Cost-effectiveness of vaccination strategies to protect older adults
Boer ,de, Pieter Taeke
DOI:
10.33612/diss.126806948
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Publication date: 2020
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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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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
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.
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
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
dis-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
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
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 AS01B 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.
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.
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.
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].
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
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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