2006); C: 3.5% E: 3.5% One-way , PSA

Between £15,146 and £26,705 depending on age if dura

-tion of protec-tion is 7.5 years and vaccina-tion costs are £65.

Vaccine cost allowed to increase to £90-£100 to hold

cost-ef

fectiveness below £30,000 threshold.

Public

Annemans et al. (2010) [41]; Belgium CUA, CEA D A model TPP , HCP and Society ≥60 (≥50, ≥65, 60- 64, 65-69, 60-69) Lifetime € (2007); C: 3% E: 1.5% One-way , PSA

€6799 (TPP), €7168 (health care) and €7137 (societal) for elderly aged ≥60 years, assuming lifelong vaccine efficacy and vaccine cost of €141. One-way sensitivity analyses showed ICERs of €4,959-19,052, all below unofficial cost-ef

fectiveness threshold of €30,000.

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Reference; country Type of analysis Model design Perspec -tive

Vaccination age in years (range) Time Horizon Currency year; Dis

-count rate

Sensitivity analysis

Cost-ef

fectiveness results, ICER (cost per QAL

Y

gained)

(Short description of the studies in

Appendix B) Funding Moore et al. (2010) [42]; UK CUA, CEA D A model HCP and Society

>50 (50- ≥100 in 5-year age- groups)

Lifetime

£ (2006); C: 3.5% E: 3.5%

One-way

,

PSA

£13,077 (NHS) and £11,417 (societal) for vaccinating elderly aged ≥50 years, assuming lifelong vaccine efficacy and vaccine cost of £105. Duration of vaccine efficacy has to exceed 10 years to remain cost-effective (£30,000 threshold).

Industry

Van Lier et al. (2010) [43]; The Nether

-lands CUA D A model Society and HCP 60, 65, 70, 75, 80 Lifetime a € (2008); C: 4% E: 1.5% One-way , PSA

Societal: €21,716-38,519 depending on age, assuming duration of vaccine efficacy of 7.5 years and vaccine cost of €83. Healthcare: €40,503 (age 60 years). Cost-ef

fec

-tive for all vaccination ages, except 80 years, if duration of vaccine efficacy was 16.1 years (€20,000 threshold).

Public a Szucs et al. (201 1) [44]; Switzerland CUA, CEA D A model TPP and Society 70-79 (60- 69, ≥65, ≥75) Lifetime CHF (NA); C: 3.5% E: 1.5% One way CHF25,538 (€16,390) from TPP and CHF28,544

(€18,320) from societal perspective for 70-79 year olds, assuming lifelong vaccine efficacy and vaccine cost of CHF266 (€171).

A 12 year duration of vaccine efficacy

resulted in an ICER of CHF31,553 (€20,251).

Industry

Bilcke et al. (2012) [45]; Belgium CUA, CEA D A model HCP 60, 70, 80, 85 Lifetime € (NA); C: 3% E: 1.5% One-way ,-Multi-way

€1251-5498 most in favor and €45,160-297,141 least in favor of vaccination depending on age and assuming vaccine cost of €1

12.

Vaccination cost needs to decrease

below €67 to be cost-ef

fective among all scenarios (unof

-ficial threshold of €30,000)

Public

Bresse et al. (2013) [46]; France CUA, CEA D A model TPP and HCP 70-79, ≥65 Lifetime € (1998); C: 4% b E: 4% b One-way , PSA €9513 from TPP

and €14,198 from societal perspective

(70-79 year olds), assuming 10 year duration of vaccine protection and vaccine cost of €125.

Industry

De Boer et al. (2013) [47]; The Nether

-lands CUA D A model Society and HCP 60, 65, 70, 75 Lifetime € (2010); C: 4% E: 1.5% One-way

€29,664-35,555 from societal and €29,881-42,004 from health care payer

’s perspective, depending on age and

assuming 12 year protection and vaccine cost of €93. Vaccination was cost-ef

fective for 60 to 75 year

-olds,

using €50,000 threshold.

When €20,000 threshold was

applied, vaccination was only cost-ef

fective assuming

lifelong duration of vaccine protection

No funding

C: costs, Can$: Canadian dollar

, CEA: Cost-ef

fectiveness analysis, CHF: Swiss franc, CUA: Cost-utility analysis, DA: Decision analytic, DES: Discrete event simulation, E:

ef

fects, HCP: Healthcare payer

’s, HZ: Herpes Zoster

, NA: Not available,

TPP:

Third-party payer

.

a: Not clearly stated, assumed by the authors, b: 2% after 30 years

Table 1: Main characteristics and results of the included studies (

continued

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34 Chapter 2

3.2.3. Model design and alternatives

A total of 13 studies used a “traditional” decision analytic model to calculate the cost-ef-fectiveness of vaccination against HZ [34-47]. Decision models which were predominantly used concern cohort models and Markov models. One study used discrete event simula-tion (DES) modeling [39]. DES models are able to track the process of individual patients through particular states instead of cohorts. This provides the model with a ‘memory func-tion’ because specific attributes can be assigned to individuals and might in specific situa-tions provide a superior alternative over adding “tunnel states” into the Markov model to artificially create memory. Within the context of the 14 studies analyzed, a total of 9 different models were used [34,35,37-40,42,45,47], as some authors adapted already available models [36,41,43,44,46]. As no country already implemented HZ vaccination in its national immu-nization program when the analysis was performed, all studies compared routine vaccination against HZ with no such vaccination.

3.2.4. Perspective

The perspective that was most often used is that of the health-care payer, which only includes medical costs [34,36,38,40- 43,45-47]. A total of 8 studies used the societal perspective, tak-ing into account medical costs as well as costs due to productivity losses [35-37,41-44,47]. The third-party payer’s (TPP) perspective, only including reimbursed medical costs, was used by four studies [39,41,44,46]. Notably, one study can provide results from multiple perspectives.

3.2.5. Target group and time horizon

All studies targeted on population groups of 60 y of age or higher, however, some studies also assessed vaccination ages below this age [34,38,41,42]. Vaccination age was explicitly varied in sensitivity analyses by all studies. Most studies indicated that vaccination was re-stricted to the immunocompetent population [35-37,39-44,46,47], as the manufacturer of the VZV vaccine states that immunocompromised patients are contraindicated for the vaccine [19]. Only one study considered a scenario in which also immunocompromised patients would be vaccinated [45]. All studies used the life-time horizon [34-47].

3.2.6. Discounting

Discounting adjusts benefits and costs for the so-called ‘time preference’, since it is generally advantageous to receive a benefit earlier or to pay costs later (see Appendix A in Supplemen-tal material). The discount rates applied are highly dependent on national guidelines of the country for which the analysis is performed. A total of 9 studies applied an equal discount rate for costs and health effects [34-40,42,46], and 5 studies discounted costs at an higher rate than QALYs (differential discounting) [41,43-45,47].

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3.2.7. Sensitivity analysis

To deal with uncertainty, studies generally perform sensitivity analyses investigating the im-pact of varying parameters on the study results (see Appendix A in Supplemental material for detailed information on different types of sensitivity analyses). All reviewed studies per-formed a one-way sensitivity analysis [34-47]. In addition, two studies perper-formed a multi-way sensitivity analysis [37,45], and nine studies a probabilistic sensitivity analysis (PSA) [35,37-43,46].

3.2.8. Quality assessment

A review of Szucs et al. [49] evaluated the quality of 11 of the included studies using the

Brit-ish Medical Journal (BMJ)’s checklist by Drummond and Jefferson [50], and the “Quality of

Health Economic Studies” evaluation tool by Ofman et al. [51]. Szucs et al. [49] concluded that the quality of these studies varied from ‘Moderate’ [37, 38, 4337, 38, 43] to ‘Moder-ate-Good’ [35,36,39-42,44]. We assessed the three other included studies using the same criteria as Szucs et al. [49] used. The study of Bilcke et al. [45] was judged as ‘Good’ and the study of Bresse et al. [46] and de Boer et al. [47] were evaluated as ‘Moderate-Good’.

3.3 Main input parameters

An overview of input parameters used for the four important domains, i.e., epidemiological, QALY losses, vaccine characteristics and costs are shown in Table 2.

3.3.1. Epidemiological input

HZ incidence is an important parameter in economic evaluations of HZ vaccination given the direct relation with HZ and PHN cases potentially to be prevented. Table 2 shows that the ranges of HZ incidence used in the various studies vary little between different countries. Studies performed in the US seem to use on average somewhat higher incidence rates as compared with the rates used in European studies, especially in the age range of 60–70 y [35-37,39]. Logically, the HZ incidence increases with age in all studies. Multiple studies used HZ incidence rates adjusted to a immunocompetent population to be in line with the included population of the vaccine efficacy data [35, 36,39,40,42,43,45]. Concerning PHN incidence, most studies quantified the number of PHN cases directly from the number of HZ cases by using proportions [34-47]. One study used a different method by quantifying HZ on the basis of a severity of illness score, in which the burdens of HZ and PHN are combined [45]. The proportion of HZ cases developing PHN varied extensively between the studies. For exam-ple, in a Dutch study the proportion PHN cases out of HZ ranged between 4.7–11.7% among the different age groups [47], whereas a British study used a range of 9–52% [40].

University of Groningen Cost-effectiveness of vaccination strategies to protect older adults Boer ,de, Pieter Taeke