77 Economics and Vaccines

Transcription

1 Economics and Vaccines J. Bos. M. Postma 1 Introduction Modeling Economic Evaluations of Vaccines: Methodological Issues Cost-Effectiveness of Vaccine Interventions Childhood Cluster Diseases Vaccination Programs Measles, Mumps and Rubella (MMR) Vaccination Diphtheria, Tetanus, Pertussis and Polio (DTPP) Vaccination Varicella Vaccination Vaccination Campaigns Against Respiratory Diseases Hemophilus influenzae Type B Pneumococcal Vaccines Meningococcal Vaccines Influenza Vaccines Vaccination Campaigns Against Sexually Transmitted Infections and Other Vaccine-Preventable Viruses Hepatitis B Human Papilloma Virus (HPV) Hepatitis A Rotavirus Discussion and Conclusion Summary Points # Springer Science+Business Media LLC 2010 (USA)

2 1336 Economics and Vaccines Abstract: Infectious diseases are an important cause of mortality and morbidity, causing approximately 27% of the total disease burden in > DALY. A large part of DALY lost due to infectious diseases could be prevented by improving existing vaccination programs for the population. Diseases such as > childhood cluster diseases, hepatitis A and B, respiratory infections caused by influenza, pneumococcal and meningococcal infections, and Hemophilus influenzae type B, are for a large part preventable by current vaccines. The implementation of new vaccine programs or/and strategies is often a costly process with long term consequences. Vaccination programs often concern a large part of the population, and have a large budget impact. Once a vaccination program has started, it is (due to equity reasons) extremely difficult to cease the program. To gain a better understanding of the potential impact on health benefits and costs of a vaccine intervention, health-economic evaluations are frequently used, which estimate the future impact on health gains and costs. Health-economic evaluations are mostly presented as one of the following four types of analysis: cost-minimization, cost-benefit, cost-effectiveness and cost-utility analysis. In this chapter, we provide an overview of the main techniques and challenges associated with health economic evaluations of vaccination programs, such as the choice of the model. Additionally, an overview of health economic evaluations that have been performed on currently implemented vaccination strategies is presented. From our analysis it follows that vaccine programs, and especially those against childhood cluster diseases, and vaccination of elderly against influenza are amongst the world s most cost-effective interventions. List of Abbreviations: BCG, bacillus Calmette-Guérin; CBA, > cost benefit analysis; > CEA, cost effectiveness analysis; > CMA, cost minimization analysis; DALY, disability adjusted life year; > DTPP, diphtheria, tetanus, pertussis and poliomyelitis; > Hib, Hemophilus influenzae type b; > HPV, human papilloma virus; > IPV, inactivated poliomyelitis vaccine; > MMR, measles, mumps and rubella; > OPV, oral poliomyelitis vaccine; > QALY, quality adjusted life year; > WTP, willingness to pay; > VZV, varicella zoster virus 1 Introduction Despite the discovery of vaccines that helped to eradicate smallpox, the launch of a global campaign to eradicate poliomyelitis, and support the control of measles, diphtheria and other diseases, infectious diseases remain the leading cause of death in developing countries (WHO, 2007). Worldwide, infectious diseases are an important cause of mortality and morbidity, causing approximately 27% of the total disease burden in DALY (Authors calculation based on WHO, 2004 data). A large part of DALY lost due to infectious diseases could be prevented by improving existing vaccination programs for the population. Diseases such as childhood cluster diseases, hepatitis B, TB, respiratory infections caused by influenza, pneumococcal and meningococcal infections, Hemophilus influenzae type B, are for a large part preventable by current vaccines but still lead to a large burden of disease and mortality. > Table -1 provides an overview of the global burden of disease caused by infectious diseases. The implementation of new vaccine programs or/and strategies is an often costly process with long term consequences, due to the fact that (1) vaccination strategies often involve vaccination of large parts of the population and (2) once a vaccination program has started, it is (due to equity reasons) extremely difficult to cease the program. Additionally, in most cases,

3 Economics and Vaccines Table -1 Overview of major infectious diseases and DALY burden worldwide a All Causes Communicable conditions Infectious and parasitic diseases Tuberculosis STDs excluding HIV HIV/AIDS Diarrheal diseases Childhood-cluster diseases (Pertussis, Poliomyelitis, Diphtheria, Measles, Tetanus) Meningitis a Hepatitis B Hepatitis C Malaria Tropical-cluster diseases: Trypanosomiasis, Chagas disease, Schitomiasis, Leishmaniasis, lymphatic filariasis, onchocerciasis Leprosy Dengue Japanese encephalitis Trachoma Intestinal nematode infections Respiratory infections Lower respiratory tract infections, Upper respiratory tract infections, Otitis media Noncommunicable diseases Injuries Adapted from (Gwatkin and Guillot, 1998) a Total does not add up since we omitted DALY burden due to perinatal conditions and nutritional deficiencies decisions with regards to vaccination programs are public health policy decisions, making rational decision making a must. A better understanding of the potential impact of an intervention will enable policy makers to prioritize intervention in public healthcare, so that the available funds are spend in such a way that health care gains are being maximized. As a result, in an increasing number of countries, for new interventions to successfully apply for reimbursement, not only their clinical effectiveness has to be proven, but also their costeffectiveness (Cookson and Mc Daid, 2003). For the estimation of potential costs and benefits of the introduction of a new public health program, health-economic evaluations are frequently used, which estimate the future impact on health gains and costs. Health-economic evaluations are mostly presented as one of four types of analysis: cost-minimization analysis (CMA), cost-benefit analysis (CBA), costeffectiveness analysis (CEA) and cost-utility analysis (CUA), of which the latter two are used most often. In cost-minimization analysis, the interventions under study are assumed to have

4 1338 Economics and Vaccines similar efficacy and equal effectiveness. Only relevant costs are compared, and the cheapest intervention is assumed to be the most efficient. In cost-benefit analysis, the benefits of the intervention are expressed in monetary values, usually as the individual s willingness to pay (WTP) for a certain risk reduction in morbidity or mortality due to a new medical intervention (Johannesson and Meltzer, 1998). Concern over the monetary valuation of the resulting human lives, led to the development of cost-effectiveness analysis as an alternative. In costeffectiveness analysis, benefits of the intervention are expressed in a natural outcome measure, such as averted infections or life years gained. In cost-effectiveness analysis, differences in quality of life are not valued. Another form of cost-effectiveness analysis is cost-utility analysis, where health gains are corrected for the quality of life of the patient. Health benefits are then mostly expressed as quality adjusted life years (QALYs) or other denominators, such as disability adjusted life years (DALYs) (Johannesson and Meltzer, 1998). In a growing number of countries, such as the Netherlands, United Kingdom, Australia, and Canada, these evaluations are being used to guide policy making on the introduction on new public vaccination programs (Cookson and Mc Daid, 2003). For instance, the decision of the Netherlands to vaccinate all infants with meningococcal C vaccine on the age of 14 months was a direct effect of the health-economic analysis (Welte et al., 2005). 2 Modeling Economic Evaluations of Vaccines: Methodological Issues In economic evaluations of healthcare interventions, net costs are related to health gains, and expressed as a ratio such as the cost-effectiveness ratio of net costs per life-year gained. Net costs are estimated by subtracting the savings on averted infectious diseases treatment costs from the costs of the vaccines and the investment costs in administration and infrastructure. Both costs and health gains are corrected for the time of occurrence using an annual > discount rate. Vaccine interventions usually have the following features, which might set them apart from other interventions in public health: 1. Preventative character: Although therapeutic vaccines are being developed against certain forms of cancer for instance, most vaccines are given as prophylaxis. Some infectious diseases, such as hepatitis B and HPV infections, have an impact on the occurrence of severe complications much later on in life. This might pose a challenge to the analyst, since often long time frames of analysis need to be modeled. 2. Large scale, hence often large budgetary impacts: Whereas economic evaluations of other pharmaceuticals often target individual patients (or small patient populations), vaccine interventions in most cases concern a larger part of the population, causing the intervention to have a large budgetary impact. Therefore, when assessing these interventions, budget impact and allocation of the total budget will form an important aspect of the final decision. 3. Targeted against infectious diseases: Although some exceptions exist, (for instance vaccines are being developed against cancer) most vaccines target specific infectious diseases. Due to the communicable character of the agents causing disease, all indirect effects of removal of the pathogen from the population on those not vaccinated should also be included in the model. This is a challenge for the analyst, since the transmission mechanism of the causing agent needs to be assessed and included in the analysis. Additionally, an

5 Economics and Vaccines 1339 intervention against an infectious disease will gradually be subject to diminishing marginal returns. This occurs since vaccinating the population leads to a diminished > force of infection, causing the incidence of disease to drop. So, as the coverage of the vaccination program increases, more and more persons need to be vaccinated in order to prevent a single case of disease. This may well cause a paradox, in which eradication of disease is even more costly than disease control by selected vaccination strategies. 4. Incongruent timing between costs associated with the intervention and the resulting health benefits: Some diseases, such as HPV infections or hepatitis B infections have an impact on the occurrence of severe complications much later in life. Thus, a large time gap might exist between the costs of the intervention and the expected benefits of the intervention. Using equal discount rates for costs and health effects might have a large impact on the costeffectiveness ratio of the vaccine. In a recent consensus statement on vaccination programs for preventing Hepatitis B, Beutels et al. (2002) re-iterate that discounting health effects significantly and negatively affects estimated cost-effectiveness of vaccination programs with long term effects. In economic evaluations, it is good practice to use data from clinical trials. However, it has been argued that for the evaluation of vaccine programs, effectiveness data from clinical trials are not transferable to a real life setting (Clemens et al., 1996; Edmunds et al., 1999). Since vaccine trials are small in relation to population based vaccination programs, they can only provide an estimate of the individual efficacy of the vaccine and do not give a good estimate for the overall effectiveness of a mass vaccination campaign in the population. By vaccinating a large group in the population, the circulation of the bacteria or virus will diminish, leading to a reduction of disease beyond the direct effects of vaccination. As a consequence, the force 1 of infection diminishes. So, by mass vaccination, a certain level of protection is also offered to those in the population who are not vaccinated (Edmunds et al., 1999). This phenomenon is called > herd immunity not correcting for it may cause an underestimation of the effect of the intervention (Edmunds et al., 1999). Another consequence of a diminished force of infection is that infections will occur at a later age. This shift in agespecific incidence can have great implications for public health, especially for diseases that have worse outcome when occurring at a later age (for instance varicella zoster infections) (Beutels et al., 2002). Cost-effectiveness analyses of vaccination programs that assess the transmission of disease, use either a static or a dynamic transmission model. The difference between a static or a dynamic model lies in the assumption of the value of the force of infection. A static model assumes that the force of infection is a constant, while in a transmission dynamic model the force of infection is a function of the number of infectious individuals in the population (Edmunds et al., 1999). In the latter, herd immunity effects of mass vaccination on the force infection are taken into account. Also, in transmission dynamic models the effects of vaccination on for instance the age-specific incidence rate are assessed. In > Table -2, an overview is presented of the most important model types and characteristics. 1 The force of infection is defined as the per-susceptible rate of infection. The force of infection can be calculated approximately by dividing the incidence by the number of susceptibles

6 1340 Economics and Vaccines. Table -2 Key characteristics of the models (Bos et al., 2008) Key assumption Model type Main features Static Constant force of infection Decision analysis/ Markov model Dynamic Force of infection is a function of the fraction infected (Age-structured) compartmental model Simple Minimal data requirements Complex Needs detailed data on transmission dynamics Able to evaluate impact of herd immunity Accounts for shift in agespecific incidence rates Gives insight in shifts in costeffectiveness ratio over time 3 Cost-Effectiveness of Vaccine Interventions In this section, we will provide an overview of most common vaccination programs in developed countries, their cost-effectiveness and the cost-effectiveness models used for the analysis. A large number of vaccines have been in use in public health interventions for quite some time, as is illustrated in > Table -3 (which is by no means exhaustive). The cost-effectiveness of an intervention is usually measured compared to the do-nothing alternative. A number of these vaccines have been in use for a long period of time, making the cost-effectiveness of these vaccines is difficult to measure. The effects of the vaccine on the epidemiology and transmission of disease depend highly on the fact that a vaccine has been given for a very long period in time before starting the analysis. Therefore, it is impossible to calculate the cost-effectiveness against the do-nothing scenario. Additionally, the decision to vaccinate against these diseases has been made a long time ago, in a time where health economic evaluations of public health interventions were not performed. However, costeffectiveness studies on adaptations of those vaccines, for instance different formulations with less side-effects and/or higher efficacy, are frequently used by policy makers. 3.1 Childhood Cluster Diseases Vaccination Programs This category consists of vaccination programs against common childhood diseases, such as measles, mumps, diphtheria, tetanus, poliomyelitis, rubella, and pertussis. Cost-effectiveness analysis of the original interventions with Measles, Mumps, Rubella vaccine (MMR) and polio and Diphtheria, Tetanus and Pertussis (DTP) vaccines have only been performed to a limited extend. These childhood vaccines are commonly cited to be among the most cost-effective interventions, and have resulted in the saving of millions of lives of infants and young children (WHO, 2008). A recent study estimated that a one-week supplemental immunization activity against measles carried out in Kenya in 2002 in which 12.8 million children were vaccinated would result in a net savings of US$12 million over the following ten years; during

7 Economics and Vaccines Table -3 Introduction of first generation vaccines Vaccine Year of introduction first generation vaccine for human use Smallpox 1798 Rabies 1885 Plague 1897 Diphtheria 1923 Pertussis 1926 Tuberculosis (BCG) 1927 Tetanus 1927 Yellow fever 1935 Injectable Polio vaccine (IPV) 1955 Oral Polio vaccine (OPV) 1962 Measles 1964 Mumps 1967 Rubella 1970 Hepatitis B 1981 Influenza 1953 Hepatitis A a 1995 Hemophilus influenza type B 1992 Pneumococcal conjugate vaccine 2000 Pneumococcal vaccine polysaccharide b 1948 Meningococcal C vaccine 1999 Meningococcal A, Y, W135 and C vaccine 2005 Adapted from Plotkin and Mortimer (1994) a and b Baker (2007) and Austrian (1981) which it would prevent 3,850,000 cases of measles and 125,000 deaths. In the United States, cost-benefit analysis indicated that every dollar invested in a childhood disease vaccine dose saves US$2 to US$27 in health expenses (WHO, 2008) Measles, Mumps and Rubella (MMR) Vaccination Since the vaccines against measles, mumps and rubella are usually given in the MMR combination vaccine, we will discuss both health-economic analyses of single vaccine interventions, such as revaccination after an outbreak of measles, as well as the cost-effectiveness of MMR vaccine. Few studies have been undertaken to assess the cost-effectiveness of the MMR vaccine since it s introduction in general vaccination programs in the second half of last century. Most studies focus on adaptations of existing formulations, or changes in target population. A single study from 1985 was found that compared vaccination with MMR

8 1342 Economics and Vaccines vaccine to the do-nothing scenario in the US, and found the intervention to be cost-saving (White et al., 1985). Without an immunization program, an estimated 3,325,000 cases of measles would occur as compared to 2,872 actual cases in 1983 with a program. Instead of an expected 1.5 million rubella cases annually, there were only 3,816 actual cases. Mumps cases were lowered from an expected 2.1 million to 32,850 actual cases. Without a vaccination program, disease costs would have been almost $1.4 billion. Expenditures for immunization, including vaccine administration costs and the costs associated with vaccine reactions, totaled $96 million. The resulting benefit-cost ratio for the MMR immunization program was approximately 14:1. The savings realized due to the use of the combination vaccine rather than single antigen vaccines totaled nearly $60 million (White et al., 1985) Measles Vaccine Despite the lack of formal cost-effectiveness studies, measles vaccination is cited to be among the most cost-effective public health interventions implemented world-wide. (WHO, 2008)A few studies have been conducted on the cost-effectiveness of additional vaccination in the case of a measles outbreak, or on measles eradication strategies. Stover et al. (1994) assessed the cost-effectiveness of a program to identify and immunize susceptible hospital employees during a measles outbreak. In three US hospitals, they compared blind MMR vaccination with targeted MMR vaccination to only those at risk (being those born from 1957 onwards). Their analysis showed that a directed MMR immunization program was projected to be costeffective compared to universal MMR vaccination of all hospital employees. However, no formal transmission model was used, making it difficult to assess the effects of vaccinating hospital workers on the transmission of measles, mumps or rubella to the patient population. Sellick et al. (1992), also showed targeted measles immunization for susceptible workers to be more cost-effective than universal vaccination. A few studies were found that assessed the cost-effectiveness of improved measles control or measles eradication within the general population. Pelletier et al. (1998) studied the benefitcost ratio of two-dose measles vaccination of infants in Canada, using a transmission dynamic model. Zwanziger et al. (2001) used a static approach to evaluate the economic impact of increasing measles immunization rates in the United States. They examined the relationship between measles incidence and the immunization rate and converted it to a linear model, which was linked to a decision analysis model to assess the cost-effectiveness. The decision analysis study by Shiell et al. (1998) used similar methodology to assess the cost-effectiveness of measles vaccination to prevent school-based outbreaks in Australia, finding favorable costeffectiveness. A study by Gay et al., used a transmission dynamic model to assess the impact of adding a second booster dose of measles vaccine for infants aged 18 months or 5 years to the national vaccination program in Canada (Gay et al., 1998). Their model analyzed the transmission between five different age groups over time. The results of this modeling study showed that a combination of a catch-up campaign and a booster vaccine for infants would have an immediate impact in reducing the transmission of measles, whereas adding only a routine second dose would still allow endemic transmission between older infants for at least years. Beutels and Gay (2003) analyzed the costs and benefits of the eradication of measles, using a transmission dynamic model that simulated ten different measles vaccination strategies for a hypothetical west-european country. The conclusion of this analysis was that very high (>95%) coverage two-dose vaccination is optimal, irrespective of past vaccination coverage. Additionally, the addition of a catch-up campaign to this two-dose vaccination strategy would

9 Economics and Vaccines 1343 be cost-saving in the case of low historical coverage (<70%). Miller et al. developed a static model for analyzing measles eradication interventions in the US (Miller et al., 1998), estimating that measles eradication would save an estimated US$ 45 million. However, in this study the transmission of measles was not incorporated giving little insight in the coverage rates needed for eradication, timing of eradication and potential age-shifts Mumps and Rubella Vaccines Few economic evaluations have been performed of these vaccines. A review study done by Hinman et al. (2002), showed that in total five economic analyses of Rubella vaccine and seven economic analyses of MMR vaccine had been performed in developed countries. This review study indicated that the comparability of the individual study results was hampered by a lack of standardization in study design and methods used. The results of these studies showed favorable cost-effectiveness for rubella and MMR vaccines, supporting the decision to include this vaccine in national vaccination programs Diphtheria, Tetanus, Pertussis and Polio (DTPP) Vaccination No specific studies were found evaluating DTP or DTPP vaccines. However, separate evaluation of pertussis vaccination and polio vaccines were found. A number of evaluations of pertussis vaccine were found comparing acellular pertussis vaccine with whole cell pertussis vaccine, where the latter vaccine formulation would have a higher incidence of side-effects (Beutels et al., 1999; Caro et al., 2005; Ekwueme et al., 2000; Tormans et al., 1998). Additionally, several studies analyze the impact of a pertussis booster vaccine given later in the infants life (Edmunds et al., 2002; Iskedjian et al., 2004; Purdy et al., 2004; Stevenson et al., 2002). All studies, except the study by Edmunds et al., used a static transmission model. All studies on whole cell pertussis versus acellular vaccine showed that the acellular vaccine was more cost-effective, since all studies projected higher efficacy rates for the acellular vaccine (Caro et al., 2005). A small number of studies were found that evaluated the effects of increasing efforts to eradicate polio (Bart et al., 1996; Kahn and Ehreth, 2003; Thompson and Duintjer Tebbens, 2006, 2007). In general, these studies concluded that the eradication of polio would be costeffective. A study by Thompson (Thompson and Duintjer Tebbens, 2006) concluded that the poliomyelitis vaccination program in the US is a highly cost-effective intervention, responsible for the prevention of hundreds of thousands of cases of paralytic poliomyelitis and premature deaths, and has yielded net economic benefits exceeding US$180,000 million. In another study by Thompson et al., a dynamic transmission model was used to assess the costs and benefits of worldwide polio eradication versus controlling poliomyelitis levels by increasing vaccine coverage (Thompson and Duintjer Tebbens, 2007). Their study supports the completion of eradication now, instead of controlling poliomyelitis Varicella Vaccination Varicella zoster virus (VZV) is a herpes virus that causes both varicella (commonly known as chickenpox) and herpes zoster. When a person becomes infected for the first time with VZV, it results in varicella, which is a mild illness (although severity increases with age). After the initial Varicella infection, VZV becomes latent in the dorsal root ganglia and can reactivate

10 1344 Economics and Vaccines after a long period to cause herpes zoster (Miller et al., 1993). Reactivation occurs in 15 25% of individuals, of which over 70% are adults (Brisson et al., 2000). Zoster is associated with severe morbidity (hospitalization occurs in 4% of cases, median duration of hospitalization of 18 days) and significant case fatality (0.07% of cases), making herpes zoster an essential issue to be considered when analyzing the epidemiology of VZV (Brisson et al., 2000). The precise relationship between varicella and zoster incidence is still unclear, it has been suggested that varicella can decrease the risk of zoster by boosting specific immunity to VZV (Brisson et al., 2000). This relationship implies that a reduction of VZV in the population may have adverse effects on the incidence of zoster. By reducing the exposure to natural varicella and shifting the average age of infection upwards, widespread vaccination would have two potentially adverse consequences. Firstly, the severity of varicella illness increases with age. Therefore infant vaccination avoids mostly cheap cases of varicella in infants, but partly replacing them by more expensive older cases. Secondly, the incidence of herpes zoster (shingles) at older ages temporarily increases if (1) periodical exposure to wild-type VZV infection (i.e., exposure to infectious children) boosts immunity to zoster, and (2) breakthrough varicella cases occur on a limited scale with relatively low infectiousness (Brisson et al., 2000). These effects may have a profound effect on the cost-effectiveness and morbidity caused by VZV (Postma et al., 2003). A live attenuated VZV vaccine has been available since the middle of the 1970s. Currently in the United States and Japan varicella vaccination is included in the childhood immunization schedule (Postma et al., 2003). Several health economic studies have been performed on the introduction of this vaccine for infants. Thiry et al. (2003) reviewed economic evaluations of varicella vaccination, identifying ten studies on infant vaccination. The studies showed costsavings from the societal perspective (benefit-to-cost ratios varying from 1.6 to 6.9). From the societal perspective it was primarily vaccine price and averted unproductive days by parents (indirect costs averted) caring for sick children that determined cost savings. However, all these studies excluded the impact of zoster on the analysis, and used no formal dynamic transmission model. A study by Edmunds et al. (2002) on the cost-effectiveness of Varicella vaccination of infants in Canada was the first to take the potential increase in zoster into account (Brisson and Edmunds, 2002). The inclusion of zoster influenced their results, raising baseline net costs per life-year gained by almost 200%. They estimated that universal infant vaccination may increase the incidence of zoster by 13% (during an analytic period of 30 years and discounted at 3%). We do note that the relationship between VZV infection and zoster as specified by Brisson and Edmunds (2002) has been challenged (Seward et al., 2002). Other theories suggest, for example, subclinical reactivation of VZV with uncertain impact on zoster. Previously, Edmunds et al. (2001) analyzed the epidemiological and economical burden of herpes zoster and its complications (in particular, after herpetic neuralgia) for England and Wales. They estimated that direct medical costs of zoster amounted to almost 70 million annually ( 1.3 per citizen). Adolescent varicella vaccination has also been studied. Banz et al. (2003), Beutels et al. (1999), and Brisson and Edmunds (2002) all indicated superior pharmacoeconomic profiles for vaccinating 12-year-olds as opposed to infants. Brisson and Edmunds (2002) conclude that the attractiveness of preteen vaccination from an economic perspective remains robust under varying plausible parameter, model and methodological, assumptions. For example, the impact of including zoster is very limited in preteen vaccination, as transmission of varicella occurs mostly through contact with very young children who continue to be infected under

11 Economics and Vaccines 1345 this strategy. Obviously, if combined with screening, only those year olds at risk are targeted (approximately 10%), limiting the budget impact of vaccination. To conclude, there is still considerable uncertainty around the interaction between Varicella vaccination and zoster. The potential adverse effects of Varicella vaccination on increases in the incidence of zoster could reverse the cost-effectiveness ratio of universal infant vaccination. Therefore, it is important to consider alternative vaccination strategies that show less sensitivity to the inclusion of potential effects on zoster, such as adolescent booster vaccination. 3.2 Vaccination Campaigns Against Respiratory Diseases Currently, vaccines are being used against Hemophilus influenzae type B, pneumococcal and meningococcal infections, and influenza. Additionally, the > BCG vaccine against TB is still being used for TB proxylaxis. However, since there is still considerable discussion on the efficacy and duration of protection of BCG vaccine in the prevention of TB, we decided not to discuss vaccines against TB in this section Hemophilus influenzae Type B Vaccination against Hemophilus influenzae type b (Hib) has been introduced in most Western countries in the early nineties. The choice to introduce the vaccine in the routine childhood vaccination programs was justified by it s high incidence of between 20 and 69 per 100,000 infants <5 years (Akumu et al., 2007). Prior to vaccination, Hemophilus influenzae type B was the most common cause of meningitis, causing in the US annually more than 20,000 cases of invasive disease (Hay et al., 1987). The case fatality rate of Hemophilus influenzae type B meningitis is approximately 5%. A number of economic evaluations have been performed in developed countries, showing a favorable cost-effectiveness. Martens et al. (1991) calculated a break-even price for the vaccine of US$ 7 for the use of the vaccine in the infant immunization program of the Netherlands. A favorable benefit to cost-ratio was found for Hib vaccination in Slovenia, (Pokorn et al., 2001) of 1.38, (including indirect costs. The cost-effectiveness ratio of Hib vaccination is highly dependent on the epidemiology. A similar study performed in Moscow showed a higher cost-effectiveness ratio of 10,842 per DALY averted as opposed to cost-savings (Platonov et al., 2006). However, this cost-effectiveness ratio is still acceptable in Western countries. Additionally, a number of studies have been performed in countries in Africa and South- America (Akumu et al., 2007). A study by Akumu et al. (2007), indicated that the incidence of Hemophilus influenzae type b meningitis would decrease from 71 per 100,000 to 8, indicating massive health benefits for this intervention. Broughton (2007) analyzed the potential costeffectiveness of introducing Hib vaccination in the infant immunization program in Indonesia. His model indicated that Hib vaccination of infants would result in averting over 76,000 cases of invasive disease per year, saving approximately 7,150 lives. The incremental costeffectiveness of such a program would be US$ 67 per DALY. These indicate the potential impact of Hib vaccination in the prevention of invasive disease such as bacteremia and meningitis, and should make policy makers aware of the massive health benefits that could be saved by introducing the Hib vaccine in endemic areas.

12 1346 Economics and Vaccines Pneumococcal Vaccines Basically, two types of pneumococcal vaccines exist: polysaccharide vaccines primarily intended for elderly populations and conjugate vaccines primarily intended for infant vaccinations. Many western countries have now large-scale polysaccharide vaccination programs for the elderly in place. A recent analysis on the cost-effectiveness of this pneumococcal vaccine in the elderly in ten European countries revealed that high potential for favorable cost-effectiveness exist (Evers et al., 2007). For these countries cost-effectiveness ranged from 3,000 to 5,000 up to a maximum of 20,000 per QALY gained. In the USA, pneumococcal vaccination of elderly is cost-effective, potentially even if the age-limit for vaccination would be lowered from 65 years down to 50 years (Sisk et al., 2003). A number of studies have been performed on the cost-effectiveness of a conjugate pneumococcal vaccine in infants, which potentially prevents meningitis, bacteremia, and otitis media. These studies have shown conflicting results. A recent review by Beutels et al. (2007) reviewed 15 studies from Finland, UK and Wales, US, the Netherlands, Spain, Switzerland, Germany, Australia and Italy. The study found a range of results ranging from cost-saving from the societal perspective (studies from Spain and Germany) to 101,452 per LYG in Canada. The largest difference between the studies was found to be the inclusion or exclusion of herd immunity effects on the adult population. Whitney et al. found a decline in invasive pneumococcal disease in adults after the introduction of pneumococcal conjugate vaccination of infants, (Whitney et al., 2003) leading to additional life years gained and medical and indirect costs saved due to the occurrence of herd immunity. To illustrate the impact of the inclusion of herd immunity on the results, a study by Bos et al. in 2004 showed a base-case cost-effectiveness of 71,703 per QALY without considering the potential effects of herd immunity, whereas the cost-effectiveness ratio improved to 15,600 per QALY when herd immunity effects were considered. Of the available studies, favorable cost-effectiveness ratios were found in Spain, Germany, Canada, the Netherlands (after inclusion of herd immunity effects), and for the UK it was found to be on the upper limit of cost-effective interventions Meningococcal Vaccines Vaccines against subtypes Neisseria meningitidis A, C, Y and W135 are currently available. Meningococcal infections, such as meningitis and septic shock are associated with high mortality rates of up to 35% and complications. Survivors often suffer from neurological or physical sequelae. A number of studies have been performed on the cost-effectiveness of meningococcal C vaccination, which has been introduced in a number of countries, such as Australia, UK, and the Netherlands. A review by Welte et al. (2005), analyzed studies from Canada, the Netherlands, UK, Australia, Portugal, Switzerland. The cost-effectiveness of the interventions was dependent mainly on the age of the vaccinated infant, and the incidence of meningococcal disease. Since infants aged >12 months only need a single dose of vaccine in order to build immunity against the pathogen, and younger infants need three doses to boost their immune system, vaccination of the first group will be more affordable. The cost-effectiveness of a single dose intervention ranged from 19,000 per QALY in Switzerland to 2,600 per QALY in the Netherlands, with the main differences found in the incidence of disease. The three dose scenario was analyzed to be less cost-effective, with cost-effectiveness ratios ranging from 55,000 per QALY in Switzerland, to 21,700 per QALY in the Netherlands.

13 Economics and Vaccines Influenza Vaccines Influenza has been frequently referred to as the last great uncontrolled plague of mankind, Elderly persons are at increased risk of developing influenza-related complications which require complex healthcare and might lead to mortality. By 1997, all but three countries in the European Union had universal vaccination programs for citizens aged 65 years. In a review by Postma et al. (2002), an overview is given of health economic studies on influenza vaccination of the elderly in developed countries. The studies provided remarkably similar results. Benefit to cost ratios ranging from 0.7 to 50 were found, indicating that in most instances the benefits of influenza vaccination of the elderly outweigh the costs associated with the program. Even in the study were a benefit to cost ratio of 0.7 was found, the costeffectiveness ratio was still below the acceptable threshold for cost-effectiveness. In particular, influenza vaccination among elderly people at higher risk, such as the chronically ill elderly, is generally found to be cost saving. A number of studies have been performed on the cost-effectiveness of influenza vaccination of healthy working adults. The results of these studies are not homogeneous; some studies report cost savings, whereas other studies report no economic benefits at all. Most differences in outcome are related to whether indirect costs due to work loss are included in the analysis, the efficacy of the vaccine in relation to the dominant influenza strains in the year of analysis, and the severity of the influenza epidemic (Postma et al., 2002). A review of 11 studies reported in western countries found that eight of the studies reported cost-savings against three studies that reported no economic benefit (Postma et al., 2002). Another review study, by Wood et al. (2000) also noted the disparity in results between the various economic studies, but also concluded that the published studies seem to suggest that influenza vaccination in the healthy, working adult would be a cost-effective health intervention, at least from the perspective of an employer. Some studies have analyzed whether vaccination of healthcare workers to protect high-risk patients would be a cost-effective strategy. A review by Burls et al. (2006) found that most costeffectiveness studies did not take the effects on patient transmission into account and therefore underestimated the cost-effectiveness of the intervention. The study by Burls et al. estimated that vaccination of healthcare workers to protect high-risk patients would be a highly costeffective intervention, with a CER between cost-saving and 405 GBP per LYG. 3.3 Vaccination Campaigns Against Sexually Transmitted Infections and Other Vaccine-Preventable Viruses Hepatitis B Hepatitis B virus (HBV) infection is still an important public health problem, despite the availability of an effective vaccine for several decades now. According to the WHO recommendation for universal routine vaccination many countries of high and intermediate endemicity have implemented routine vaccination. Implementation of such programs is often done at the infant age or young adolescent age, with a combined catch-up program. Favorable cost-effectiveness of implementing these programs has been evidenced broadly (Beutels, 2001), (Beutels et al., 2002). For example, the specific Italian implementation of vaccination

14 1348 Economics and Vaccines in 1992 of a combined universal infant schedule and catch-up of 12-years olds was chosen after careful examination of economic data (Bonanni et al., 2003). Discussions on introducing universal vaccination for infants and/or adolescents are currently going on in countries that currently only vaccinate selected target populations (such as the UK and the Netherlands) and in developing countries for which vaccination becomes feasible due to recent price reductions Human Papilloma Virus (HPV) Recently, two Human papilloma virus vaccines have been registered for prophylactic use. Trials have proved efficacy up to 5 years; long-term effectiveness has yet to be demonstrated in follow-up of the initial trails and post-marketing research. Both vaccines have proven to be highly effective against HPV-types 16 and 18, that are associated with 70% of cervical cancers worldwide (Paavonen et al., 2007; Parkin and Bray, 2006). Slight differences seem to exist between both vaccines, potentially influencing exact cost-effectiveness profiles of both. In particular, one is quadrivalent, also protecting against genital warts caused by types 6 and 11 (Gardasil), whereas the other is bivalent only, but claiming higher likelihood for long-term protection (Frazer, 2007). Various cost-effectiveness analyses have already been performed, generally building on cost-effectiveness analyses for cervical cancer screening (Dasbach et al., 2006). Notably, vaccination is assumed to be implemented on top of the existing screening programs. All cost-effectiveness models for the HPV-vaccines generally assume no deterioration in the coverage of the screening. Additional vaccination of young teenage boys might be considered, but is less likely to be cost-effective (Dasbach et al., 2006). Approximately 20 publications are now available on the cost-effectiveness of HPVvaccination. For effectiveness, most of these models build on the observations in the trials for HPV-infections of the vaccine-types, rather than hard endpoints such as pre-cancerous stages and cervical cancer. Generally, acceptable cost-effectiveness of around US50,000 per QALY or lower are estimated for vaccinating young teenage girls. One concern generally expressed from the cost-effectiveness analyses is that a slight deterioration in the coverage of screening could easily offset the savings and health benefits of vaccination. So, implementation of vaccination should be combined with campaign to sustain screening coverage rates, and such costs should be included in the cost-effectiveness analyses of vaccination Hepatitis A Hepatitis A vaccines have been available for over a decade. With the disease impact primarily affecting developing rather than developed countries, the picture of universal vaccination differs strongly from Hepatitis B. In particular, many developed countries have strategies implemented on vaccinating risk groups, such as ethnic minorities and travelers to Hepatitis A endemic regions. In a recent review, none of the cost-effectiveness studies yet being performed for the Hepatitis A vaccine were done for a developing country (Anonychuk et al., 2008). Costeffectiveness studies have up to now primarily evaluated targeted vaccination, such as vaccinating antibody-negatives only, prison inmates and the military (Jefferson et al., 1994). Additionally, some studies have been done specifically addressing the cost-effectiveness of vaccinating chronic Hepatitis C patients with Hepatitis A vaccine (Jacobs et al., 2002).

15 Economics and Vaccines 1349 Findings indicate that favorable cost-effectiveness is highly unlikely the older the patient is and if antibody screening is performed prior to vaccination. More cost-effectiveness studies are needed and standardization of the approach should be enhanced Rotavirus After initial drawbacks on the use of rotavirus vaccines due to suspected intussusception, recently two vaccines are being marketed worldwide (Rotarix and RotaTeq). Safety and efficacy have been shown in various clinical trials for the respective 2- and 3-dose schedules (Vesikari et al., 2006). Rotavirus infection is considered to be the most prevalent cause of acute gastroenteritis globally. Currently, the vaccine is initially considered for the developed world, where mortality and serious morbidity is relatively low. A small number of cost-effectiveness studies have been done on rotavirus vaccination, however these publications either lack comparability by using QALYs or do not include the full scale of savings and health gains (Widdowson et al., 2007). In particular, due to lack of valid data, rotavirus episodes without hospitalization are not yet factored into the models, leading to underestimation due to the omission of potential work loss of parents. In the absence of more robust information on these aspects, models are yet very sensitive to mortality assumed for rotavirus. Typically, mortality is assumed at approximately 1 per 100,000 infants annually, however valid registrations of rotavirus deaths may be lacking in many countries. Generally, from the cost-effectiveness analyses it appears that rotavirus vaccination may not be highly cost-effective, with cost-effectiveness ratios varying from 50,000 to 100,000 per QALY from the health-care payer perspective (Jit and Edmunds, 2007). Only marginally better ratios were found from the societal perspective for England and Wales (Jit and Edmunds, 2007). If however from the societal perspective parental work and QALY losses are included related to those cases of disease without health-care services visits involved, cost-effectiveness may improve dramatically. For the Belgium situation cost-saving potentials were reported (Bilcke et al., 2007). Cost-effectiveness ratios are highly sensitive to the QALY impact assumed. Up to now only one study is available on the specific quality-of-life aspects of rotavirus infection (Sénécal et al., 2006). In particular, a prospective study was designed in Canada to estimate QALY-impacts for the infants involved and the caregivers using the Health Utilities Index and the Visual Analogue Scale. However, more research is needed to further underpin this crucial parameter in rotavirus cost-effectiveness analysis. Also, we note that further discussions on including QALY impacts for caregivers are required and that current standards for cost-effectiveness analysis do not include QALY loss with caregivers. 4 Discussion and Conclusion In this chapter, we have provided a brief overview of the main challenges that are associated with modeling the economic impact of vaccines. Often, the vaccines are given as prophylaxis, and concern a very large part of the population. The latter implies that the budget impact is a prominent issue to consider prior to the introduction of new vaccination programs. Moreover, it is difficult to stop a program once it has been started, due to reasons of equity. Therefore, with assessing these interventions, budget impact and allocation of the total budget forms an important aspect of the final decision.

16 1350 Economics and Vaccines Most vaccines yield benefits not only for the direct beneficiary, but also for the nonvaccinated population. This phenomenon, called herd immunity, is an important aspect of vaccines. Lastly, due to the preventative character of vaccine interventions, benefits might occur later in life, which should be valued according to the preferences of the population. Vaccine interventions are a public health decision, affecting many citizens directly, and have long term budgetary consequences. Therefore, decision regarding new vaccination programs should consider all aspects of the intervention carefully. To assess the economic and health impact of the intervention, health economic studies such as cost-effectiveness analysis are being used. By using cost-effectiveness analysis, decision makers gain an understanding of those interventions that provide best value for money and that should be prioritized in order to maximize the utility gains in the population. In this chapter, we have provided an overview of health economic evaluations of most vaccines that have been introduced in the developed world. Most of the vaccines that have been introduced all exhibit favorable cost-effectiveness ratios, ranging from cost saving or highly costeffective for childhood cluster vaccines, Hemophilus influenzae type b vaccine, influenza vaccination for the elderly, meningococcal C vaccine and hepatitis A and B vaccine for infants. For some vaccination programs, the cost-effectiveness is very sensitive to changes in certain assumptions, such as the relation with zoster for the varicella vaccine, the occurrence of herd immunity with the pneumococcal conjugate vaccine for infants, and whether or nor screening rates for cervical cancer will decline as a result of HPV vaccination. Each of these assumptions has the potential to change an intervention from cost-effective towards not costeffective or vice versa. Although the cost-effectiveness studies are extremely sensitive to changes in these assumptions they serve a clear purpose in showing decision makers the impact of such changes. It is worth noting that most of the vaccine interventions prior to the 1990s have been implemented with only limited guidance of health economic studies. However, there are signs that economic evaluations are increasingly being used for guidance on whether or not to implement a new vaccination program. Welte et al. (2005) investigated whether or not health economic data played a role in the decision to start national vaccination programs against meningococcal C infections, and found a clear relationship between increasing incidence rates for meningococcal C infections and the commissioning of an health economic study on vaccination. This indicates that health economic studies are starting to play a more important role in decision making on the introduction of new vaccination programs. However, it needs to be kept in mind that, health economic data are only a single consideration next to for instance equity, or ethical reasons. Summary Points Infectious diseases are an important cause of mortality and morbidity, causing approximately 27% of the total disease burden in DALY. A large part of DALY lost due to infectious diseases could be prevented by improving existing vaccination programs for the population. Diseases such as childhood cluster diseases, hepatitis A and B, respiratory infections caused by influenza, pneumococcal and meningococcal infections, and Hemophilus influenzae type B, are for a large part preventable by current vaccines. The implementation of new vaccine programs or/and strategies is a costly process with long term consequences. To gain a better understanding of the potential impact on health