University of Groningen
Health economics of tick-borne diseases Smit, Renata
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Health Economics of Tick-Borne Diseases
Renata Šmit
1
This work was performed within the Research Institute SHARE (Science in Healthy Ageing and healthcaRE) of the University Medical Center Groningen, Faculty of Medical Science, University of Groningen.
The printing of this thesis was financially supported by the University of Groningen, the Research Institute SHARE of the Faculty of Medical Sciences and the Groningen Graduate School of Science.
Author: Renata Šmit
Cover: Image of tick by CanStockPhoto Printed by GrafiMedia
ISBN: 978 90 367 9019 2 (printed version) ISBN: 978 90 367 9018 5 (electronic version)
© Renata Šmit, 2016. All rights reserved. No part of this thesis may be reproduced or transmitted in any form or by any means without written permission of the author. The copyright of previously published chapters of this thesis remains with the publisher or journal.
2
Health Economics of Tick -Borne Diseases
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op
vrijdag 18 november 2016 om 12.45 uur
door
Renata Šmit
geboren op 11 juli 1971 te Ljubljana, Slovenië
3
Promotores Prof. M.J. Postma Prof. K. Poelstra
Beoordelingscommissie Prof. H.W. Frijlink Prof. A.W. Friedrich Prof. E. McIntosh
4
To my Mom and Dad – for your continuous support and love
5
6
TABLE OF CONTENTS
Chapter 1 Introduction 9
Chapter 2 Vaccines for tick borne diseases and cost effectiveness of 25 vaccination: a public health challenge to reduce the diseases’ burden
Chapter 3 Review of tick borne encephalitis and vaccines: clinical 33 and economical aspects
Chapter 4 Lyme borreliosis: reviewing potential vaccines, clinical 61 aspects and health economics
Chapter 5 The burden of tick borne encephalitis in disability 93 adjusted life years (DALYs) for Slovenia
Chapter 6 Cost effectiveness of tick borne encephalitis vaccination 121 in Slovenian adults
Annex 6.1 Some details on Cost effectiveness of tick borne 141 encephalitis vaccination in Slovenian adults
Annex 6.2 Further details on Cost effectiveness of tick borne 145 encephalitis vaccination in Slovenian adults
Chapter 7 Discussion and Conclusions 153
Summary 165
Samenvatting 167
Bibliography 169
Acknowledgements 170
Research Institute for Health Research (SHARE ) 172
Curriculum Vitae 175
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8
CHAPTER 1
Introduction
9
10 Introduction
Introduction Vaccination is one of the most health and cost effective public interventions with long term benefits. Vaccination can protect individuals of all age groups against potentially serious infectious diseases and it can save many human lives [1]. Vaccination can be beneficial for children and adolescents in terms of growing into healthy, productive adults that can fully contribute to the economic progress of a society. Vaccination of older adults can be beneficial in terms of having a healthier and independent life. Healthy older adults can be an active family member and they can contribute to the society. Therefore, promoting vaccination for all ages and healthy ageing throughout whole life can contribute to the health of the population as a whole [2,3]. Decision making when considering inclusion, substitution or exclusion of specific vaccine in the national vaccination programme is a demanding, time consuming and complex process [4,5]. Decision makers need information on disease epidemiology and disease burden, vaccine safety and quality and efficacy/effectiveness, duration of immunity, herd immunity, ethical and humanitarian viewpoint of vaccine, logistics and availability, vaccine licensure status, equity and preference and acceptability, and comparison with other intervention and experience of other countries when deciding on vaccination policy [6,7]. Next, health economics and financial evaluations are playing a growing role in the final decision on vaccination policy and allocation of public health resources. A basis for a decision making can be served by making a comparison of two or more vaccines/vaccination programmes in terms of costs and health benefits. The main types of this kind of economic evaluation are cost effectiveness analysis (CEA) and cost benefit analysis (CBA) [6,7,8]. CEA is the most often used in decision making process on vaccination, and its importance is only increasing. In CEA, the costs are compared to the health outcomes of at least two vaccines. Health outcomes are expressed in natural units such as cases avoided or number of life years saved. CEA results are presented as an incremental cost effectiveness ratio (ICER). The ICER is calculated as follows:
= (1)
11 Chapter 1
= (2)
Where: • Intervention A = vaccination. • Intervention B = comparator. When intervention A is a new vaccine, then its comparator is usually “no vaccination.” • Costs are expressed in a monetary unit. • Health outcomes are expressed in natural units (number of cases prevented or number of life years or number of deaths prevented).
The ICER is shown as cost per health outcome, expressed in natural units. CEA is used to find the most cost effective vaccination strategy between different vaccines. It is also used for resource allocation and reimbursement decision making of vaccination [4,6,7,8]. A special type of CEA is cost utility analysis (CUA) in which health outcomes are measured in terms of quality adjusted life years (QALYs) or disability adjusted life years (DALYs). The ICER (cost utility ratio) is calculated as follows:
= = (3)
In CUA, the ICER is shown as cost per QALYs gained or cost per DALYs averted. QALYs are defined as a measure of the value of patients’ health states. QALYs are one measure that combine both the quantity and the quality of patients’ life. One QALY means one year living in perfect health. QALYs are calculated as follows:
= ℎ ℎ + ℎ ℎ (4)
Where: • Utility or weights = relative value between 0 (death) and 1 (perfect health), expressed as preference from the patient’s perspective for a specific health state.
12 Introduction
QALYs can be used to estimate the disease burden. QALYs are one of criteria that can be used for making a decision and for allocation of finite public health resources [4,6,7,8,9]. DALYs are one measure that combines both premature death (YLLs) and disability due to morbidity (YLDs). DALYs are calculated as follows:
DALYs = YLLs + YLDs (5)
Where: • YLLs = the number of life years lost due to premature death. • YLDs = the number of life years lost due to disability, weighted with a factor between 0 (perfect health) and 1 (death) that reflects the severity of disability.
The DALYs methodology, which was first introduced by Murray and co workers in the Global Burden of Disease project, is usually used to estimate the burden of disease. The World Health Organization (WHO) defines DALYs as the lost years of healthy life. The WHO recommends calculation the burden of the disease expressed in DALYs [6,10]. DALYs can be used to compare relative burdens among different diseases and among different populations [11] and they can be used to prioritize of limited public health resources [12]. Therefore, DALYs can be a useful tool in the decision making process. In cost benefit analysis (CBA), both costs and health benefits are measured in monetary units. In CBA, net benefit is calculated by deducting value of costs from value of health benefits. If net benefit is positive then the vaccination programme is recognized as an optimal investment. Benefit cost ratio is calculated by dividing health benefits by costs. If benefit cost ratio is higher than 1 then a vaccination programme is recognized an optimal investment. Health benefits are difficult to express in monetary units, therefore CBA is not often used for the economic evaluation of vaccines/vaccination programme [6,7,8] In contrast with CEA, CUA and CBA, the cost analysis (CA) compares only the costs of a vaccines/vaccination programme with the costs of its comparator(s). The cost minimization analysis (CMA) compares costs of different vaccines/vaccination programmes to find the cheapest alternative, assuming their efficacy and effectiveness are the same [7,8,9].
13 Chapter 1
Budget impact analysis (BIA) is used to estimate the financial impact of a vaccine for a specific public healthcare budget. BIA is usually conducted in addition to a CEA to give a full economic evaluation of a new vaccine before its introduction into a national vaccination programme or for its reimbursement. BIA can be a useful tool for budget planning and forecasting [6,9]. Financial sustainability analysis is used to evaluate the current and future resources that are required to maintain funding the whole vaccination programme after a new vaccine introduction [6,7]. Decision makers have to decide which vaccination strategy to implement into the national programme to reduce disease burden and to increase benefits to society. Decision makers are also responsible for effective allocation of public health resources. Financial public health resources are often limited, therefore decision makers pay attention to societal returns on financial investment in public health [6,7,8]. Therefore, a return on investment (ROI) analysis is used to evaluate the efficiency of financial investment in public health. The ROI is calculated as the difference in the gain from investment and the cost of investment (net profit), divided by the cost of investment. The result of ROI is expressed as a percentage [13]. Health economics plays an important role in the evaluation of vaccination policy. A CEA is the traditional method used to make an economic analysis. It is the method used most often in the decision making process and it is becoming ever more important. Many aspects need to be taken into consideration when conducting CEA of vaccines/vaccination programme. These aspects are as follows:
1. Framing the CEA First, the problem/study question and target audience need to be defined. At this stage, model structure need to be determined based on the natural course of the disease. Also the type of decision model relating to the problem/study question needs to be decided. Next, the type of economic evaluation, nature of the intervention, target population, the choice of comparators, and perspective need to be defined. Finally, the time horizon needs to be determined. The choice of the length of time horizon is dependent on the characteristics of vaccine, target population, as well as type of the model and it should include all relevant costs and health outcomes [6,8].
14 Introduction
2. Assessing the costs of the vaccination programme In the perspective of the health care payer, the direct medical and direct nonmedical costs are considered. In the perspective of the society, also indirect costs are taken into account. In direct medical costs, for example vaccine programme costs, prescription drugs, hospital costs, emergency room costs, outpatients’ costs, costs of diagnosis tests, costs of physician specialist visits, surgical procedures and special education can be evaluated. Vaccination program costs include the costs of vaccine and the costs associated with administering the vaccine. In direct nonmedical costs, for example costs of administrative overhead, parent/caregiver lost time from work can be evaluated. Indirect costs were costs due to loss of productivity and they included the costs due to absence from work. It is advisable that CEA is conducted from the societal perspective, because all direct and indirect costs on the society are included in the analysis. However, it is encouraged that CEA is conducted also from other perspectives [6,8].
3. Assessing the effects of the vaccination programme - Vaccine efficacy and vaccine effectiveness Vaccine efficacy may be expressed a percentage and it measures reduction of disease in a vaccinated group compared to unvaccinated group. Data on the efficacy of vaccine should be taken from the literature reviews or they could be obtained using meta analysis research synthesis or from randomized controlled clinical trials. Vaccine effectiveness is defined as the vaccine’s ability to prevent disease with its impacts and effects that are measured in the real world [6]. In CEA of vaccination, factors influencing results are age, boosting intervals and the number of doses of vaccine. Also all relevant adverse events of vaccine should be included in CEA evaluation [6].
- Vaccine protection and duration of vaccine protection A ‘leaky’ vaccine is one, which prevents disease but does not prevent infection. Transmission could occur at just as higher rate from individuals with this “partial” protection as from unvaccinated individuals. For example, vaccines against tick borne encephalitis or vaccines against Lyme borreliosis are known as ‘leaky’ vaccines. An 'all or nothing ' vaccine fully protects vaccinated individuals from infectious diseases. In a model for evaluating cost effectiveness of vaccination a life span
15 Chapter 1 protection named neglecting waning or waning protection of vaccine can be applied. When information on vaccine waning is not well known then waning uncertainty can be handled by different scenarios analysis [5].
- Choosing the health outcome measures Final health outcomes such as number of cases prevented or number of life years or number of deaths prevented should be used to evaluate effectiveness of the vaccination programme. However, intermediate health outcome can be used when final health outcomes are not known. CUA, as a special type of CEA, is a preferred type of economic evaluation with QALYs or DALYs as health outcome measures. However, it is also encouraged to conduct a CEA, using natural units as outcome measures [6,8].
4. Infectious disease modelling Mathematical models are used for estimating the burden of infectious disease and evaluating the effectiveness of vaccination and its impact on disease transmission. Mathematical modelling is important in health economics and policymaking. The model choice should depend mainly on type of infection, transmission route of pathogen, endemic situation, vaccine characteristics and study question [6]. Dynamic transmission models describe the spread of infectious disease in populations. Dynamic transmission models are used when evaluating the impact of vaccination on the transmission of a pathogen in the population. They can also be used when evaluating the impact of vaccination on pathogen’s ecology, like serotype replacement effects [14]. In dynamic models, the force of infection (i.e. the probability that a susceptible individual becomes infected) can change with time [14]. Individuals move through a number of mutually exclusive compartments. Movement between compartments is estimated using differential mathematical equations, with age or time as continuous variables [6]. The simple dynamic model is S I R model with susceptible (S), infectious (I), recovered (R) compartments. This simple S I R model can be expanded, adding for example an exposed (E) compartment, leading to S E I R model with susceptible (S), exposed (E), infectious (I), recovered (R) compartments. In the absence of lifelong immunity, S I S model should be considered with susceptible (S), infectious (I), susceptible (S) compartments [6]. In dynamic transmission models indirect effects, for example herd immunity, age shift,
16 Introduction and serotype replacement effects are incorporated into the model. Indirect effects have influence on cost effectiveness of vaccination, therefore indirect effects need to be taken into account in infectious disease modelling [14]. In static models, the force of infection does not change with time [6,14]. Static models do not take into account interaction between individuals as well as indirect effects. Not taking into account indirect effects might underestimate the value of vaccination [5,14]. However, a static model, such as, for example, a Markov model can be used to evaluate the impact of vaccination when indirect effects can be ignored because they are not important and they cannot cause harm [6,14]. In a Markov model, the individual is in one of a finite number of health states. Individuals move from one to another health states based on transition probabilities during one cycle. Transitions occur over the fixed time interval, costs and utilities are assigned to each health states. A limitation of the Markov model is the assumption that transition probabilities of the Markov process have no memory for prior cycles. This limitation is called the Markovian assumption. This limitation can be resolved with the use of complex models or tunnel states. Tunnel states act as temporary states, lasting more than one Markov cycle [15]. When vaccination coverage is very low or when vaccination has no impact on disease transmission, then static and dynamic models demonstrate similar results [14]. Both static and dynamic models can be deterministic (random process is not incorporated in model) as well as stochastic (random process is incorporated in model) [6].
5. Model calibration and validation Calibration means adjusting of model parameter estimates that model results can more accurately reflect “real world”. Calibration is needed, for example, if input data are adapted from one setting to another, if input data are old or changes have occurred since their collection. Inputs can be adjusted, for example, manually, random with the use of Monte Carlo methods or by using Nelder Mead method. The internal validity of the model should be tested prior its use to ensure that the model is robust. The external validity of the model can be tested by comparing the results with the results of other models and explaining differences if they exist [5,6,9].
17 Chapter 1
6. Uncertainty in CEA One way sensitivity analysis tests the impact on results when changing the value of one parameter while keeping all others parameters constant. Threshold analysis is a form of one way sensitivity analysis and it can be useful for price negotiation. Multi way sensitivity analysis tests the impact on results when changing the value of two or more parameters at the same time [6]. Probabilistic sensitivity analysis (PSA) handles uncertainty on all parameters simultaneously [6]. Model structural uncertainty can be handled by scenario analysis. Therefore, alternative model structures with different assumptions are constructed [6].
7. Discounting In CEA of vaccination, all future values should be discounted to their net present value. Both the time horizon and the value of discount rate play an important role in conducting a CEA. The discounting formulae for cost and utility for each health outcomes are presented as follows:
= ∑ (6)
= ∑ (7)
Where:
• Utility 0 = input utility (quality weights) for each health state.
• Cost 0 = input cost for each health state. • Rate = discount rate for costs and utility for each health state.
There are continuous debates regarding the use of discount rates. The same discount rate for costs and utilities for health outcomes is the most commonly used, however different discount rates for costs and utilities for health outcomes can also be used. Lower rates for health effects are applied in some countries such as in Belgium, and the Netherlands. In France, costs and health outcomes are discounted in the first 30 years at the rate of 4% and in the following years of 2% rate [5,6,8,9].
18 Introduction
8. Presentation and reporting of CEA results Results of CEA of vaccination should be presented as ICER that can help to determine the most cost effective vaccination strategies. Mostly there is no single threshold below which a vaccination strategy should be accepted because of uncertainty about estimates of costs and health outcomes and cost effectiveness [6,16]. In some countries like in Canada, in the USA and in the UK the cost effectiveness threshold range is used to help to determine which vaccination strategy should be accepted. WHO CHOICE (CHOosing Interventions that are Cost Effective) recommends that the country use specific gross domestic product as an indicator of cost effectiveness [6]. The results of CEA can be presented in the table and in the form of graph. Graphically presentation of results include mostly cost effectiveness (CE) plane, tornado diagram, scatter plots, and cost effectiveness acceptability curve (CEAC). CE plane presents differences in costs and health outcome for different strategies. Tornado diagram presents ICER results from one way sensitivity analysis. ICER results from PSA can be presented using scatter plots on CE plane. Next, a very useful approach for presenting ICER results is CEAC. CEAC summarizes ICER results by plotting the probability that a vaccination strategy is cost effective according to a range of threshold willingness to pay (WTP). WTP is threshold ICER below which a vaccine would be reimbursed [6,9]. CEA of vaccination is important criterion for decision making and its importance is increasing. In addition, other criteria are playing an important role in the decision making process. Therefore, multi criteria decision analysis need to be included in the decision process. Decision makers need to be aware of broader effects and benefits of vaccination on population for all age groups when deciding on vaccination policy [6].
TBDs are one of the most rapidly spreading/expanding infectious diseases worldwide in which pathogen (virus, bacterium, protozoa, fungi) transmits from a vertebrate host like birds, rodents, or other larger animals to a person during tick feeding [17]. The incidence of many TBDs is rising and new foci have appeared mostly due to changes in human leisure activities, increasing mobility, changes in agricultural habits, climate change on ticks and vertebrate hosts, and increasing number of vertebrate hosts and ticks and their shifts in geographical distribution [17]. New tick
19 Chapter 1 borne pathogens have been identified like bacteria Borrelia miyamotoi, bacteria Borrelia mayonii , Bourbon virus . Tick borne encephalitis (TBE) is the most commonly reported TBDs in Europe, whereas LB could be considered as an epidemic threat worldwide [17]. The incidence of TBDs is likely under estimated due to weak diagnostics and surveillance, therefore the true burden of these diseases is not recognized [17]. TBDs vary tremendously in their severity. Some TBDs are also life threatening such as human granulocytotropic anaplasmosis, human monocytotropic erlichiosis, tick borne relapsing fever, tularaemia, Rocky Mountain spotted fever [17]. Ticks can often transmit more than one pathogen like Borrelia burgdorferi , Anaplasma phagocytophilum , babesiosis, Babesia microti , TBE virus [17]. It was shown that the course of disease in Lyme patients who are co infected with Babesia microti is more serious and complicated than in patients who are infected with only B. burgdorferi (Krause et al. 1996) [17]. TBE virus causes TBE, a serious infection of the central nervous system, which may lead to long term or permanent neurological sequelae or even death [18]. The infectious organism spirochete Borrelia burgdorferi sensu lato genospecies complex can cause LB. Different pathogenic genopecies cause various manifestation of LB that differ between North America and Europe and also within Europe. LB is a multi system infectious disease, patients may suffer both acute and persistent manifestations [17]. Therefore, early diagnostic and early proper antibiotic treatment is crucial to prevent long term sequelae that may seriously affect patients’ quality of life [17]. Only in the USA, very few deaths due to LB have been reported, mostly associated with lyme carditis [19]. Using repellents, protective clothing, avoidance of risk exposure to infected ticks, more efficient vector control strategies and education of the general population about TBDs are ways of protection against TBDs [17]. However, more efforts to improve prevention against these diseases are needed. Vaccination can be effective intervention to protect individuals against TBDs [17]. However, there are no human vaccines against TBDs available in the USA. Currently, only vaccines for viral infections such as TBE are available [17]. Despite that TBE vaccines are well tolerated, safe and efficient, their application is likely under used to efficiently reduce TBE burden at the European level. Therefore, effective, safe, and well tolerable vaccines against TBDs are needed. Development of TBDs vaccine faces numerous difficulties and obstacles such as diversity of human tick borne pathogens and their
20 Introduction antigenic variation [17]. For example, a huge obstacle in developing LB vaccines presents antigenic variation of the LB spirochetes, including the differences between LB strains in Europe and the USA [17, Chapter 4]. Currently, huge efforts are orientated towards development of novel, improved LB vaccine. For example, multivalent OspA vaccines candidates are in the clinical phase of development and could effectively protect individuals against LB globally [17]. Studies in mice showed that potential anti tick vaccine based on tick salivary gland proteins obtained from Ixodes ricinus could protect individuals not only against LB but also against other TBDs [20]. Therefore, potential anti tick vaccines could be highly cost effective public health intervention [20]. Health economic evaluation is an important tool that can help to formulate efficient strategies for prevention and control of diseases to reduce their burden. Reducing TBDs’s burden presents a huge public health challenge.
Aim of this doctoral thesis TBDs reflect an increasing burden and public health concern worldwide. [17]. Therefore, efficient strategies for prevention and control of TBDs are needed, likely leading to reduction of diseases’ burdens. The aim of my doctoral thesis is to evaluate health economics of TBDs, focus on TBE and LB, and to evaluate their impact on public health. In particular, developing models based on the natural course of these diseases to assess the costs and health outcomes and cost effectiveness of vaccination. Currently, scarcity of health economics studies presents an important knowledge gap in the field of TBE and LB. Previously, only one study on cost benefit of vaccination against TBE among French Troops, using a decision tree was published in 2005 [21]. Next, burden of TBE was expressed only by the incidence and mortality data [18]. Lastly, in the period between 1999 and 2002 three studies on cost effectiveness of vaccination with monovalent OspA vaccine against LB only for USA were published [22,23,24]. Therefore, this thesis adds novelty and makes an important contribution to the field of health economics and cost effectiveness of vaccination for TBE and LB. Findings presented in this thesis can help to improve the guidance for efficient prevention and control of these diseases, travel health recommendations, occupational health policies, leading likely in reduction of diseases’ burden and improving population health. The findings of this thesis can be of high relevance to global public health.
21 Chapter 1
Structure of this doctoral thesis After this introductory chapter, the thesis begins by describing TBDs. TBDs are becoming high public health threat worldwide. Reducing TBDs burden is a huge public health challenge. Chapter 3 provides a broad overview of TBE, focus on epidemiology, vaccines, TBE’s clinical and health economic aspects, given the gap of health economic evaluation of TBE and cost effectiveness of vaccination. Chapter 4 provides a broad overview of LB, including epidemiology, the state of the science on diagnostic tools, the clinical manifestation of LB and the challenges for physicians in the treatment of this disease, describes LB vaccine candidates, given the scarcity of cost effectiveness of LB vaccination. In Chapter 5, full burden of TBE, expressed in DALYs is estimated. TBE burden in DALYs, including correction for TBE under estimation is estimated for the first time. This study presents a novelty in the field of TBE health economics. The disease burden model, calculations of correction factors for TBE and their application as done in Chapter 5 reflect an innovative approach in TBE DALYs calculation. TBE burden in DALYs has not been specified by the Global Burden of Disease studies. Potential strategies to reduce TBE burden are suggested. In Chapter 6, cost effectiveness of TBE vaccination, using a Markov model is evaluated. The use of the Markov model to evaluate the cost effectiveness of vaccination against TBE is an innovation. Annexes to Chapter 6 provide details on the Markov model. Chapter 7 provides an overall discussion and conclusions.
References 1. World Health Organization (WHO). The Initiative for Vaccine Research Strategic Plan 2010 2020. Available from: www.who/int/vaccine_research/documents/en/ [Accessed: February 2016]. 2. Postma M, Carroll S, Brandão A. (2015). The societal role of lifelong vaccination. Journal Of Market Access & Health Policy, 3. 3. Quilici S, Smith R, Signorelli C. (2015). Role of vaccination in economic growth. Journal Of Market Access & Health Policy, 3. 4. Postma MJ. Public health economics of vaccines in the Netherlands: methodological issues and applications. Journal of Public Health 2008;16,(4):267 27.
22 Introduction
5. Ultsch B, Damm O, Beutels P Bilcke J et al. Methods for Health Economic Evaluation of Vaccines and Immunization Decision Frameworks: A Consensus Framework from a European Vaccine Economics Community. Pharmacoeconomics 2016;34(3):227 44. 6. World Health Organization (WHO). WHO guide for standardization of economic evaluations of immunization programmes. WHO/IVB/08.14. Available from: www.who.int/vaccines documents/ [Accessed: February 2016]. 7. Pan American Health Organization (PAHO). Introduction and implementation of new vaccines: Field Guide. Washington, D.C., PAHO © 2010 (Scientific and Technical Publication No.632). 8. Centers for Disease Control and Prevention (CDC). CEA of a Vaccination Program. Framing an Economic Evaluation. CDC Econ Eval Tutorials. Available from: www.cdc.gov/owcd/ [Accessed: July 2010]. 9. Guidelines for the Economic Evaluation of Health Technologies in Ireland. Issued: November 2010. Available from: www.hiqa.ie/publication/guidelines economic evaluation health technologies ireland/ [Accessed: February 2016] 10. Murray CJ. Quantifying the burden of disease: the technical basis for disability adjusted life years. Bull World Health Organ. 1994;72: 429–445. 11. Mangen MJ, Plass D, Havelaar AH, Gibbons CL, Cassini A, Mühlberger N et al. The pathogen and incidence based DALY approach: an appropriated methodology for estimating the burden of infectious diseases PLoS One 2013;8(11):e79740. 12. Van Lier E, Havelaar A. Disease burden of infectious diseases in Europe: a pilot study 2007. Available from: www.researchgate.net/profile/Arie_Havelaar/publication/27453442_Disease_burde n_of_infectious_diseases_in_Europe_a_pilot_study/links/004635272cbb29f37800 0000.pdf. [Accessed: March 2014]. 13. Return On Investment – ROI. Definition. Available from: www.investopedia.com/terms/r/returnoninvestment.asp/ [Accessed: April 2016]. 14. Pitman R, Fisman D, Gregory S, Zaric GS, Postma MJ et al. Dynamic Transmission Modeling: A Report of the ISPOR SMDM Modeling Good Research Practices Task Force 5. Value in Health 2012;15:828 – 834. 15. Frank A. Sonnenberg FA, Robert Beck JR. Markov models in medical decision making: a practical guide. Med Decis Making. 1993 Oct Dec;13(4):322 38. 16. Ess SM, Szucs TD. Economic evaluation of immunization strategies. Clin Infect Dis 2002 Aug 1;35(3):294 7. 17. Institute of Medicine (IOM). 2011. Critical needs and gaps in understanding prevention, amelioration, and resolution of Lyme and other tick borne diseases: the
23 Chapter 1
short term and long term outcomes. Washington (DC): The National Academies Press. Available from: www.iom.edu/ [Accessed: August 2015] 18. Kollaritsch H, Krasilnikov V, Holzmann H, et al. Background document on vaccines and vaccination against tick–borne encephalitis. Geneva: WHO Strategic Advisory Group of Experts on Immunization. Available from: www.who.int/immunization/sage/previousapril2011/en/index.html/ [Accessed: September 2011]. 19. Centers for disease control and prevention (CDC). Three sudden cardiac deaths associated with lyme carditis United States, November 2012–July 2013. Available from: www.cdc.gov/mmwr/preview/mmwrhtml/mm6249a1.htm/ [Accessed June 2015]. 20. Sprong H, Trentelman J, Seemann I, et al. ANTIDotE: anti tick vaccines to prevent tick borne diseases in Europe. Parasit Vectors 2014;21:7–77. 21. Desjeux G, Galoisy Guibal L, Colin C. Cost benefit analysis of vaccination against tick borne encephalitis among French troops. Pharmacoeconomics 2005;23(9): 913 26. 22. Meltzer MI, Dennis DT, Orloski KA. The cost effectiveness of vaccinating against Lyme disease. Emerg Infect Dis. 1999;5:321–328. 23. Shadick NA, Liang MH, Phillips CB, et al. The cost effectiveness of vaccination against Lyme disease. Arch Intern Med. 2001;161:554–561. 24. Hsia EC, Chung JB, Schwartz JS, et al. Cost ‐effectiveness analysis of the Lyme disease vaccine. Arthritis Rheum. 2002;46:1651–1660.
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CHAPTER 2
Vaccines for tick borne diseases and cost effectiveness of vaccination: a public health challenge to reduce the diseases’ burden
Renata Šmit Maarten J Postma
Expert Review of Vaccines 2016; 15(1):5 7
25
26 Vaccines for tick borne diseases and cost effectiveness of vaccination: a public health challenge to reduce the diseases’ burden Abstract Tick borne encephalitis (TBE) and Lyme borreliosis (LB) are tick borne diseases (TBDs), and both present an increasing burden worldwide. Vaccination as public health intervention could be the most effective way to reduce this burden. TBE vaccines are available, but vaccines against LB are still in the phase of development. At the European level, TBE vaccines are likely under administered to effectively prevent the disease. Cost effectiveness of vaccination is a helpful tool in the decision making process to include novel vaccines in the national vaccination program or to extend current programs, and its role is only increasing. Cost effectiveness studies on TBE vaccines have been performed in Slovenia, Sweden, Finland and Estonia so far. Cost effectiveness studies with the novel vaccines against LB are expected to be performed in the near future.
Keywords: Tick borne diseases (TBDs) • tick borne encephalitis (TBE) • Lyme borreliosis (LB) • vaccines • cost effectiveness
27 Chapter 2
Tick borne diseases (TBDs) are one of the most rapidly expanding infectious diseases worldwide. Many new human tick borne pathogens are discovered and several novel TBDs are recognized. Therefore, TBDs’ burden may exceed the currently estimated burden.[1] TBDs are becoming an increasing public health concern globally.[1] Increasing burden of TBDs shows that current available public health interventions and approaches are not effective enough. Vaccination could be a very effective and highly cost effective intervention for preventing morbidity of the TBDs.[1,2] Whereas vaccines against Lyme borreliosis (LB) have not yet been developed, vaccines against tick borne encephalitis (TBE) are available. Development of TBDs’ vaccines faces numerous difficulties and challenges mainly due to diversity of human tick borne pathogens. Antigenic variations of the LB spirochetes present an enormous obstacle in developing LB vaccines, inclusive the differences between LB strains in Europe and the USA.[1] However, recently huge progress in vaccine development has been seen for LB. [3] At the moment, no human TBDs’ vaccines are licensed in the USA [1]; however, vaccines against TBE are licensed for use in Europe and Russia. [4] In 1998, one of two developed monovalent vaccines, based on outer surface protein A (OspA), was licensed against LB for the use only in the USA.[5] In 2002, this vaccine was withdrawn from the USA market, mainly because of safety concerns related to potential occurrence of arthritis.[5] Currently, in Europe, huge efforts focus on development of a novel multivalent based OspA vaccine. The risk for occurrence of potential arthritis with this novel vaccine seems eliminated.[3] At the moment, this novel vaccine potentially presents the most effective future protection against LB in the USA, Europe and Asia.[3] Other LB vaccines that include proteins such as OspB, OspC or DNA binding protein HU alpha are in different stages of development.[1] Also, various cocktails of several borrelia outer membrane and tick proteins are potential candidates for development of Lyme vaccines.[6] Tick proteins may be used for the development of an anti tick vaccine for effective prevention not only against LB but also against other human TBDs in Europe. Notably, vaccination with an anti tick vaccine could be a highly cost effective public health intervention that can reduce the burden of TBDs and therefore their impact on the society.[2] Cost effectiveness is an important consideration nowadays prior to introduction of large scale vaccination. Cost effectiveness analysis (CEA) concerns an economic evaluation comparing costs and health outcomes, mostly expressed in quality adjusted life years (QALYs), for vaccination versus no vaccination strategies.
28 Vaccines for tick borne diseases and cost effectiveness of vaccination: a public health challenge to reduce the diseases’ burden
Results of CEAs are presented as incremental cost effectiveness ratios (ICERs). The ICER is calculated as the difference in the cost of vaccination and no vaccination, divided by the difference in the health outcomes produced by vaccination and no vaccination. CEAs are supportive to government national committees advising on vaccination strategies, such as the Dutch Health Council, UK’s Joint Committee on Vaccination & Immunization, the Belgium “Knowledge Center” and the “Ständigen Impfkommission” at the German Robert Koch Institute, on optimal use and reimbursement of new or existing vaccines. TBE can affect the central nervous system, which may result in long term/permanent neurological sequelae or even death.[4] At the European level, TBE presents an increasing public health concern with vaccination against TBE less widely used than possible to reduce the disease burden. Cost effectiveness studies of TBE vaccines to support inclusion/expansion of TBE vaccination in national vaccination programs against TBE are needed. In 2012, the first study on the cost effectiveness of two licensed Western European vaccines was published, using a Markov model.[7] The use of the Markov model for evaluating the cost effectiveness of TBE vaccination was an innovation.[7] The Markov model was developed on the basis of the natural course of the disease.[7] Results were expressed in costs per QALY, showing that vaccination of adults aged 18–80 is cost effective (inclusive boosters) from the view of the health care payer and even cost saving from the societal perspective in Slovenia. [7] The ICER for vaccination amounted to approximately €15,000–20,000 per QALY gained from the view of the health care payer.[7] The recognition of the importance of this study [7] can be seen when considering its impact. Firstly, in the Swedish county Sörmland, the County Council used this Markov model for their decision about TBE vaccination.[8] Results did not show favorable cost effectiveness for all ages.[8,9] Secondly, in Finland, the cost effectiveness study – using the same approach – showed that vaccination brings economic savings from the health care payer perspective with specific plausible assumptions on incidence of the disease, and respiratory paralysis and on duration of treatment.[10] When the incidence of cases of respiratory paralysis would be reduced from 1/3 to 1/9 per year at the same incidence of the disease and duration of treatment, vaccination against TBE would still be cost effective with an ICER at €16,000 per QALY gained from the health care perspective.[10] Also, for lowered assumptions on disease incidence, vaccination against TBE remained cost effective.[10] Only at an incidence of the disease below
29 Chapter 2
5/100,000, vaccination could become not cost effective with an ICER higher than €100,000 per QALY gained.[10] Based on this cost effectiveness study, the TBE immunization working group in Finland made a recommendation on vaccination against TBE.[10] Thirdly, an Estonian study [11] showed that vaccination of the whole population comes with an ICER of €61,000 per QALY gained, using a Markov model. Vaccination against TBE for the population ≥50 years is more cost effective, with an ICER of €25,000 per QALY gained from the health care perspective. Next to the cost effectiveness of vaccination against TBE in Slovenia,[7] the burden for TBE was measured in disability adjusted life years (DALYs) for the same country, using the updated DALYs methodology.[12,13] Notably, corrections for under estimation were taken into account.[12,13] The burden of TBE was not previously expressed in DALYs. The burden model was developed based on the health outcomes of the natural course of the disease.[12,13] Results of the study showed that total DALYs amount to 3,450 [12,13] presenting a relative high burden as measured in DALYs compared with estimates for other infectious diseases from the Global Burden of Disease 2010 study for Slovenia. High TBE burden presents a public health challenge for more efficient policies and actions to reduce TBE in Slovenia, inclusive of an extended vaccination campaign in Slovenia. Taking into account the fact that in Slovenia and various similar countries, likely very low vaccination coverage exists,[14] ample room for improvement exists. Also, vaccination can add to a rising awareness about the disease that is proposed to also currently reduce the burden of TBE.[12] In Austria, it has been shown that extended TBE vaccination can be beneficial from both the health and economic perspectives.[15] LB, the most common reported TBD, affects mostly the skin, joints, nervous system and heart.[16] Especially if LB is left untreated, it may lead to serious complications.[16] LB has even been suggested to potentially also be deadly.[1] LB is an increasing public health concern in many parts of the USA, across Europe and globally. Only in the USA, some studies on cost effectiveness of vaccination with monovalent OspA vaccine against LB were performed, showing that the vaccine could be cost effective at high risks of infection.[17–19] However, no cost effectiveness studies with LB vaccines have been performed in Europe.[20] CEA is crucial to support decision making and guiding the choices to be made in the allocation of resources, as well as to determine strategic planning priorities.
30 Vaccines for tick borne diseases and cost effectiveness of vaccination: a public health challenge to reduce the diseases’ burden
Further research on cost effectiveness of vaccines against TBDs is needed, in particular regarding upcoming LB vaccines. Currently, such studies are being planned. With TBDs being a serious public health concern, awareness of TBDs and increasing knowledge about TBDs among the general population remain important. Increasing investment in research, development and implementation of novel TBDs vaccines can crucially add to this, to further reduce the diseases’ burden and ultimately lead to substantial health benefits and financial returns.
Financial & competing interests disclosure Prof. MJ Postma received grants and honoraria from various pharmaceutical companies, but these are unrelated to this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
References 1. Institute of Medicine (IOM). 2011. Critical needs and gaps in understanding prevention, amelioration, and resolution of Lyme and other tick borne diseases: the short term and long term outcomes. Washington (DC): The National Academies Press. [cited 2015 Aug]. Available from: www.iom.edu. 2. Sprong H, Trentelman J, Seemann I, et al. ANTIDotE: anti tick vaccines to prevent tick borne diseases in Europe. Parasit Vectors. 2014;21:7–77. 3. Wressnigg N, Pöllabauer E, Aichinger G, et al. Safety and immunogenicity of a novel multivalent OspA vaccine against Lyme borreliosis in healthy adults: a double blind, randomised, dose escalation phase 1/2 trial. Lancet Infect Dis. 2013;13:680–689 4. Kollaritsch H, Krasilnikov V, Holzmann H, et al. Background document on vaccines and vaccination against tick–borne encephalitis. Geneva: WHO Strategic Advisory Group of Experts on Immunization. [cited 2011 Sep]. Available from: www.who.int/immunization/sage/previousapril2011/en/index.html/. 5. Poland GA. Vaccines against Lyme disease: What happened and what lessons can we learn? Clin Infect Dis. 2001;52(Suppl 3):s253–8. 6. Schuijt TJ, Hovius JW, van der Poll T, et al. Lyme borreliosis vaccination: the facts, the challenge, the future. Trends Parasitol. 2011;27(1):40–47. 7. Šmit R. Cost effectiveness of tick borne encephalitis vaccination in Slovenian adults. Vaccine. 2012;30:6301–6306.
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8. Ola Engman K, Kallings Larsson C, Feldman I. Halsoekonomisk analys av allman TBE vaccinering av inv ˙anarna I Sormland; 2013. [cited 2013 Aug]. Available from: http://www.landstingetsormland.se/PageFiles/37448/(9)%20H%C3%A4lsoekonomisk%20a nalys%20av%20allm%C3%A4n%20TBE vaccinering%20av%20inv%C3%A5narna%20i%20S%C3%B6rmland.pdf. 9. Askling HH, Insulander M, Hergens MP, et al. Tick borne encephalitis (TBE) vaccination coverage and analysis of variables associated with vaccination, Sweden. Vaccine. 2015;33(38):4962–4968. 10. Työpaperi. Pitäisikö TBE rokotusohjelmaa laajentaa? Puutiaisaivokuumerokotustyöryhmän raportti. [cited 2015 Aug]. Available from: http://www.julkari.fi/bitstream/handle/10024/110860/URN_ISBN_978 952 245 627 4.pdf?sequence=1. 11. Jürisson M, Taba P, Võrno T, et al. Puukentsefaliidi vastase vaktsineerimise kulutõhusus Eestis. Tartu: Tartu Ülikooli tervishoiu instituut;2015. The cost effectiveness of tick borne encephalitis vaccination in Estonia. [cited 2015 Aug]. Available from: http://rahvatervis.ut.ee/bitstream/1/6065/2/TTH13_Tick borne_encephalitis_vaccination_summary.pdf. 12. Šmit R, Postma MJ. Disability adjusted life years (DALYs) as a composite measure to express the burden of tick borne encephalitis (TBE) in Slovenia. Value Health. 2014;17(7):A666. 13. Šmit R, Postma MJ. Review of tick borne encephalitis and vaccines: clinical and economical aspects. Expert Rev Vaccines. 2015;14:737–747. 14. Kunze U. TBE–awareness and protection: the impact of epidemiology, changing lifestyle, and environmental factors. Wien Med Wochenschr. 2010;160:252–255. 15. Kunz C. TBE vaccination and the Austrian experience. Vaccine. 2003;21:S50–5. 16. Stanek G, Fingerle V, Hunfeld K, et al. Lyme borreliosis: clinical case definitions for diagnosis and management in Europe. Clin Microbiol and Infec. 2011;17(1):69–79. 17. Meltzer MI, Dennis DT, Orloski KA. The cost effectiveness of vaccinating against Lyme disease. Emerg Infect Dis. 1999;5:321–328. 18. Shadick NA, Liang MH, Phillips CB, et al. The cost effectiveness of vaccination against Lyme disease. Arch Intern Med. 2001;161:554–561. 19. Hsia EC, Chung JB, Schwartz JS, et al. Cost ‐effectiveness analysis of the Lyme disease vaccine. Arthritis Rheum. 2002;46:1651–1660. 20. Šmit R, Postma MJ. Lyme borreliosis: reviewing potential vaccines, clinical aspects and health economics. Expert Rev Vaccines. 2015;28:1–13.
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CHAPTER 3
Review of tick borne encephalitis and vaccines: clinical and economical aspects
Renata Šmit Maarten J Postma
Expert Review of Vaccines 2015;14(5):737 47
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34 Review of tick borne encephalitis and vaccines: clinical and economical aspects
Abstract Tick borne encephalitis (TBE) disease is an increasing burden not only locally but also globally. In most endemic countries, vaccination coverage is too low to reduce the TBE burden significantly; however, vaccination is the most effective protection against TBE, with various vaccines currently available. In spite of rising awareness of TBE, little attention is directed toward the health economics of the disease. The purpose of the present review is to compile information on TBE and its explicit clinical and economical aspects. Given the scarcity of studies, the authors conclude that more attention is needed for health economics of TBE. Notably, this would help establish guidance on efficient policies for TBE prevention, reduce disease burden and achieve population health benefits.
Keywords: Health economics • tick borne encephalitis • vaccination • vaccines
35 Chapter 3
Three genetically closely related subtypes of the tick borne encephalitis virus (TBEV) cause TBE; that is, the European, Siberian and Far Eastern subtypes [1]. The European subtype of the virus is mostly found in Europe, the Siberian subtype occurs mainly in the Urals, Siberia and Far Eastern Russian provinces and the Far Eastern subtype is prevalent in Far Eastern Russia, China and Japan [1,2]. All three subtypes co circulate in the Baltic states and Finland [3,4]. The tick Ixodes ricinus is the main transmitter of the European, whereas I. persulcatus spreads the two other subtypes [1,5]. Next to being directly tick borne and tick transmitted, TBEV can also be transmitted by unpasteurized dairy products [5]. TBE is a serious viral infectious disease of the CNS, which may lead to long term or permanent neurological sequelae or even death [6]. Sequelae of the disease may affect the patients’ quality of life and may require changes in their lifestyle [6]. Course of the disease, disease severity and fatality because of TBE depend on virus subtypes [1]. Disease caused by the Far Eastern subtype of the virus is usually severe, frequently with encephalitic symptoms and mortality rates between 5 and 35% [1]. Disease with the Siberian subtype is less severe, with a tendency to develop chronic infection with diverse neurological symptoms and mortality rates between 1 and 3% [1]. The European subtype of the virus usually causes a biphasic course of the disease [1]. The first stage of the disease is characterized by symptoms similar to flu and the second stage of the disease often manifests as meningitis, meningoencephalitis or meningoencephalomyelitis [1]. Mortality rate due to TBE in adults caused by European subtype of virus is less than 2% [1]. In many parts of Europe, Asian Russia, Siberia and the Far East, the incidence is increasing and new foci have appeared because of increasing mobility, changes in lifestyle, human leisure activities, agricultural practices and effects of climate changes on vectors and reservoir hosts [2,7]. TBE is becoming a high burden locally as well as globally. It is believed that the incidence of TBE is underestimated [1,2,7] and the true burden of TBE can therefore not be known [8]. Yet recently, the real burden measured in disability adjusted life years (DALYs) was estimated for Slovenia, inclusive of correction for underestimation, to show the full burden of the disease in this Central European country [9]. Currently, national guidelines, specific recommendations and public health interventions for prevention and control of TBE differ between countries and even within one country [10]. However, consistently in most endemic countries,
36 Review of tick borne encephalitis and vaccines: clinical and economical aspects vaccination coverage is very low and inefficient to adequately reduce the TBE burden [11,12]. Yet, TBE vaccines are safe, efficacious and well tolerated and present the only real option of effective and successful prevention [2,13,14]. Currently, four registered vaccines exist: FSME Immun® (Baxter, Vienna, Austria) and Encepur®(Novartis Vaccines, Marburg, Germany) are based on the European subtype and are used mainly in Europe (further referred to as Western European vaccines), whereas the TBE Moscow vaccine® (Chumakov Institute, Moscow, Russia) and EnceVir® (Scientific Production Association Microgen, Tomsk, Russia) are based on the Far Eastern subtype and are used mainly in Russia (further referred to as Russian vaccines) [2,14]. Ways to protect against the disease is wearing suitable clothes and shoes, using repellents, avoiding tick infected areas and consuming adequately pasteurized dairy products. However, vaccination is the most effective and potentially most successful route to prevent TBE [12] and thus reducing the burden of TBE. Slovenia is an endemic country with a high incidence rate of TBE and low vaccination coverage [2,11]. TBE causes high costs for healthcare insurances and the society because of hospitalization and frequent long term and permanent neurological sequelae [2]. One recent cost–effectiveness study of vaccination was directed at Slovenia [15]. In many countries, including Slovenia, cost–effectiveness of vaccines represents an important criterion for inclusion in national immunization programs. Therefore, also for Slovenia, an economic evaluation on TBE vaccination was clearly needed to help decide whether TBE vaccination could be included into the national immunization program. The cost–effectiveness of TBE vaccination for adults was evaluated for Slovenia, using a Markov model constructed on the basis of the natural history of the disease [15]. The results were shown as the cost per quality adjusted life year (QALY) gained of vaccination from the view of the healthcare payer and the society [15]. On the basis of the study [15], Slovenia took a positive decision on the inclusion of the vaccine in the national program. Also, based on the study [15] and applying its model [15], the County Council of Sornland in Sweden decided positively on vaccination against TBE [16]. Also other countries are encouraged to evaluate the cost–effectiveness of TBE vaccination [14], so that health authorities decision making on programmatic vaccination can be adequately informed by analyses of the cost–effectiveness in those countries as well. Even though awareness about TBE is increasing, too little attention seems to be oriented toward health economics of the disease. Yet, such studies can help to
37 Chapter 3 formulate more specific guidelines for efficient prevention and control of TBE to reduce the disease burdens locally and globally. The purpose of the present review is to compile information on TBE and its health economic aspects.
Epidemiology TBE is endemic in areas from Alsace Lorraine and Scandinavia to the North Eastern parts of China and Northern Japan [2,17,18,19]. Surveillance in TBE endemic areas is based mostly on the number of TBE reported cases [18,19]. Within Europe, Slovenia, Estonia, Lithuania, Latvia and Russia are countries with the highest incidence of TBE reported cases [2,20]. Between 2005 and 2009, the incidence rate in the whole country of TBE reported cases per 100,000 population was 14.07 in Slovenia, 11.10 in Estonia, 10.59 in Lithuania, 8.76 in Latvia, 7.02 in the Czech Republic, 2.15 in Switzerland, 1.99 in Sweden, 1.16 in Slovakia and 0.94 in Austria (relatively low because of high proportions already vaccinated populations [19]; notably, 6.02 in the nonvaccinated population) [21]. Lower incidence rates are found in some other countries: 0.66 in Poland, 0.60 in Hungary, 0.44 in Germany and 0.39 in Finland [19]. Russia not only has areas of high incidence of TBE reported cases but also large nonendemic areas [19]. In 2006, the national average incidence rate was 2.44, but in Siberia the incidence was more than 5 times higher, including some areas where it was even 10 times higher than the national average [2,18]. High incidence rates of TBE were also reported from North West Russia [18,19]. In his studies [18,19], Süss described the epidemiological overview of TBE in Europe, the Far East and Asia. He presented the number of TBE reported cases in endemic countries, such as Austria, Croatia, the Czech Republic, Denmark, Estonia, Finland, France, Germany, Hungary, Italy, Latvia, Lithuania, Norway, Poland, Russia, Slovakia, Slovenia, Sweden and Switzerland, as well as in the non European TBE endemic countries China, Kazakhstan, Mongolia, Japan, South Korea and Kyrgyzstan in different time periods of observation, described fluctuations in TBE cases and emergence of new TBE foci. Between 1990 and 2007, a total of 157,584 TBE reported cases were documented in Europe. Of these, 50,486 reported cases were registered in Europe without Russia [18]. Between 1976 and 1989, a total of 38,572 TBE reported cases were documented in Europe, and of these, 20,328 TBE cases were reported in Europe without Russia [18]. The comparison of these two periods shows an increase in TBE reported cases over 300% in Europe and almost 200% in
38 Review of tick borne encephalitis and vaccines: clinical and economical aspects
Europe without Russia [18]. Since 1990, the number of TBE reported cases has drastically increased [18], partially because of the introduction of mandatory reporting of TBE cases in some countries, better surveillance and improved diagnosis, particularly in the less developed countries of Europe, where the health systems have improved substantially over these years [2]. As indicated, one exception referred to Austria where the number of TBE reported cases has decreased with an increase in vaccination coverage [21–24]. The number of TBE cases fluctuates annually between and within countries [18,19]. In 2006, 7424 TBE cases were reported in Europe and 3914 in Europe without Russia, while in 2007 the number of reported TBE cases fell to 5462 in Europe and 2364 in Europe without Russia [18]. This corresponds to a reduction of 60% [18]. From 2006 to 2007, a decrease in the number of TBE reported cases was seen in almost all European countries except in Sweden, Norway and Hungary, where the number of TBE reported cases further increased and in Latvia where no changes in the number of TBE reported cases was observed [18]. Furthermore, for the Czech Republic, Germany, Poland, Lithuania, Slovakia, Slovenia and Switzerland, the number of TBE reported cases for 2008 was the same as for 2007 [18]. Annual TBE fluctuations are a well known phenomenon as described both by Mantke et al. [25] and Heinz et al. [21]. Fluctuations in TBE cases may be caused by several factors, of which the most important are behavioral and environmental changes [26]. Consistently, over the past years, endemic areas have spread north and westward in Europe and within already affected countries [27]. New foci have emerged in Denmark [28], Finland [4,19], Sweden [29], Norway [30], Austria [31], Germany [32], Switzerland [33], Slovakia [34], Russia/Siberia [34] and Romania [8]. TBE endemic areas are also expanding to higher altitudes as reported for Austria [35] and for the Czech Republic [36]. The spread of endemic areas is expected to continue further to currently still nonendemic areas [37]. Furthermore, TBE spread was illustrated in recent findings of Süss [34], comparing the number of TBE reported cases between 1991 and 2000 with those between 2001 and 2010, showing an increase of TBE reported cases by approximately 100% in Scandinavian countries (Sweden, Finland and Norway) and 144% in Central European countries (Czech Republic, Germany, Switzerland and Poland). Yet, decreases were reported for the Baltics states (Estonia, Latvia and Lithuania) by 65% and by 42% in Russia [34].
39 Chapter 3
In non European endemic countries, such as China, Kazakhstan, Mongolia, Japan, South Korea and Kyrgyzstan, the epidemiological picture is not reliable, mainly because of inaccurate reporting of TBE, diagnostics not being performed regularly and very low awareness of the disease [19]. Yet, TBE is well known to be endemic in China, with endemic foci having been identified mostly in the North Eastern North Western and South Western parts of the country [19]. Notably, main endemic areas are in the province of Heilongjiang [19]. From 1980 to 1998, 2202 TBE cases were registered; however, absolute numbers of TBE cases are not representative because TBE is not a notifiable disease in China and cross reactivity with other flaviviruses, especially Japanese Encephalitis virus, hampers proper diagnosis [19,38]. In Kazakhstan, endemic areas are identified in the eastern parts of the country and in the region of Almaty. From 2004 to 2009, in total, 245 TBE cases were reported in Kazakhstan [19]. However, it is believed that this number is significantly affected by underreporting [19]. In Mongolia, some endemic areas were described closely to the Russian border, in the North of the country, in the provinces of Selenga and Bulgan and around the capital city Ulanbataar [39]. In 2008, the first patient died with a formal diagnosis of TBEV meningoencephalitis. The TBEV was isolated from the brain and was identified as genetically closest related to the Far Eastern subtype of virus [39,40]. In Japan, in 1993 one TBE case was reported from the southern part of Hokkaido. TBEV serosurveys in domestic animals and virus isolations from ticks also suggested TBE foci in Hokkaido [19,41]. In South Korea, TBEV has been isolated from ticks (Haemaphysalis longicornis, I. nipponensis) in several regions and surprisingly was found to be the European subtype of virus [42]. In Kyrgyzstan, TBE cases have not been reported yet [19]. Although it is believed that the incidence of TBE is underestimated, the epidemiological overview on TBE in Europe, the Far East and Asia presented by Süss demonstrates the importance of TBE from the individual as well as the healthcare perspective even at its currently measured level [18]. Surveillance and notification schemes are not uniform, not always mandatory and affect the incidence and prevalence estimates of disease in endemic areas [1,25]. Surveillance of TBE endemic areas based on TBE cases is not reliable because the number of TBE reported cases do not adequately reflect prevalence of TBEV and, therefore, the risk of infection [18,19]. This is illustrated by a high vaccination
40 Review of tick borne encephalitis and vaccines: clinical and economical aspects coverage in Austria and a low number of TBE reported cases, while a significant risk of infection still exists [8,23]. Although TBE was already mandatorily notifiable in 16 EU/EEA countries in 2011 [25], numbers of TBE reported cases are not fully comparable between endemic countries, because of significant differences in the quality and quantity of the diagnostics, case definitions and reporting in different endemic countries [1,25,43]. Many countries with mandatory notification use a case definition based on clinical and laboratory data; however, these definitions vary between countries [19]. Some endemic countries, such as Switzerland, Russia, Latvia, Lithuania, Slovakia and Norway, do not have a formal case definition at all [19]. Therefore, the overall epidemiology and burden of TBE at the European level remains unclear [43]. From 2012 onward, TBE is a notifiable disease in the EU with a new common case definition to allow comparability of numbers of TBE reported cases between countries, to improve knowledge about the disease and to provide better mapping of the disease, thus providing a clearer view on the epidemiology of the virus and the corresponding burden of TBE [43].
Burden measured in DALYs Mostly, the disease burden is expressed in terms of the incidence [2,10]. However, the burden of the disease can be better estimated by DALYs, which integrate data on incidence/prevalence, mortality, seriousness of disease and sequelae and, therefore, give a more comprehensive insight into the burden of the disease than, for example, incidence alone [44]. According to the WHO, DALYs are defined as lost years of healthy life [45]. In the report of the Dutch National Institute of Public Health & the Environment, it was shown that the relative burden measured in DALYs is different when compared with the relative burden measured just by incidence or mortality data for seven selected infectious diseases (influenza, measles, HIV, campylobacteriosis, infection with enterohemorrhagic Escherichia coli, salmonellosis and tuberculosis) in selected European countries [44]. Notably, for these diseases, the incidence is not considered to provide an overall and complete view of the burden of the disease [44]; this is likely similar for TBE. In 2014, the burden of TBE measured in DALYs was estimated for Slovenia, by using the updated DALYs methodology first introduced by Murray et al. in the Global Burden of Disease project [9]. According to the methodology of Murray et al., DALYs
41 Chapter 3 are sum of the number of life years lost due to premature death and the number of life years lost due to disability, weighted with a factor between 0 (perfect health) and 1 (death) that reflects the severity of the disability [45]. The DALYs calculations for Slovenia were based on the health outcomes of the natural course of TBE [9]. Corrections for under ascertainment and underreporting were included to show the true burden of the disease [9]. The study showed that from the population perspective total DALYs amount to 3450, while from the individual perspective, they amount to 3.1 per case [9]. It was concluded that TBE presents a relatively high burden from both these perspectives in Slovenia and that the neurological sequelae have the largest impact on the overall TBE burden [9]. Burden of TBE expressed in QALYs, taking into account both the quantity and quality of life for the whole population [46], was also calculated for adults in Slovenia using a Markov model [15]. Notably, the exact scope of the study was discussed in letter [47]. Findings of these DALY and QALY studies [9,46] showed that the burden of TBE in Slovenia is centered in adults, with age having a strong influence on TBE burden. The exact course of TBE and case fatality depend on various components; for example, increasing severity of disease with increasing age and death risk depending on virus subtypes, resulting in differences in specific estimates of DALYs and QALYs. QALYs and DALYs reflect criteria, next to various others, that can be used for effective planning and prioritizing of limited public health resources [44].
Diagnosis All three human pathogenic subtypes of TBEV can cause TBE with a wide spectrum of symptoms, from subclinical to biphasic courses, characterized by a first stage with symptoms similar to flu, followed by an asymptomatic period and in approximately one third of cases, a second stage of the disease characterized with CNS involvement [1]. The second stage of TBE manifests with signs of meningitis, meningoencephalitis or meningoencephalomyelitis and the appearance of specific antibodies in the serum and cerebrospinal fluid (CSF) [1]. Routine laboratory diagnosis of TBE is mainly based on detection of specific antibodies by serological methods, usually ELISA [48– 50]. However, reverse transcription PCR (RT PCR) techniques, based on TBEV detection, can also be valuable tools for TBE diagnosis [49,50]. In the first stage of the disease, TBE can be diagnosed by TBEV isolation from the blood or by virus RNA detection in blood or CSF, using RT PCR techniques [48].
42 Review of tick borne encephalitis and vaccines: clinical and economical aspects
During the second stage of the disease, CNS complications occur and most patients are hospitalized [48]. IgM and IgG antibodies appear at the same time with the occurrence of the neurological symptoms [48]. These antibodies can be detected in serum or CSF by serological methods, using ELISA, neutralization tests or immunofluorescence assay [49]. During the second stage of the disease, the TBEV isolation and the RT PCR techniques are only of limited value for TBE diagnosis because TBEV may not be present anymore in the blood and CSF [48]. Yet, RT PCR techniques can be valuable for the early diagnosis of TBE in the first stage of the disease, early differentiation of TBEV infections from other tick transmitted infections (Lyme borreliosis, anaplasmosis), discrimination among TBEV subtypes, as well as for those patients where antibodies are not detectable [49,50]. These techniques are important for epidemiological studies [50]. In fatal cases, RT PCR techniques can be used for TBEV detection from the brain and other organs [47]. IgM antibodies may persist for many weeks after TBEV infection or after the first and second TBE vaccination [2]. Without information on history of TBE vaccinations, positive serological findings caused by recent vaccination may lead clinicians to suspect TBE also in cases of non TBEV related CNS manifestations [2]. Therefore, confirmation of the diagnosis of TBE by detection of IgG antibodies is recommended, but it is necessary to monitor increased IgG titers 1–2 weeks later as well, which is rarely performed [49]. The major limitation of ELISA is that cross reacting antibodies in IgG ELISA might be shown in persons who were previously exposed to other flaviviruses through infections or vaccination, potentially leading to false positive results [2,48,49]. This is an increasing problem in Europe because many people travel to countries where other flavivirus are endemic [48]. In persons where cross reacting antibodies are suspected, a highly specific neutralization test that requires specialized laboratories for detection of TBEV is recommended [2,14,49]. Although PCR techniques are very valuable methods for TBEV diagnosis, they are not used much in practice [50].
Vaccines The outbreaks of the disease in the former Soviet Union presented huge public health concerns in 1937, and the first vaccine against TBE was prepared from the mouse brain around that time [14]. The first generation of vaccines was efficacious, but it
43 Chapter 3 caused frequent adverse events, which stimulated the development of modern, more purified and safe vaccines [13,14,37]. These modern vaccines are the Western European vaccines FSME Immun and Encepur, both based on the European subtype of virus, the Russian TBE Moscow vaccine, EnceVir [2,14,37] and the Chinese vaccine (Changchun Institute of Biological Products, China) [38]; all three are based on the Far Eastern subtype of virus [2,51]. Notably, on the composition, safety, efficacy of the Chinese vaccine, only very little is published (and this vaccine will not be addressed anymore below). Western European and Russian vaccines are produced according to the WHO manufacturing requirements, with all TBE vaccines containing formalin inactivated TBEV and aluminium hydroxide as an adjuvant [2]. The use of different stabilizers and different strains of TBEV reflect the main differences among these four vaccines in the production process [2]. The stabilizer used in FSME Immun and TBE Moscow vaccine is human albumin, and sucrose is used as a stabilizer in Encepur and Encevir. FSME Immun is based on the Neudoörfl strain and Encepur is based on the K23 strain of TBEV. The TBE Moscow vaccine is based on the Sofjin strain and EnceVir on the 205 strain of TBEV [2]. Western European vaccines are used in adults and children aged ≥1 years [14]. Registration schedules require a primary series of three doses for both Western European vaccines [14]. Conventional schedules require the second dose being administered 1–3 months after the first and the third dose 5–12 months after the second (for Encepur the third dose is given 9–12 months after the second) [14]. ‘Accelerated’ or ‘rapid’ schedules for both Western European vaccines are used in case of emergency mainly for travelers and armed forces, but still require at least 3 weeks to establish protection against TBE [52,53]. The ‘accelerated’ schedule requires the second dose to be given 14 days after the first, and the third dose is given 5–12 months after the second (for Encepur 9–12 months) [14]. The ‘rapid’ schedule for Encepur requires the second dose after the 7 days, the third dose after 21 days and the fourth dose 12–18 months after the third [14]. For both Western European vaccines, the manufacturers recommend the first booster to be given 3 years after the primary series and subsequent boosters at intervals of 5 years for persons below 50 or 60 years of age [14]. For persons aged 50 or ≥60 years, it is recommended that subsequent booster intervals do not exceed 3 years [37,53–62], based on the fact that persons aged 50 or ≥60 years develop relatively lower antibody titers [63]. However,
44 Review of tick borne encephalitis and vaccines: clinical and economical aspects recommended intervals for subsequent booster doses vary by age and countries [64]. Currently, no standardized recommendations for booster intervals are available and adequate immunosenescence remains a challenge [14]. In Austria, 3 year intervals are recommended for persons aged ≥60 years [14]. In Switzerland, booster intervals of 10 years are recommended after the first three doses [65]. Extended booster intervals can be important for reducing costs of vaccination and improving patients’ compliance [14]. The Russian vaccines are used in adults and children aged ≥3 years [14]. Conventional schedules have the second dose 1–7 months after the first dose for the TBE Moscow vaccine and for Encevir the second dose is given 5–7 month after the first dose [2]. For both Russian vaccines, the third dose is given 12 months after the second dose [2]. The first booster is given 3 years after the third dose, and subsequent boosters are recommended at 3 year intervals [2] For Encevir, there is also a ‘rapid’ schedule, where a second double dose is given 1–2 months after the first dose [2]. The third double dose is required 1–3 months after the second double dose [2]. A fourth dose is given after 6–12 months after the third double dose and first booster is given 3 years after the fourth dose and subsequent boosters are recommended at 3 years interval [2]. Vaccination schedules for TBE vaccines are presented in TABLES 1 & 2.
Table 1 . Conventional schedule for TBE vaccines.
Primary series First Subsequent booster boosters First dose Second dose Third dose FSME Immun® Index date 1 3 months 5 12 months 3 years 5 (3) years a Encepur® Index date 1 3 months 9 12 months 3 years 5 (3) years b TBE Moscow Index date 1 7 months 12 months 3 years 3 years vaccine® Encevir® Index date 5 7 months 12 months 3 years 3 years
For patients aged ≥50 or 60 years, it is recommended by the manufacturers that subsequent booster intervals do not exceed 3 years. a For patients aged ≥60 years, the 3 years interval is recommended. b For patients aged ≥50 years, the 3 years interval is recommended. TBE: Tick borne encephalitis
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Table 2. »Accelerated« and »rapid« schedules for TBE vaccines.
Primary series First Subsequent booster boosters First dose Second dose Third dose Fourth dose Accelerated schedule FSME Index date 14 days 5 12 months / 3 years 5 (3) years a Immun® Encepur® Index date 14 days 9 12 months / 3 years 5 (3) years b Rapid schedule Encepur® Index date 7 days 21 days 12 18 months 3 years 5 (3) years b Encevir® Index date c1 2 months c1 3 months 6 12 months 3 years 3 years
For patients aged ≥50 or 60 years, it is recommended by the manufacturers that subsequent booster intervals do not exceed 3 years. a For patients aged ≥60 years, the 3 years interval is recommended. b For patients aged ≥50 years, the 3 years interval is recommended. c For Encevir® the second and the third doses are doubled.
Safety According to the Cochrane review [13] and the WHO position paper [14], TBE vaccines are safe. Side effects were common for all TBE vaccines, but none were severe or life threatening [13,14]. This is stated by other studies as well [13,22,64,66– 75], although there is relatively little data available for the Russian vaccines to support that [2,14]. According to the Russian National Regulatory Authority, both Russian vaccines are safe and well tolerated [2,14]. However, in both 2010 and 2011, EnceVir was associated with high fever and allergic reactions, particularly in children. Currently, EnceVir is not recommended for vaccination of children below the age of 17 years [14].
Immunogenicity The efficacy of TBE vaccines is determined based on their immunogenicity, measured by the induction of protective antibodies [2]. Protective antibodies appear after TBE vaccination, and serological tests such as ELISA, neutralization test or hemagglutination inhibition are used for antibody detection [2,48]. Both Western European and Russian vaccines are reported to be highly immunogenic [2]; however, data on TBE vaccines’ immunogenicity are not directly comparable because there is no international standardized test of immunogenicity [2]. Numerous observational studies as well as randomized controlled trials confirm the strong immunogenicity after the primary series of currently available TBE vaccines [13,22,23,56,57,68,70,74,76–84]. More data on immunogenicity are available for the Western European vaccines than for the Russian vaccines [14].
46 Review of tick borne encephalitis and vaccines: clinical and economical aspects
Several observational studies demonstrated the duration of protection to be 3 years and above after the primary series of currently available vaccines in adults and children [58,72,85,86,86]. Findings by Schosser et al. [79] suggest that extended intervals between the first two or three vaccinations with Western European vaccines do not deteriorate the success of the subsequent vaccination. According to recent studies by Schosser et al. [87] and Askling et al. [88] single vaccination with FSME Immun resulted in adequate TBEV antibody titers in the majority of subjects, in which the intervals after the last vaccination was longer than recommended. These data suggest that subjects with irregular vaccination histories can attain protection after a single catch up vaccination and do not need to repeat the primary vaccination course. In addition, although Heinz et al. [21] reported high field effectiveness in irregularly vaccinated people, the field effectiveness in regularly vaccinated people was found to be superior with high statistical significance.
Field effectiveness In 1981, an extended vaccination campaign was launched in Austria, with subsequent implementation of a universal vaccination program [23]. Vaccination coverage of persons receiving at least one dose of vaccine increased from 6% at the beginning of the program to 88% in 2006, leading to drastic reductions in TBE [22,23]. Studies on field effectiveness in Austria between 1994 and 2001 showed effectiveness of 96 and 100% after two and three doses of FSME Immun, respectively [23]. Studies on field effectiveness of TBE vaccination in Austria between 2000 and 2006 showed the overall effectiveness in regularly vaccinated persons at 99% with no statistically significant differences between age groups [22]. In Austria, both Western European vaccines are available, but FSME Immun is predominately used. The general notion is that both Western European vaccines can be used interchangeably [64]. Therefore, studies on field effectiveness of TBE vaccination are generally considered representative for both Western European vaccines [2]. During the period between 2000 and 2006, about 2800 TBE cases and 20 deaths were prevented by vaccination [22]. In their recent study, Heinz et al. [21] compared incidences in the highly endemic countries of the Czech Republic, Slovenia and Austria to estimate potential effectiveness of increasing vaccination coverage in Austria. For all three countries, extensive annual and longer range fluctuations and shifts in distributions of patients
47 Chapter 3 were found, suggesting major variations and complex interplay of factors influencing risk for exposure to the TBEV [21]. On the basis of these findings, they projected a strong decline in TBE incidence for Austria to about 16% of that of the prevaccination area because of vaccination [21]. The incidence in the nonvaccinated population would remain as high as it was during the prevaccination era [21]. In addition, it was shown that the field effectiveness of TBE vaccination in regularly vaccinated patients could be estimated at 96–99% [21]. During 2000–2011, vaccination was estimated to have prevented more than 4000 TBE cases and 15 to 30 deaths caused by TBE in Austria [21]. In the highly endemic Sverdlovsk region in Russia, vaccination against TBE has been mandatory since 1995, and a mass vaccination program was initiated in 1996 [81,89]. Since 2001, TBE vaccination has been obligatory for children aged ≥7 years and since 2008 for individuals aged ≥15 months [81,89]. Vaccination coverage increased from 35% at the beginning of the program to 88% in 2010, resulting in decreasing TBE and death caused by TBE [81,89]. Mandatory vaccination has prevented an estimated 3300 TBE cases, 63 deaths caused by TBE and 600 cases of disability [81,89].
Duration of protection & booster dose Long term serological studies show very low rates of waning of protective antibodies titers during first 3–5 years after the booster following the primary series with both Western European vaccines [90]. This demonstrates long term antibody persistence following booster vaccination [2]. In 2009, an Austrian study indicated that protection against TBE persists for at least 6 years following a booster vaccination [73]. Increasing age has been shown to be associated with infection, as the immune system is weaker and elderly are more susceptible to infection [73,91]. Signs of immunosenescence, reflected by significantly lower antibody levels, were detected not only in patients aged >60 years but also in the age group between 50 and 60 years [91]. In the case of TBE vaccination, TBE antibody titers are significantly lower in the elderly, suggesting that risks of antibody levels declining below the threshold of protection are higher in elderly [91]. In the study by Aberle et al. [92], it was shown that the number of antigen specific memory B cells induced by primary vaccination was about threefold lower in the elderly and also the antibody response per memory B cell after revaccination was strongly reduced. However, according to a recent study
48 Review of tick borne encephalitis and vaccines: clinical and economical aspects by Stiasny et al. [93], healthy elderly people are able to produce antibodies in response to TBE vaccination with similar avidity and functional activity as young individuals, although at lower titers. WHO recommends regular booster doses according to the recommended vaccination intervals for the age group >50 years until more information becomes available [14]. Also, regular antibody titer controls in elderly are advisable [73]. In 2013, one other Austrian study showed that 8 years after booster vaccination, seroprotection rate was still 87% [91]. However, between 8 and 10 years after booster vaccination, high percentages of persons lost protective antibody titers, with levels declining below the threshold of protection, implying the need for a booster dose [91]. Data on persistence of antibodies levels beyond 3 years are not available for Russian vaccines [37].
Cross-protection In mouse models, Western European and Russian vaccines show mutual cross neutralization and protection against all three TBEV subtypes [37]; yet, clinical documentation is scarce [94]. In vivo mouse studies and in vitro studies by Hayasaka et al. [95] showed that FSME Immun induces protection against all three subtypes of the virus. In 2007, Leonova et al. [96] concluded that Encepur for adults induces protection against European and the Far Eastern subtypes of virus. In 2009, the same authors concluded that all TBE vaccines induced protection against the Far Eastern subtype of the virus [83]. In 2011, it was concluded by Orlinger et al. [97] that FSME Immun showed equally efficacious protection against the European, Siberian and Far Eastern subtypes of virus. Further support for this conclusion was presented by Fritz et al. [98]. Western European vaccines can be interchanged; however, no such clinical evidence exists for the Russian vaccines [37].
Vaccination coverage National guidelines, recommendations and public health interventions for prevention and control of TBE differ between countries and even within one country [10]. It has been documented that public health interventions in Austria and Sverdlovsk successfully increased vaccination coverage, and that TBE cases have correspondingly reduced significantly [22,23,81,89]. Within Europe, Latvia was one of the countries with the highest number of TBE cases for many years [99]. Currently, Latvia is one of
49 Chapter 3 the European countries with the highest vaccination coverage [8]. After 1999, numbers of TBE reported cases were decreasing because of intensive vaccination, while the vaccination coverage was increasing and reaching up to 39% for the whole population in 2009 and up to 22% in children nationwide, with maxima up to 77% in highly endemic regions. TBE cases in children, as percentage of all cases, decreased from 12.5% in 2001 to 3.6% in 2010, mainly because of recommendations and implementations within the national vaccination program for children [8]. In Switzerland, booster intervals of 10 years are recommended to increase TBE vaccination coverage [14]. However, the impact of this measure on TBE incidence has still to be seen with time. In some endemic countries with high TBE incidence, vaccination coverage is too low to control the disease effectively [12]. In 2006, vaccination coverage in terms of persons receiving one or two doses of vaccine was 6% in Lithuania, 11% in the Czech Republic, 12% in Sweden, 13% in Germany, 13% in Switzerland and 14% in Estonia [100]. In 2007, increases in vaccination coverage in Switzerland up to 17% were seen [11]. In 2008, increased vaccination coverage was seen in Estonia up to 20%, Sweden up to 13% and Lithuania up to 10% [11]. In 2009, vaccination coverage in the Czech Republic was 16% and Slovenia 13% [11]. Therefore, these rates are relatively low compared with other vaccines and ample room for improvement still exists.
Economic burden & cost–effectiveness of vaccination In 1981, an extended vaccination campaign was started under the national universal vaccination program in Austria [23]. Interventions increased vaccination coverage and correspondingly reduced the number of TBE cases [22]. In 1993, the economic benefits of vaccination were evaluated [101]. The total economic benefits of vaccination campaigns in Austria between 1981 and 1990 was evaluated at €24 million 1 through reducing costs for inpatients care, loss of productivity and premature retirement. Similarly, the estimated economic benefits of vaccination campaigns between 1991 and 2000 were €60 million 1 [101]. Also, it was estimated that the TBE vaccine may be cost–effective in Austria and potentially other countries where TBE is widespread and highly endemic [101]. In 2003, it was concluded by Kunz [23] that TBE will no longer be a public health problem in Austria if the universal national vaccination program is continued. In 2005, cost–benefit of
50 Review of tick borne encephalitis and vaccines: clinical and economical aspects vaccination against TBE among French troops was calculated using a decision tree [102]. The results were shown as the net costs (saved) calculated as the difference in vaccination program costs and costs prevented by vaccination [102]. Results demonstrate that the net benefit is negative [102]. It was concluded that the vaccination program against TBE for French military personnel should not be implemented [102]. In 2012, a study on the cost–effectiveness of TBE vaccination in Slovenia was undertaken, using a Markov model for the natural course of TBE [15]. The results were shown as the incremental cost–effectiveness ratios calculated as the difference in the cost of vaccination and no vaccination, divided by the difference in the QALYs corresponding to vaccination and no vaccination, respectively [15]. Analyses were performed from the views of both the healthcare payer and the society [15]. Results illustrate that vaccination against TBE is cost–effective for adults from the healthcare payer’s perspective, whereas from the societal perspective vaccination brings overall economic savings in Slovenia [15]. Findings of the study [15] also demonstrated that costs of hospitalization increase with the age and TBE may be considered to cause relatively high costs for both the healthcare insurance and the society as a whole in Slovenia.
Expert commentary TBE is a CNS disease that may result in long term or permanent neurological sequelae and death. These neurological sequelae can impair patients’ quality of life and require changes in their lifestyle. TBE is a spreading/emerging infectious disease and new foci are appearing and will further appear in the future, both in countries already affected and in ‘new’ countries. It is believed that incidence of TBE is underestimated. TBE presents an increasing burden, not only locally but also globally. Raising awareness of TBE, its consequences and the benefits of TBE vaccination in endemic as well as nonendemic countries, among travellers, professionals working outdoors and their employers is extremely important.
1In the original study [101], costs are expressed in Austrian Schillings (ATS). In the present review, these costs are converted to Euros (€), using the conversion calculator, available from www.unitconversion.org/eu currency/austrian schillings to euros conversion.html [Last accessed August 2014].
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Awareness may help to increase coverage of vaccination and so reduce the disease burden further. Consequences of TBE have significant impact on patients working capacity and potentially TBE could be identified as an occupational disease/hazard in the future if it is not already considered like that in some areas. There is no specific treatment for TBE, but effective, safe and well tolerated TBE vaccines provide effective protection against TBE. The cost–effectiveness of TBE vaccination was evaluated for Slovenia. Also, other countries are encouraged to evaluate the cost– effectiveness of TBE vaccination, with the explicit suggestion to apply the Markov model [15] to other countries, such as Sweden. Ideally, consistent evaluation and comparison of incremental cost–effectiveness ratios could result at the European level. TBE causes high costs for health insurance and society; therefore, potentials for a favorable health economic profile exist in many settings.
Five-year view In the coming years, it is expected that TBE will further spread to nonendemic areas. It is expected that standardization of reporting and diagnostics procedures will be developed, including international standard testing of immunogenicity. Furthermore, guidelines for exact booster intervals can be expected. More clinical studies in connection with immunogenicity and safety should be undertaken for the Russian and Chinese vaccines and health–economic studies on TBE should be performed. More efficient policies and interventions for prevention and control of TBE, occupational health policies and consensus of travel recommendations locally and globally will be developed, likely resulting in increasing vaccination coverage and decreasing burdens of the disease with time.
Key issues • Tick borne encephalitis (TBE) is a CNS disease that may result in long term/permanent neurological sequelae, relevant quality of life impacts and even death. • TBE presents an increasing burden not only locally but also globally, ideally to be estimated in disability adjusted life years. • Vaccination is the most effective protection against TBE with effective, safe and well tolerated vaccines being available; however, coverages are still relatively low.
52 Review of tick borne encephalitis and vaccines: clinical and economical aspects
• There is a need for efficient guidance, recommendations and policies for (cost effective) prevention of TBE to reduce the disease burden. • Scarce evidence (notably, for Slovenia) illustrates that TBE vaccines can be highly cost–effective.
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the article. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
References Papers of special note have been highlighted as: • of interest •• of considerable interest
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54. Loew Baselli A, Poellabauer EM, Pavlova BG, et al. Prevention of tick borne encephalitis by FSME IMMUN_ vaccines: review of a clinical development programme. Vaccine 2011;29(43):7307 19 55. Zent O, Hennig R. Post marketing surveillance of immediate allergic reactions: polygeline based versus polygeline free pediatric TBE vaccine. Vaccine 2004;23(5): 579 84 56. Zent O, Hennig R, Banzhoff A, Michael B. Protection against tick borne encephalitis with a new vaccine formulation free of protein derived stabilizers. J Travel Med 2005;12(2):85 93 57. Scho¨ndorf I, Beran J, Cizkova D, et al. Tick borne encephalitis (TBE) vaccination: applying the most suitable vaccination schedule. Vaccine 2007;25(8):1470 5 58. Zent O, Jilg W, Plentz A, et al. Kinetics of the immune response after primary and booster immunization against tick borne encephalitis (TBE) in adults using the rapid immunization schedule. Vaccine 2003; 21(32):4655 60 59. Rendi Wagner P, Kundi M, Zent O, et al. Immunogenicity and safety of a booster vaccination against tick borne encephalitis more than 3 years following the last immunisation. Vaccine 2004;23(4):427 34 60. Rendi Wagner P, Hoeller K, Kollaritsch H. Immunization recommendations for travel in the Mediterranean area. Wien KlinWochenschr 2004;116(19 20):652 60 61. Plentz A, Jilg W, Schwarz TF, et al. Long term persistence of tick borne encephalitis antibodies in adults 5 years after booster vaccination with Encepur_ Adults. Vaccine 2009;27(6):853 6 62. Schöndorf I, Scho¨nfeld C, Nicolay U, et al. Response to tick borne encephalitis (TBE) booster vaccination after prolonged time intervals to primary immunization with the rapid schedule. Int J Med Microbiol 2006;296:208 12 63. Jelinek T. TBE—update on vaccination recommendations for children, adolescents, and adults. Wien Med Wochenschr 2012; 162(11 12):248 51 64. Zent O, Bro¨ker M. Tick borne encephalitis vaccines: past and present. Expert Rev Vaccines 2005;4(5):747 55 65. Recommendations on immunization against tick borne encephalitis]. Bulletin des Bundesamtfür Gesundheit (Schweiz) 2006;13:225 31 66. Baumhackl U, Franta C, Retzl J, et al. A controlled trial of tick borne encephalitis vaccination in patients with multiple sclerosis. Vaccine 2003;21:S56 61 67. Zent O, Banzhoff A, Hilbert A, et al. Safety, immunogenicity and tolerability of a new pediatric tick borne encephalitis (TBE) vaccine, free of protein derived stabilizer. Vaccine 2003;21(25):3584 92 68. Loew Baselli A, Konior R, Pavlova B, et al. Safety and immunogenicity of the modified adult tick borne encephalitis vaccine FSME IMMUN ®: results of two large phase 3 clinical studies. Vaccine 2006; 24(24):5256 63
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69. Rendi Wagner P, Paulke Korinek M, Kundi M, et al. Antibody persistence following booster vaccination against tick borne encephalitis: 3 year post booster follow up. Vaccine 2007;25(27):5097 101 70. Schoendorf I, Ternak G, Oroszlàn G, et al. Tick Born Encephalitis (TBE) Vaccination in Children. Hum Vaccin 2007;3(2):42 7 71. Weinzettel R, Ertl S, Zwiauer K. FSME monitoring: monitoring of adverse events of tick borne encephalitis vaccines by selected paediatricians and general practitioners. Wien Med Wochenschr 2007;157(5 6): 107 10 72. Loew Baselli A, Poellabauer E, Pavlova BG, et al. Seropersistence of tick borne encephalitis antibodies, safety and booster response to FSME IMMUN ® 0.5 ml in adults aged 18 67 years. Hum Vaccin 2009; 5(8):551 73. Paulke Korinek M, Rendi Wagner P, Kundi M, et al. Booster vaccinations against tick borne encephalitis: 6 years follow up indicates long term protection. Vaccine 2009;27(50):7027 30 74. Pöllabauer EM, Fritsch S, Pavlova BG, et al. Clinical evaluation to determine the appropriate paediatric formulation of a tick borne encephalitis vaccine. Vaccine 2010;28(29):4558 65 75. Pöllabauer EM, Pavlova BG, Lo¨w Baselli A, et al. Comparison of immunogenicity and safety between two paediatric TBE vaccines. Vaccine 2010;28(29):4680 5 76. Andersson CR, Vene S, Insulander M, et al. Vaccine failures after active immunisation against tick borne encephalitis. Vaccine 2010;28(16):2827 31 77. Gorbunov M, Pavlova L, Vorob’eva M, et al. Results of clinical evaluation of EncoVir vaccine against tick borne encephalitis. Epidem Vaccinoprophil 2002;49 78. Krassilnikov I, Mischenko I, Sharova O, Vorobjova M. Development of technology of tick borne encephalitis vaccine (strain 205). Int J Med Microbiol 2002;291:173 79. Schossera R, Kaiserb R, Mansmannc U, et al. Seropositivity before and seroprotection after a booster vaccination with FSME Immun adults in subjects with a time interval of > 4,5 years since the last TBE vaccination. In International Jena Symposium on tick borne diseases, Weimar 2009 80. Stiasny K, Holzmann H, Heinz FX. Characteristics of antibody responses in tick borne encephalitis vaccination breakthroughs. Vaccine 2009;27(50):7021 6 81. Romanenko VV, Esiunina MS, Kiliachina AS. Experience in implementing the mass immunization program against tick borne encephalitis in the Sverdlovsk Region.Vopr Virusol. 2007;52(6):22 5 82. Ehrlich HJ, Pavlova BG, Fritsch S, et al. Randomized, phase II dose finding studies of a modified tick borne encephalitis vaccine: evaluation of safety and immunogenicity. Vaccine 2003;22(2): 217 23
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83. Leonova GN, Pavlenko EV. Characterization of neutralizing antibodies to Far Eastern of tick borne encephalitis virus subtype and the antibody avidity for four tick borne encephalitis vaccines in human. Vaccine 2009;27(21):2899 904 84. Wittermann C, Scho¨ndorf I, Gniel D. Antibody response following administration of two paediatric tick borne encephalitis vaccines using two different vaccination schedules. Vaccine 2009;27(10):1661 6 85. Vene S, Haglund M, Lundkvist Å, et al. Study of the serological response after vaccination against tick borne encephalitis in Sweden. Vaccine 2007;25(2):366 72 86. Il’ichenko TE, Bilalova GP, Stavitskaya NX, et al. [Organization of Public Health]. Siber J Med 2009;2:50 5 87. Schosser R, Reichert A, Mansmann U, et al. Irregular tick borne encephalitis vaccination schedules: the effect of a single catch up vaccination with FSME IMMUN ®. A prospective non interventional study. Vaccine 2014;32(20):2375 81 88. Askling HH, Rydgard C, Ostlund MR, Vene S. TBE in an elderly vaccinated couple. Don’t forget booster doses to the elderly! Lakartidningen 2011;108(29 31): 1441 2 89. Kunze U. Tick borne encephalitis: new paradigms in a changing vaccination environment. Wien Med Wochenschr 2011; 161(13 14):361 4 90. World Health Organization (WHO). Grading of scientific evidence – Tables IVa and IVb (duration of protection after primary immunization only and after primary immunizations plus one booster dose). 2014. Available at: http://www.who. int/immunization/TBE_duration_protection.pdf [Last accessed August 2014] 91. Paulke Korinek M, Kundi M, Laaber B, et al. Factors associated with seroimmunity against tick borne encephalitis virus 10 years after booster vaccination. Vaccine 2013; 31(9):1293 7 92. Aberle JH, Stiasny K, Kundi M, Heinz FX. Mechanistic insights into the impairment of memory B cells and antibody production in the elderly. Age 2013;35(2):371 81 93. Stiasny K, Aberle JH, Keller M, et al. Age affects quantity but not quality of antibody responses after vaccination with an inactivated flavivirus vaccine against tick borne encephalitis. PLoS One 2012; 7(3):e34145 94. World Health Organization (WHO). Grading of scientific evidence – Table III (induction of cross protection). 2014 Available at: http://www.who.int/entity/immunization/TBE_grad_crossprotection.pdf [Last accessed August 2014] 95. Hayasaka D, Goto A, Yoshii K, et al. Evaluation of European tick borne encephalitis virus vaccine against recent Siberian and far eastern subtype strains. Vaccine 2001;19(32):4774 9
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96. Leonova GN, Ternovoi VA, Pavlenko EV, et al. Evaluation of vaccine Encepur_ Adult for induction of human neutralizing antibodies against recent Far Eastern subtype strains of tick borne encephalitis virus. Vaccine 2007;25(5):895 901 97. Orlinger KK, Hofmeister Y, Fritz R, et al. A tick borne encephalitis virus vaccine based on the European prototype strain induces broadly reactive cross neutralizing antibodies in humans. J Infect Dis 2011;203(11): 1556 64 98. Fritz R, Orlinger KK, Hofmeister Y, et al. Quantitative comparison of the cross protection induced by tick borne encephalitis virus vaccines based on European and Far Eastern virus subtypes. Vaccine 2012;30(6):1165 9 99. Süss J. Epidemiology and ecology of TBE relevant to the production of effective vaccines. Vaccine 2003;21:S19 35 100. Kunze U. Conference report of the 9 th meeting of the International Scientific Working Group of Tick Borne Encephalitis (ISW TBE): tick Borne Encephalitis: From epidemiology to current vaccination recommendations. Vaccine 2007;25(50): 8350 1 101. Schwarz B. Health economics of early summer meningoencephalitis in Austria. Effects of a vaccination campaign 1981 to 1990. Wien Med Wochenschr 1993; 143(21):551 5 102. Desjeux G, Galoisy Guibal L, Colin C. Cost benefit analysis of vaccination against tick borne encephalitis among French troops. Pharmacoeconomics 2005;23(9): 913 26
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CHAPTER 4
Lyme borreliosis: reviewing potential vaccines, clinical aspects and health economics
Renata Šmit Maarten J Postma
Expert Review of Vaccines 2015;14(12):1549 61
61
62 Lyme borreliosis: reviewing potential vaccines, clinical aspects and health economics
Abstract Lyme borreliosis (LB) is a multisystem infectious disease with a growing burden in many parts of North America, Asia and Europe. Persistent infection of LB can usually be treated effectively with antibiotic therapy, but it may be followed by post treatment Lyme disease syndrome. Therefore, it is important to begin with treatment in the early phase of the disease. Vaccination shows potential as the most effective way of preventing LB and reducing its burden in these continents. It is concluded that there is a need for continuous effort in research from all perspectives on LB, especially regarding prevention with novel vaccines, their development, clinical efficacy and cost–effectiveness. This review may help to further develop (cost ) effective strategies for prevention and control of the disease to reduce its burden and achieve population wide health benefits.
Keywords: Borrelia burgdorferi • cost effectiveness • health economics • Lyme borreliosis • Lyme disease • treatment • vaccines
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Lyme borreliosis (LB) or Lyme disease is a serious multisystem infectious disease, affecting mostly the skin, joints, nervous system and heart [1] and may lead to serious long term sequelae, particularly if left untreated [2]. The disease is caused by the infectious organism spirochete Borrelia (B.) burgdorferi sensu lato genospecies complex, which is transmitted by the bite of an infected tick of the genus Ixodes type [3]. There are currently at least 18 genospecies of spirochete B. burgdorferi sensu lato, of which B. burgdorferi sensu stricto (further B. burgdorferi ) is the only human pathogen of LB in North America [4]. In Europe, the most important human pathogens causing the disease are B. afzelii , B. bavariensis , B. burgdorferi , B. garinii and B. spielmanii , while B. bissetti , B. lusitaniae and B. valaisiana are rarely found in patients [5–8]. These diverse human pathogenic genospecies cause different clinical manifestations of the disease, also differing between North America and Europe and even across Europe [9,10]. All pathogenic genospecies of B. burgdorferi sensu lato can cause red colored skin rash named erythema migrans (EM) [11]. European genospecies of B. burgdorferi sensu lato, such as B. afzelii, are associated most with skin manifestations such as acrodermatitis chronica atrophicans [12,13], mostly found in Central, Eastern, Northern Europe and Scandinavia [14–16]. B. garinii can cause Lyme neuroborreliosis [12,13], mostly found in Western Europe [14]. B. burgdorferi seems to be the most arthritogenic [17]; however, it is rarely found in Europe and Russia [18]. The tick Ixodes scapularis, transmitting LB, predominates in the Northeast and Northern Midwest America, whereas the tick Ixodes pacificus predominates in the Western America [19]. The transmitters of LB in Europe are the ticks Ixodes ricinus and Ixodes persulcatus, with the latter predominating in the Northeastern Europe. The tick I. persulcatus predominates in Asia [19]. LB is endemic in many parts of North America, Asia and Europe, and the number of reported LB cases is increasing and geographically expanding [11,20]. Therefore, LB is presenting an increasingly higher burden for societies. It is believed that the number of reported cases of the disease is highly underestimated mainly due to inconsistent reporting of LB cases [11,20,21]. Both early and persistent infection of LB can usually be treated effectively with antibiotic therapy, but they may be followed by post treatment Lyme disease syndrome [22,23]. Therefore, it is important to begin with treatment in the early phase of the disease [22,23]. There is continuous debate and controversial points of
64 Lyme borreliosis: reviewing potential vaccines, clinical aspects and health economics view exist mostly on the (prolonged) duration of antibiotic therapy, especially in patients with persistent symptoms after the use of standard antibiotic therapy, and on the exact health benefit of such therapy [24]. However, vaccination would be the most effective way to prevent LB [25,26]. Two monovalent, recombinant outer surface proteins A (OspA) vaccines from one strain of B. burgdorferi were developed for protection against LB primarily and first considered for application in the USA. One of these two vaccines was licensed in 1998 [27,28]. In the USA, several studies [29–31] on the cost–effectiveness of vaccination against LB showed that the licensed vaccine was cost effective for individuals at high risk of infection. In 2002, this vaccine was voluntarily withdrawn by the manufacturer SmithKline Beecham (now named GlaxoSmithKline) as safety was always a concern [32]. Notably, it was considered that the vaccine might cause arthritis [33,34] and consequently the vaccine is a commercial failure so far [32]. The health concerns regarding the Lyme vaccine that was withdrawn were found less. Currently, there is no vaccine against LB available. Developing a new generation of vaccines is a challenge due to the huge antigenic and genetic complexity of the LB spirochetes and general lack of knowledge about the antigenic structure of borrelia surface proteins [35]. Novel multivalent OspA vaccines are still in the phase of development [36,37]. Recent research results have already shown that these novel vaccines are promising to become one of the most effective options to reduce the public health burden of LB in North America, Asia and Europe, likely without the suggested safety concerns of its predecessors [25,36,37]. LB is a high public health concern and warrants much more attention than currently provided [11,20]. In Europe, little is known about the health and economic impact of LB on the quality of life, health care systems and the broader society. Therefore, there is an urgent need to assess health and cost outcomes of the disease and cost–effectiveness of vaccination, with the novel vaccine potentially to be marketed within 5 years. The purpose of the present review is to discuss LB disease, with a focus on vaccines, clinical efficacy and potential cost– effectiveness. This review may help to further develop effective strategies for improved prevention and control of the disease to reduce its health and economic burdens. Notably, favourable prospects for cost– effectiveness may further boost vaccine development and marketing.
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Epidemiology LB is endemic in many parts of North America, Asia and Europe [11,20]; however, in North America and Europe, it seems most widespread and frequently reported compared to Asia [22,23]. In Europe, the highest number of reported cases was found in the Baltic states, and in North Sweden, Austria, Slovenia, the Czech Republic, Germany and Central Europe [11,20]. Every year, more than 30,000 cases of LB are reported in the USA; however, new estimates show that this figure can be about 10 times higher due to underreporting [38]. In the USA, LB has been a mandatory notifiable disease since 1991 [39], while in Europe it is such in 16 out of the 30 (27 EU and 3 EFTA) European countries in total [11,20]. Due to different surveillance systems, reporting habits and case definitions used across Europe [11,20], it is only possible to make relatively crude estimates of the number of reported LB cases, amounting to about 85,000 cases every year in Europe [11,20]. Also, the direct comparison of the numbers of reported cases among countries [11,20] is difficult. Some European countries have no case definition for LB and laboratory diagnosis is not standardized, which may lead to under reporting [11,20]. In the USA and in Europe, several epidemiological studies describe a 2–3 to 6 fold increase in the number of reported cases of the disease over the past decade [40,41]. In many European countries, the number of reported cases has increased since the 1990s [11,20], with particularly significant increases in Germany, the Netherlands and the UK over the past two decades [42–44]. The number of reported cases has expanded to new geographic areas, as well as toward higher altitudes and latitudes [45,46], mainly due to changes in vector abundance and changes in latitudinal or altitudinal distributions of ticks, environmental factors and behavioural changes [11,20]. Notably, the overall epidemiology and burden of LB in Europe remains unclear, and a strong need for LB surveillance at the European level exists [11,20]. A case definition and a case classification for LB conform to the system applied with notifiable diseases is needed [11,20]. This is, however, challenging due to a number of clinical, laboratory and epidemiological characteristics of LB complicating diagnosis and classifications [11,20]. Overall, prevention and control of the disease need to be improved at the European level [11].
66 Lyme borreliosis: reviewing potential vaccines, clinical aspects and health economics
Coinfection Ticks can carry various microorganisms such as Anaplasma phagocytophilium, Babesia spp., tick borne encephalitis virus and other pathogens [20], leading to a variety of clinical manifestations in patients [47]. Sometimes manifestations can overlap sufficiently for one infection to be overlooked, potentially resulting in the failure of treatment [48]. Coinfection with Babesia microti can lead to relatively serious disease [49]. Coinfection with tick borne encephalitis virus can lead do diagnostic dilemmas and delay in antibiotic therapy of LB [48]. However, the frequency of coinfection with other microorganisms and their effects on LB epidemiology, diagnosis, clinical manifestation and treatment of LB are not very well studied yet and poorly understood [9,23].
Diagnosis Diagnosis is primarily based on clinical manifestation of the disease, physical examination of patients and assessments of likely exposure to an infected tick [2]. EM, a ring shaped, red colored skin rash is a characteristic sign of early Lyme disease at a stage when antibodies have not yet developed. At this stage, diagnosis of LB is based on clinical examination (perhaps with history) as negative serological tests do not rule out infection [3,50,51]. Laboratory testing to confirm or exclude LB is needed for all patients suffering disseminated Lyme disease [9,52]. In the latter type of patients, laboratory testing to confirm or exclude the disease is needed, using culture, serology and/or PCR testing.
Culture Culture of B. burgdorferi spirochetes from skin biopsy is the gold standard used to confirm LB [53–55]. However, due to low numbers of viable B. burgdorferi spirochetes present in patients’ biopsies and the nature of B. burgdorferi s.l. strains, it may lead to negative results despite active infection [2,3,23]. For this reason and also because culturing the Lyme bacterium is difficult, time consuming and requires highly trained expertise and specialists, this technique is not recommended as the first choice for clinical diagnosis [2].
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Serology Serological assays reflect the indirect technique of first choice. It is the most widely and usually the first laboratory technique used to confirm LB by detection of the presence of IgM and IgG antibodies in blood or cerebrospinal fluid [2]. In some European countries, diagnosis by solely the ELISA is recommended [2]. ELISA has a specificity of 95–98% [23]. Novel generation tests use either semipurified antigens, purified antigens, recombinant antigens or synthetic peptides [23]. In other European countries and also in the USA, a two step approach is recommended, with ELISA as the first test for detecting antibodies [2,23,56]. In the case of a positive ELISA test result, confirmation of LB with a second laboratory assay of immunoblot to detect IgM and IgG antibodies (most often used is Western blot) is recommended [2,23,56]. If the immunoblot also detects the presence of antibodies, the test result is considered to be positive [56]. IgM antibodies can be detected during the first few weeks of infection, but testing might give false positive results. IgG antibodies can be detected later than IgM antibodies during 4–6 weeks of infection, and testing gives more reliable results [57]. A minimum standard of at least 90% specificity for ELISA and 95% specificity for the immunoblot should be achieved [23]. In the USA, skipping the first test and just doing the immunoblot is not recommended by the CDC to avoid false positive results, misdiagnosis and unsuitable treatment [56]. Advantages of a serological assay are that it is easy to obtain samples, laboratory facilities are widely accessible and tests show acceptable sensitivity and specificity [2]. However, serological assays also have their limitations. Notably, a duration of about 2–6 weeks applies before antibodies generally are detectable, implying that some patients with EM or LNB who have not developed antibodies’ response to the infection yet will show negative results [51,58,59]. From week 6 onward, most patients will have sufficient antibodies to the bacterium to give positive test results in both the ELISA and the immunoblot assays [3]. Seroreactivity can persist for months or years after antibiotic therapy. PCR positivity may also persist for at least weeks and perhaps longer, after live spirochetes are no longer present [60]. Finally, cross reactivity provides another limitation with potential false positive ELISA results if antibodies recognize other similar structures, including erlichial infection [23,61]. In general, IgM antibodies demonstrate more cross reactivity than IgG antibodies. Still, the immunoblot assay can confirm or reject any cross reactivity [23,61].
68 Lyme borreliosis: reviewing potential vaccines, clinical aspects and health economics
As mentioned, a serological test only cannot prove borrelia infection, and additional testing next to a good understanding of clinical manifestations of LB is extremely important for adequate diagnosis of LB [9,62].
Polymerase chain reaction PCR is the most accurate direct technique for detection of the bacterium’s genetic material DNA [2]. PCR identification of DNA in synovial fluid samples is successful in more than 50% of untreated patients [63,64], DNA can be detected in 50–70% of skin biopsies in patients with EM and ACA [65,66] and in15–30% in CSF samples of patients with acute LNB [54,66–68]. PCRs on urine or blood samples are not recommended for routine diagnosis [22,69,70]. Currently available diagnostic tools, primarily based on serology, are appropriate for diagnosis of early Lyme disease in most cases [71]. Finally, laboratory tests’ standardization is needed to enable comparison of test results from different laboratories [11].
Clinical manifestations Clinical manifestations of LB, most often involve the skin, nervous system, joints and heart [1,22]. Manifestations are slightly different in children than in adults with shorter duration of symptoms and better prognosis [72]. Clinical manifestations of LB can generally be divided into three stages, labeled early Lyme disease (stage 1), early disseminated Lyme disease (stage 2) and late disseminated Lyme disease (stage 3), associated with diverse disease symptoms and durations for developing symptoms after the infectious tick bite [73]. Early Lyme disease (stage 1) is typically characterized by EM that may show within a few days or weeks after the bite of the infected tick [2]. EM is a red colored skin rash occurring in approximately 70–80% of infected cases in the USA [74] and 60–80% in the Europe [75], and it is the most frequent clinical manifestation of the disease worldwide [22,23]. However, the rash is not always present or is not recognized by patients, overlooking EM [9]. EM is self limiting; however, it may persist for several months [76,77]. If it is left untreated, spirochetes can disseminate to other tissues and parts of the body [76,77] and may cause multiple EM (more frequently in the USA than in Europe), meningitis, cranial neuritis, radiculoneuritis, peripheral neuritis, carditis, atrioventricular nodal block or migratory
69 Chapter 4 musculoskeletal pain [73]. Very few deaths due to LB have been reported, mostly resulting from heart block as one of the very Lyme borreliosis rare manifestations of the disease [23]. Three sudden deaths were reported in young men from Lyme carditis [78]. Finally, Lyme arthritis should be mentioned, which generally occurs in Europe [73]. This stage of the disease is referred to as early disseminated Lyme disease (stage 2) [73]. Symptoms of late disseminated Lyme disease (stage 3) can appear after months or years (usually after periods of latent infection) [73]. It can include intermittent or persistent Lyme arthritis as the most common manifestation of stage 3 in the USA, chronic encephalopathy or polyneuropathy and acrodermatitis chronica atrophicans as the most common manifestation of stage 3 in Europe [73]. In some patients, it takes several months to fully and completely recover following appropriate treatment [2]. Still, some patients report persistent symptoms after they completed the recommended course of antibiotic therapy even beyond several months [23]. Reasons may be failure to eradicate the organism, reinfection, residual damage or immune mediated inflammation that persists after spirochetal eradication [9]. These persistent symptoms in properly treated patients, again, are rare [2]. Some evidence suggests that persistent symptoms mainly occur in patients with the nervous system being affected, resulting in residual paresthesia, paresis, hearing deficit, ataxia, incontinence and cognitive impairment [2,79,80]. Also, persistent symptoms seem present in some acrodermatitis chronica atrophicans patients who experienced severe tissue damage prior to treatment [2,81] and in patients with antibioticrefractory Lyme arthritis, who do not respond to further antibiotic treatment [2,82]. The latter is primarily seen in the USA [23]. Lyme arthritis is due primarily to infection, and autoimmune induced pathology seems to be a feature of antibiotic refractory Lyme arthritis only [83]. The persistence of spirochetes and the release of spirochetes antigens into the synovial fluid despite treatment may explain the recurrence of arthritis [83].
Post-treatment Lyme disease syndrome Some patients report persistent symptoms labeled as post treatment Lyme disease syndrome, including fatigue, irritability, emotional liability, disturbance in sleep, reduce performance and concentration and memory problems [2,11,23]. These symptoms are often noticed already at the start of a borrelia infection, but they can also occur in the later stages of the disease and can persist for more than 6 months
70 Lyme borreliosis: reviewing potential vaccines, clinical aspects and health economics even after appropriate antibiotic treatment of a proven manifestation of LB [2]. They commonly occur during or after other diseases, including infectious diseases. Many studies so far have, however, not yet proven that persistent borrelia infection is the necessary cause of such symptoms, and also such studies have not shown benefits from prolonged antibiotics therapy to avoid these persistent symptoms [84–88].
Treatment LB can be effectively treated with early and appropriate antibiotic therapy to avoid late disseminated stages of LB and consequently its long term sequelae [23]. Also patients with already late disseminated stage of the disease can benefit from antibiotic therapy, although clinical recovery may be incomplete [9]. In the USA, the Infectious Disease Society of America published the updated treatment guideline for LB in 2006 [22]. The most common treatment for the various clinical manifestations of LB in the USA is presented in TABLE 1. In Europe, there is no consensus on the treatment [23]. In the various European countries, the choice of the specific antibiotic treatment depends on the clinical manifestation of the disease, availability of antibiotics, economic situation, national treatment recommendation and guidelines [23]. The guidelines from the Czech Republic, Denmark, Finland, France, the Netherlands, Norway, Poland, Slovenia, Sweden and Switzerland show great similarities in antibiotic choice and minor differences in dosing and duration of LB treatment [24]. In general, patients respond well to oral antibiotics. Patients in whom the CNS is affected should be treated several weeks with intravenous antibiotics [9].
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Table 1. The most common treatment for different clinical manifestation of LB adults & children based on the Infectious Disease Society of America guideline [22].
Clinical Route Drug Treatment Duration of manifestation treatment (days) Adults Children Erythema migrans Oral Doxycycline 100 mg twice age ≥8 years: 14 (10 21) Borrelia per day 4 mg/kg per lymphocitoma day in 2 divided doses Oral Amoxicillin 500 mg 3 50 mg/kg per 14 (14 21) times per day day in 3 divided doses Oral Cefuroxime 500 mg twice 30 mg/kg per 14 (14 21) axetil per day day in 2 divided doses Lyme carditis Oral a 14 (14 21) Parentenal b Ceftriaxone 2 g once per 50 75 mg/kg 14 (14 21) day per day Neurologic Lyme Parentenal Ceftriaxone 2 g once per 50 75 mg/kg 14 (10 28) disease day per day Parentenal Cefotaxime 2 g every 8 150 200 14 (10 28) hours mg/kg per day divided into three or four doses Parentenal Penicillin G 18 24 million 0.2 0.4 14 (10 28) units per day million divided into units/kg per doses given day divided every 4 hours into doses given every 4 hours Oral Doxycyline 200 400 mg 4 8mg/kg per 10 28 per day in two day in two divided doses divided doses Lyme arthritis Oral Doxycyline 100 mg twice Age ≥8 years: 28 days per day 4mg/kg per day in two divided doses Oral Amoxicillin 500 mg three 50 mg/kg per 28 days times per day day in three divided doses Oral Cefuroxime 500 mg twice 30 mg/kg per 28 days axetil per day day in two divided doses Acrodermatitis Oral c 21 days chronica atrophicans a Oral antibiotics (doxycycline, amoxicillin, cefuroxime axetil) used to treat patients with EM are recommended as treatment of outpatients patients with Lyme carditis. b Parenteral antibiotic such as ceftriaxone is recommended as initial treatment of hospitalized patients with Lyme carditis. c Acrodermatitis chronica atrophicans may be treated with the same antibiotics (doxycycline, amoxicillin, cefuroxime axetil) used to treat patients with EM.
Debates are ongoing regarding the exact choice of antibiotics, prolonged duration of antibiotic therapy (in particular, in patients with persistent symptoms after standard antibiotic therapy) and the exact amount of health benefit of such therapies achieved [24]. So far, persistent infection with viable borrelia has not been
72 Lyme borreliosis: reviewing potential vaccines, clinical aspects and health economics documented after standard antibiotic treatment for stage and manifestation of disease [89] and neither is it proven that persistent borrelia infection is the unequivocal cause of persistent symptoms if benefit from prolonged treatment with antibiotics is not shown [90]. Significant risks of adverse events from long term antibiotic therapy may reflect concerns [71,91]. Animal data suggest the presence of persistent nucleic acids of B. burgdorferi in tissues after antibiotic treatment [92]; however, the presence of nucleic acids B. burgdorferi in tissues does not necessarily mean the presence of viable organisms [93]. Obviously, the relevance of the animal model for humans should be further assessed [93].
Reinfection Studies demonstrate that reinfection is possible, particularly when the reinfecting strain is different [94]. Patients with early infection who recover from antibiotic therapy are susceptible to reinfection [95,96]. Patients treated for early LB seem to not develop an immunological response that is protective against reinfection. Reinfection has been documented in patients who were treated for early infection, mostly with EM symptoms, and not yet in patients with persistent infection of LB such as Lyme arthritis [3,95,96].
OspA & OspC outer surface proteins B. burgdorferi sensu lato is characterized by high diversity and variety of outer membrane proteins [97]. Some of these proteins have an essential role in the transmission of spirochetes ‘traveling’ from the tick’s midgut through the hemolymph to salivary glands and finally to the host [98]. The most noticeably outer membrane proteins are the OspA and the outer surface proteins C (OspC) [97]. OspA is a 31 kDa lipoprotein, attached to the outer membrane of B. burgdorferi by its N terminal lipid moiety [99,100]. OspC is a 21 kDa lipoprotein, with a predominantely helical structure [101,102]. It forms a homodimer tethered to the outer membrane by an N terminal tripalmioyil – glyceril cisteine moiety [101]. Antigenic heterogenity is related with OspC but not with OspA [103]. In the transmission process of B. burgdorferi, spirochetes upregulate OspA while entering the tick and binding to the tick receptor for OspA [98]. This enables spirochetes to persist inside the ticks between blood meals [98]. During tick feeding, spirochetes downregulate OspA and upregulate other proteins including OspC, while spirochetes
73 Chapter 4 transmigrate to the tick salivary glands and eventually to the host [98]. Therefore, OspA proteins are expressed mostly in the tick’s stomach, while OspC is expressed as the spirochete moves from the tick’s mid gut to the salivary gland, where it binds to the tick’s salivary gland protein, Salp15. The spirochete is then injected into the host, where OspC is rather quickly downregulated [98]. Several borrelia outer membrane proteins have been evaluated as potential vaccine candidates against LB such as OspA, OspC, OspB, DbpA, BBK32 and RevA [98]. Among them, the OspA and OspC vaccine candidates are most promising so far. However, only OspA has been extensively evaluated as a vaccine candidate so far [103].
The monovalent OspA vaccine candidates In 1990, it was shown that high titers of antibody to OspA protein showed protection against borrelia infection in mice [104,105]. In 1992, it was demonstrated that vaccination with an OspA vaccine induced long term protective immune response in mice [106]. After initial success of OspA vaccination in hamsters, dogs and monkeys [107,108], intensive effort in developing a human vaccine against LB was shown in 1990. Two monovalent recombinant vaccines were developed based on OspA serotype 1 derived from B. burgdorferi [27,28]. These two monovalent vaccines were designed to protect against B. burgdorferi for use only in the USA [27,28]. The reason that anti OspA vaccine prevents transmission of B. burgdorferi is that antibodies ingested by the feeding tick kill the bacteria present in the tick’s midgut and expressing OspA at the time the tick begins to feed [109]. Both vaccines demonstrated adequate efficacy and safety [27,28]. However, only one of both vaccines was licensed and marketed. SmithKline Beecham manufactured a monovalent recombinant adjuvanted OspA vaccine, using the OspA B. Burgdorferi strain ZS7 [27]. In 1998, the vaccine was licensed for people aged between 15 and 70 years [27,32]. The vaccine was well tolerated, showing 76% efficacy after three doses over a 12 month period and 49% after two doses [27]. The efficacy of the vaccine in preventing asymptomatic infection was 83% in the first year and 100% in the second year [27]. No significant adverse effects were reported [27]. One of the drawbacks of the licensed vaccine was that the vaccine was designed to protect only against B. burgdorferi strains [27,32]. Next, the vaccine induced antibody titers did not persist for a very long time; therefore,
74 Lyme borreliosis: reviewing potential vaccines, clinical aspects and health economics multiple boosters to maintain long term protection could be needed [27,32]. Furthermore, the vaccine was licensed only for adults [27,32]. In the original study, safety and efficacy data were lacking for children younger than 15 years of age [27,32]. Later, two studies were conducted to address safety and efficacy of the licensed vaccine in children [110,111]. A double blind randomized study, involving children aged between 5 and 15 years, showed that the monovalent adjuvant OspA vaccine was well tolerated and highly immunogenic. Seroconversion occurred in 99% of the 250 children [111]. A second study, a controlled clinical trial, involving children and adolescents aged between 4 and 18 years, demonstrated that monovalent adjuvant OspA vaccine was well tolerated, safe and immunogenic [110]. Mild and moderate systemic reactions were similar to those in the original study [110]. One of the major drawbacks of the licensed vaccine was worry that the vaccine might cause arthritis in genetically susceptible individuals with the HLA DRB1*0401 allele by a molecular mimicry between an epitope of OspA 1 for T helper cells and an epitope of human lymphocyte function associated antigen 1 [33]. Subsequent studies suggested that the association between the OspA epitope and Lyme arthritis was due to the fact that presentation of this epitope was particularly inflammatory in DRB1*0401 positive individuals with Lyme arthritis and not due to molecular mimicry between OspA and human lymphocyte function associated antigen 1 [34]. Also, subsequent studies suggested that molecular mimicry mechanism did not induce Lyme arthritis [34]. Vaccination with OspA did not induce arthritis in 0401 transgenic mice, and case and control comparisons in human vaccine trials did not show an increased frequency of arthritis among OspA vaccinated individuals [34]. The second vaccine, a recombinant monovalent nonadjuvanted OspA vaccine, using the OspA B. burgdorferi strain B31 was manufactured by Pasteur Merieux Connaught [28,32]. The vaccine showed an efficacy of 92% after three doses and 68% after two doses, and no difference in the rate or severity of adverse events in vaccine versus placebo recipients was noticed [28,32]. Safety concerns that came up ended the commercialization of both vaccines. In 2002, the manufacturer SmithKline Beecham decided to withdraw the vaccine from the market due to poor public acceptance, and Pasteur Merieux Connaught decided not to apply for a license of its own vaccine [32,112].
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The multivalent OspA vaccine candidates The development of a new generation of vaccines to protect against human pathogenic borrelia species with different OspA serotypes is challenging because the vaccine has to induce protection against each individual OspA serotype [36]. However, two novel multivalent OspA vaccines, both in the phase of development, handle these challenges [36,37]. Recently, a novel multivalent OspA vaccine manufactured by Baxter, was designed to protect against the four major B. burgdorferi species such as B. burgdorferi (OspA serotype 1), B. afzelii (OspA serotype 2), B. garinii (OspA serotype 3, OspA serotype 5 and OspA serotype 6) and B. bavariensis (OspA serotype 4) [37]. Therefore, the vaccine is broadly designed to protect against all important B. burgdorferi species in USA, Europe and potentially globally [25,37]. This novel vaccine should protect against 99% of neuroborreliosis, a serious manifestation of LB occurring in Europe [113]. The hypothetical risk of T cell cross reactivity has been eliminated by replacing the putative crossreactive OspA 1 epitope with the corresponding OspA 2 sequence and therefore eliminating the risk for occurrence of potential arthritis [37]. In Phase I and II studies, it was demonstrated that this novel multivalent LB vaccine is safe, highly immunogenic and well tolerated after the three primary vaccinations in healthy seronegative and seropositive adults for B. burgdorferi [37]. Notably, the study showed that 91–100% of vaccinated individuals achieve total IgG ELISA antibody response for protection after the three primary vaccinations and 91– 100% of individuals after booster vaccination [37]. No serious adverse events were reported [25]. It is likely that repeated boosters are needed to maintain high levels of antibody response for protection [25,37]. Preclinical results of a second novel multivalent OspA vaccine manufactured by Valneva SE (Lyon, France) showed that this potential adjuvanted vaccine, using three vaccination, could provide protection in mouse against the three major B. burgdorferi species such as B. burgdorferi (OspA serotype 1), B. Afzelii (OspA serotype 2) and B. garinii (OspA serotype 5) causing the disease [36]. Using a novel development approach, safety concerns that the vaccine might trigger arthritis was eliminated [36]. Furthermore, introduction of a lipidation signal that ensures the addition of an N terminal lipid moiety results in higher anti OspA antibody titers
76 Lyme borreliosis: reviewing potential vaccines, clinical aspects and health economics
[36]. It was concluded that this novel vaccine could potentially be suitable for global protection against LB [36]. Effective protection by OspA vaccines depends on high circulating of anti OspA antibody levels, requiring frequent boosters to maintain long term protection [36]. The duration of protection elicited by OspA vaccines has never been clearly defined so far.
The OspC vaccine candidates OspC is a promising basis for second generation LB vaccine candidates because of its expression profile, protective and antigenicity features [114]. Anti OspC vaccines would likely prevent transmitted B. burgdorferi from establishing local infections that may subsequently (when OspC expression is downregulated) disseminate and cause more serious disease [115,116]. Some complexities are involved, with genetic and antigenic variabilities of OspC proteins presenting difficulties in developing OspC vaccine [117]. Vaccination with a single OspC vaccine is protective [115]. However, the protective range is narrow, most likely because of specific intertype variation of epitopes [115]. However, specific protective OspC epitopes allow developing chimeric polyvalent recombinant OspC vaccines [118]. These protective vaccines may effectively enhance protection against LB and could be suitable for wider prophylaxis of LB [102,115]. In 1999, Immuno AG (now named Baxter, Austria) manufactured a 5 valent adjuvanted OspC vaccine, composed of recombinant OspC B. burgdorferi strain and two strains each from B. afzellii and B. garinii [119]. The study showed that more than 95% individuals achieving antibody response for protection after the three primary vaccinations [119]. Phase I of the development process showed that this vaccine was safe and well tolerated, and no significant adverse events were reported [119]. However, erythema and swelling developed at the injection site in half of the individuals included in the Phase I trial [120]. Data of a Phase II trial on the safety and preliminary efficacy of a 14 valent OspC vaccine, manufactured by Baxter, were never published due to reactogenicity for the skin at the injection site. This multivalent vaccine could protect against the most clinical B. burgdorferi strains [97]. Different vaccinogens, such as a cocktail of several borrelia outer membrane proteins, tick proteins or combinations, eliciting anti borrelia and anti tick immune
77 Chapter 4 responses all reflect promising approaches for development future Lyme vaccines [98].
Cost–effectiveness of vaccination Some cost–effectiveness analyses of vaccination with the monovalent OspA vaccine [29–31] were performed in the USA; however, no such studies yet exist in Europe. An urgent need for these is noted by the authors. In 1999, a study was performed on the cost–effectiveness of vaccination against LB for the USA [29]. Methodologically, a decision tree was used and a 1 year time horizon was taken into account [29]. Complications included in the model were cardiac sequelae, late arthritis and neurologic consequences [29]. In a specific letter to the editor on the original, the lack of potential post treatment Lyme disease syndrome in the model was discussed, including the absence of persisting myalgia, arthralgia, headache, fatigue and neurocognitive deficits [121]. Results of the study showed that with a probability of contracting the disease of 1%, the societal net costs of vaccination amount to approximately US$4500 per case averted with yearly boosters [29]. Obviously, economic benefit would be highest in persons whose probability of contracting the disease would be higher than 1% [29]. In 2001, the clinical effectiveness and cost– effectiveness of vaccination against LB was evaluated using a Markov model [30]. Arthritic, cardiac and neurologic sequelae, as well as a post treatment Lyme disease syndrome, were included in the model [30]. The latter state included arthralgia, fatigue and difficulties to concentrate [30]. Results of the study showed that at a probability of contracting the disease of 1%, the incremental cost–effectiveness ratio would be US$62,300 per quality adjusted life year gained from the societal perspective, corresponding with US$5300 per case averted during a 10 years period (excluding annual boosters) [30]. Again, it was concluded that from an economic point of view, vaccination against LB seems most attractive in persons with probabilities of contracting the disease above 1% [30]. In 2002, clinical effectiveness and cost–effectiveness of the then licensed vaccine were evaluated, also using a Markov model [31]. Arthritic, cardiac and neurologic sequelae were included in the model [31]. However, ‘chronic Lyme disease’ (arthralgias/myalgias associated with post treatment Lyme disease syndrome) was not modeled. Also issues about misdiagnosis, public anxiety related to the disease were not taken into account [31]. Analyses were based only on direct costs in the healthcare system [31]. Results of the
78 Lyme borreliosis: reviewing potential vaccines, clinical aspects and health economics study showed that at a probability of contracting the disease of 1%, the incremental cost–effectiveness ratio amounts to about US$9900 per case averted with a yearly booster and US$4500 with a 3 yearly booster [31]. Both analyses applied a 10 year period as the time horizon investigated [31]. It was found that vaccination against LB is more effective and brings economic benefits at probabilities of contracting the disease higher than 10% with yearly boosters and with 3 yearly boosters if this probability exceeds 5% [31]. It was concluded [31] that LB vaccine can be considered cost effective for individuals living in endemic areas with frequent exposures to infected ticks [31]. Despite some differences among these three studies [29–31], all three studies have a similar conclusion that vaccination against LB may be cost effective if the risk of contracting the disease exceeds 1%. However, the physician’s decision to vaccinate should be made on an individual’s risk for LB, taking into account endemicity of the disease in the local geographic area and the individual exposure to infected tick [31]. Some characteristics of the studies on cost–effectiveness of vaccination with the monovalent OspA vaccine against LB and results as summarized above are shown in TABLE 2.
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Table 2. Some characteristics and results of studies on cost effectiveness vaccination with the monovalent OspA vaccine against LB.
Author and Comparison Economic Study Setting Study Model Time Cycle Costs publication study type population and perspective horizon lenght year country Meltzer et al., Vaccination CEA 1 General adult Primary Societal Decision 1 year Not Direct
1999 [29] was compared population care and tree applicable and with no the indirect vaccination hospital, USA
Shadick et al., Vaccination CEA 1 Population of Commu Societal Markov 10 years 1 year Direct
2001 [30] was compared persons nity and with no living in care, indirect vaccination endemic USA areas with a probability of contracting LB of 1%
Hsia et al., Vaccination CEA 1 Hypothetical Primary Health care Markov 10 years 1 year Direct
2002 [31] was compared cohort of care, only with no 20,000 USA vaccination persons aged between 15 and 70 years
80 Lyme borreliosis: reviewing potential vaccines, clinical aspects and health economics
Measure of Discount rate Vaccine efficacy Booster Sensitivity Results health for costs and dose analyses outcomes benefits Number of 3% for costs only 85% Yearly Multi way At 0.5% probability of contracting LB and vaccination costs LB cases of $50, the ICER 2 expressed in case averted, was $4,466 and averted at vaccination costs of $100 the ICER 2 was $16,231 and at vaccination costs of $200, the ICER 2 was $39,761 At 1% probability of contracting LB and at costs of vaccination of $50 the ICER 2 expressed in case averted was $1,416, at costs of vaccination of $100 the ICER 2was $4,467 and at vaccination costs of $200 it was $16,231 At 3% probability of contracting LB and vaccination costs of $50, the ICER 2 expressed in case averted was $5,337 and at vaccination costs of $100, the ICER 2 was $3,377 and at cost of vaccination of $200, the ICER 2 was $545. Sensitivity analysis showed that the probability of contracting the disease is the most important factor, followed by cost of treating sequelae, the probability of early detection and treatment of LB.
Number of 3% for costs and 62% with 2 doses / One way At 1% probability of contracting LB, the ICER 2 was LB cases QALYs 3 and and $62,300/QALY 3and costs per case averted were $5,300 averted and 87% with 3 two way Results were most sensitive to the treatment effectiveness QALYs 3 and cost of vaccination for the 3 shot series. At treatment gained effectiveness of 80%, the ICER 2 would be $18,800/QALY. At effectiveness of 100%, the ICER 2 would be $301,900/QALY. At vaccination costs of $50, the ICER 2 would be $6,900/QALY gained and at vaccination costs of $300, the ICER 2 would be $145,300/QALY gained.
Number of 3% for costs only 49% in the first Yearly One way At 0.0067% average national probability of contracting LB, LB cases year and 76% in and and the ICER 2 was $1,600,000 per case averted with a yearly averted the second 3 yearly two way booster and $830,000 with 3 yearly boosters At 1% probability of contracting LB, the ICER 2was $9,900 per case averted with a yearly booster and 4,500 with 3 yearly boosters One way sensitivity analysis showed that ICER 2 increases as the duration and efficacy of vaccine increase, however ICER 2 decreases as the vaccine cost increases. Two way sensitivity analysis showed that the threshold was affected by the cost of cerfrtriaxone treatment, the cost of rheumatologic sequelae, the efficacy of the antibiotics, the probabilitiy of arthritis seuelae and probability of occurrences of EM
1 CEA compares costs and health outcomes of vaccination and no vaccination strategies. 2 The ICER is calculated as the difference in the cost of vaccination and no vaccination, divided by the difference in the health outcomes produced by vaccination and no vaccination. 3 QALY is a measure of the value of health outcomes, taking into accounts both the quantity and quality of life. CEA: Cost–effectiveness analysis; ICER: Incremental cost–effectiveness ratio; QALY
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Expert commentary LB is a serious disease and therefore an important public health concern, presenting relevant health and economic burdens. So far, it has not been given the public health attention it warrants. Therefore, more attention has to be orientated toward prevention and control of the disease, including vaccine development and use. Also, further research on the pathogenesis of LB, etiology, related complications and coinfection with other microorganisms is needed, allowing better understanding of the disease and further improved treatments, especially of patients with persistent symptoms. Also, development of new diagnostic approaches, indicating probable persistent infection in patients with sequelae and developing tests that could distinguish between active and past borrelia infection, is warranted. Diagnostic laboratory standardization, enabling valid comparisons of test results, has to be considered. Vaccine development and use of vaccines is a core element in facing this public health threat. A new vaccine against LB is promising and likely will ensure effective and safe prophylaxis against LB. Studies on the cost–effectiveness of vaccination have been done in the USA, but are urgently needed in Europe to inform decision makers on vaccination benefits and help in developing improved strategies and recommendations for prevention and control of the disease. First analyses of cost–effectiveness indicate potential for favourable health economic outcomes for vaccination.
Five-year view In coming years, likely diagnostics and treatments of LB will be further improved and the vaccine will be further developed. Increased awareness of the public health threat is, however, needed and might boost this development. Also, cost–effectiveness studies of vaccination with the potential novel vaccine will likely be performed for various localities, inclusive Europe. An important health economic issue will be to analyze the optimum booster interval that shows the most beneficial effect of vaccination against LB for public health at still acceptable costs. Therefore, improved strategies and recommendations for prevention and control of the disease will likely be introduced to reduce health and economic burden, leading to population benefits.
82 Lyme borreliosis: reviewing potential vaccines, clinical aspects and health economics
Key issues • Lyme borreliosis is an infectious multisystem disease that may lead to serious long term sequelae, affecting patients’ quality of life and causing high health and economic burdens for societies. • A potential novel multivalent outer surface proteins A vaccine against Lyme borreliosis, still in the phase of the development, promises to be the most effective prophylaxis against the disease in the endemic areas of USA, Europe and Asia • Cost–effectiveness studies with this novel vaccine are needed for efficient guidance, recommendations and policies for prevention of Lyme borreliosis, to (cost )effectively reduce the disease burden and achieve population benefits
Financial & competing interests disclosure Prof Maarten J Postma received grants and honoraria from various pharmaceutical companies, inclusive of those developing and producing vaccines. However, all grants and honoraria are fully unrelated to the specific topic of this paper. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
References Papers of special note have been highlighted as: • Of interest •• Of considerable interest
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48. Cimperman J, Maraspin V, Lotricˇ Furlan S, et al. Concomitant infection with tick borne encephalitis virus and Borrelia burgdorferi sensu lato in patients with acute meningitis or meningoencephalitis. Infection 1998; 26(3):160 4 49. Krause PJ, Telford SR, Spielman A, et al. Concurrent Lyme disease and babesiosis: evidence for increased severity and duration of illness. JAMA 1996;275(21):1657 60 50. Rizzoli A, Hauffe HC, Carpi G, et al. Lyme borreliosis in Europe. Eurosurveillance 2011;16(27):19906 51. CBO. Conceptrichtlijn Lymeziekte 2015 2012 52. Nadelman RB, Wormser GP. Lyme borreliosis. Lancet 1998;352(9127):557 65 53. Ornstein K, Berglund J, Nilsson I, et al. Characterization of Lyme borreliosis isolates from patients with erythema migrans and neuroborreliosis in southern Sweden. J Clin Microbiol 2001;39(4):1294 8 54. Aguero Rosenfeld ME. Lyme disease: laboratory issues. Infect Dis Clin North Am 2008;22(2):301 13 55. Strle F, Ruzic Sabljic E, Cimperman J, et al. Comparison of findings for patients with Borrelia garinii and Borrelia afzelii isolated from cerebrospinal fluid. Clin Infect Dis 2006;43(6):704 10 56. Centers for disease control and prevention (CDC). Two step Laboratory testing process. 2015. Available from: www.cdc . gov/lyme/diagnosistesting/LabTest/TwoStep/index.html 57. Centers for disease control and prevention (CDC). Understanding the immunoblot test. 2015. Available from: www.cdc.gov/lyme/diagnosistesting/labtest/twostep/westernblot/index.html 58. Steere AC, McHugh G, Damle N, Sikand VK. Prospective study of serologic tests for lyme disease. Clin Infect Dis 2008; 47(2):188 95 59. Lebech A, Hansen K, Brandrup F, et al. Diagnostic value of PCR for detection of Borrelia burgdorferi DNA in clinical specimens from patients with erythema migrans and Lyme neuroborreliosis. Mol Diagn 2000;5(2):139 50 60. Lazarus JJ, McCarter AL, Neifer Sadhwani K, Wooten RM. ELISA based measurement of antibody responses and PCR based detection profiles can distinguish between active infection and early clearance of Borrelia burgdorferi. Clin Dev Immunol 2012;2012:138069 61. Wormser GP, Horowitz HW, Nowakowski J, et al. Positive Lyme disease serology in patients with clinical and laboratory evidence of human granulocytic ehrlichiosis. Am J Clin Pathol 1997;107(2): 142 7 62. Strle F. Principles of the diagnosis and antibiotic treatment of Lyme borreliosis. Wien Klin Wochenschr 1999;111(22 23): 911 15
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63. Jaulhac B, Chary Valckenaere I, Sibilia J, et al. Detection of Borrelia burgdorferi by DNA amplification in synovial tissue samples from patients with Lyme arthritis. Arthritis Rheumatism 1996;39(5):736 45 64. Priem S, Rittig MG, Kamradt T, et al. An optimized PCR leads to rapid and highly sensitive detection of Borrelia burgdorferi in patients with Lyme borreliosis. J Clin Microbiol 1997;35(3):685 90 65. Wilske B. Diagnosis of Lyme borreliosis in Europe. Vector Borne Zoonotic Diseases 2003;3(4):215 27 66. Cerar T, Ogrinc K, Cimperman J, et al. Validation of cultivation and PCR methods for diagnosis of Lyme neuroborreliosis. J Clin Microbiol 2008;46(10):3375 9 67. Issakainen J, Gnehm HE, Lucchini GM, Zbinden R. Value of clinical symptoms, intrathecal specific antibody production and PCR in CSF in the diagnosis of childhood Lyme neuroborreliosis. Klin Padiatr 1996; 208(3):106 9 68. Ornstein K, Berglund J, Bergstro¨m S, et al. Three major Lyme Borrelia genospecies (Borrelia burgdorferi sensu stricto, B. afzelii and B. garinii) identified by PCR in cerebrospinal fluid from patients with neuroborreliosis in Sweden. Scand J Infect Dis 2002;34(5):341 6 69. Aguero Rosenfeld ME, Wang G, Schwartz I, Wormser GP. Diagnosis of lyme borreliosis. Clin Microbiol Rev 2005;18(3):484 509 70. Marques A, Brown MR, Fleisher TA. Natural killer cell counts are not different between patients with post Lyme disease syndrome and controls. Clin Vaccine Immunol 2009;16(8):1249 50 71. Aguero Rosenfeld ME, Wormser GP. Lyme disease: diagnostic issues and controversies. Exp Molec Diagnost 2015(0):1 4 72. Skogman BH, Glimaker K, Nordwall M, et al. Long term clinical outcome after Lyme neuroborreliosis in childhood. Pediatrics 2012;130(2):262 9
• An excellent general review of clinical manifestation of Lyme borreliosis 73. Steere AC. Lyme Borreliosis. In: Kasper D, Fauci A, Hauser S, et al. editors. Harrison’s Principles of Internal Medicine. 19 edition. McGraw Hill, New York; 2015. Available from: http://accessmedicine.mhmedical.com. proxy ub.rug.nl/content.aspx? bookid=1130&Sectionid=79737623 [Last accessed 15 June 2015] 74. Centers for disease control and prevention (CDC). Signs and Symptoms. 2015. Available from: www.cdc.gov/lyme/signs_symptoms/ 75. European centre for disease prevention and control (ECDC). Borreliosis. 2015. Available from: http://ecdc.europa.eu/en/healthtopics/emerging_and_vectorborne_diseases/tick_borne_di seases/lyme_disease/pages/index.aspx
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76. Maraspin V, Lotric Furlan S, Cimperman J, et al. Erythema migrans in the immunocompromised host. Wien Klin Wochenschr 1999;111(22 23):923 32 77. Fu¨rst B, Glatz M, Kerl H, Mu¨llegger R. The impact of immunosuppression on erythema migrans. A retrospective study of clinical presentation, response to treatment and production of Borrelia antibodies in 33 patients. Clin Exp Dermatol 2006;31(4): 509 14 78. Centers for disease control and prevention (CDC). Three sudden cardiac deaths associated with lyme carditis United States, November 2012–July 2013. Available from: www.cdc.gov/mmwr/preview/mmwrhtml/mm6249a1.htm [Last accessed June 2015] 79. Ackermann R, Rehse Ku¨pper B, Gollmer E, Schmidt R. Chronic neurologic manifestations of erythema migrans borreliosis. Ann N Y Acad Sci 1988;539(1):16 23 80. Kaiser R. Clinical courses of acute and chronic neuroborreliosis following treatment with ceftriaxone. Nervenarzt 2004;75(6):553 7 81. Mu¨llegger RR, Glatz M. Skin manifestations of Lyme borreliosis. Am J Clin Dermatol 2008;9(6):355 68 82. Steere AC, Angelis SM. Therapy for Lyme arthritis: strategies for the treatment of antibiotic refractory arthritis. Arthritis Rheumatism 2006;54(10):3079 86 83. Wormser GP, Nadelman RB, Schwartz I. The amber theory of Lyme arthritis: initial description and clinical implications. Clin Rheumatol 2012;31(6):989 94 84. Krupp LB, Hyman LG, Grimson R, et al. Study and treatment of post Lyme disease (STOP LD): a randomized double masked clinical trial. Neurology 2003;60(12): 1923 30 85. Kaplan RF, Trevino RP, Johnson GM, et al. Cognitive function in post treatment Lyme disease: do additional antibiotics help? Neurology 2003;60(12):1916 22 86. Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 2001;345(2):85 92 87. Seidel M, Domene AB, Vetter H. Differential diagnoses of suspected Lyme borreliosis or post Lyme disease syndrome. Eur J Clin Microbiol Infect Dis 2007;26(9):611 17 88. Fallon BA, Keilp JG, Corbera KM, et al. A randomized, placebo controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology 2008;70(13): 992 1003 89. Feder Jr HM, Johnson BJ, O’Connell S, et al. A critical appraisal of “chronic Lyme disease”. N Engl J Med 2007;357(14): 1422 30 90. Wormser GP, Nowakowski J, Nadelman RB. Duration of treatment for Lyme borreliosis: time for a critical reappraisal. Wien Klin Wochenschr 2002; 114(13 14):613 15 91. Klempner MS, Baker PJ, Shapiro ED, et al. Treatment trials for post Lyme disease symptoms revisited. Am J Med 2013; 126(8):665 9
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92. Embers ME, Barthold SW, Borda JT, et al. Persistence of Borrelia burgdorferi in rhesus macaques following antibiotic treatment of disseminated infection. PLoS One 2012; 7(1):e29914 93. Wormser GP, Schwartz I. Antibiotic treatment of animals infected with Borrelia burgdorferi. Clin Microbiol Rev 2009;22(3):387 95 94. Nadelman RB, Hanincova´ K, Mukherjee P, et al. Differentiation of reinfection from relapse in recurrent Lyme disease. N Engl J Med 2012;367(20):1883 90 95. Krause PJ, Foley DT, Burke GS, et al. Reinfection and relapse in early Lyme disease. Am J Trop Med Hyg 2006;75(6):1090 4 96. Nadelman RB, Wormser GP. Reinfection in patients with Lyme disease. Clin Infect Dis 2007;45(8):1032 8 97. Hanson MS, Edelman R. Progress and controversy surrounding vaccines against Lyme disease. Expert Rev Vaccines 2003;2(5):683 703 98. Schuijt TJ, Hovius JW, van der Poll T, et al. Lyme borreliosis vaccination: the facts, the challenge, the future. Trends Parasitol 2011;27(1):40 7 99. Barbour AG, Tessier SL, Todd WJ. Lyme disease spirochetes and ixodid tick spirochetes share a common surface antigenic determinant defined by a monoclonal antibody. Infect Immun 1983;41(2):795 804 100. Bergstro¨m S, Bundoc V, Barbour A. Molecular analysis of linear plasmid encoded major surface proteins, OspA and OspB, of the Lyme disease spirochaete Borrelia burgdorferi. Mol Microbiol 1989;3(4):479 86 101. Fuchs R, Jauris S, Lottspeich F, et al. Molecular analysis and expression of a Borrelia burgdorferi gene encoding a 22kDa protein (pC) in Escherichia coli. Mol Microbiol 1992;6(4):503 9 102. Earnhart CG, Rhodes DV, Marconi RT. Disulfide mediated oligomer formation in Borrelia burgdorferi outer surface protein C, a critical virulence factor and potential Lyme disease vaccine candidate. Clin Vaccine Immunol 2011;18(6):901 6 103. Embers ME, Narasimhan S. Vaccination against Lyme disease: past, present, and future. Front Cell Infect Microbiol 2013;3 104. Fikrig E, Barthold SW, Kantor FS, Flavell RA. Protection of mice against the Lyme disease agent by immunizing with recombinant OspA. Science 1990; 250(4980):553 6 105. Schaible UE, Kramer MD, Eichmann K, et al. Monoclonal antibodies specific for the outer surface protein A (OspA) of Borrelia burgdorferi prevent Lyme borreliosis in severe combined immunodeficiency (scid) mice. Proc Natl Acad Sci USA 1990; 87(10):3768 72 106. Fikrig E, Barthold SW, Kantor FS, Flavell RA. Long term protection of mice from Lyme disease by vaccination with OspA. Infect Immun 1992;60(3):773 7
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107. Lovrich SD, Callister SM, DuChateau BK, et al. Abilities of OspA proteins from different seroprotective groups of Borrelia burgdorferi to protect hamsters from infection. Infect Immun 1995;63(6): 2113 19 108. Chang YF, Appel MJ, Jacobson RH, et al. Recombinant OspA protects dogs against infection and disease caused by Borrelia burgdorferi. Infect Immun 1995;63(9):3543 9 109. de Silva AM, Telford SR III, Brunet LR, et al. Borrelia burgdorferi OspA is an arthropod specific transmission blocking Lyme disease vaccine. J Exp Med 1996;183(1):271 5 110. Sikand VK, Halsey N, Krause PJ, et al. Safety and immunogenicity of a recombinant Borrelia burgdorferi outer surface protein A vaccine against lyme disease in healthy children and adolescents: a randomized controlled trial. Pediatrics 2001;108(1):123 8 111. Feder HM, Beran J, Van Hoecke C, et al. Immunogenicity of a recombinant Borrelia burgdorferi outer surface protein A vaccine against Lyme disease in children. J Pediatr 1999;135(5):575 9 112. Plotkin SA. Correcting a public health fiasco: The need for a new vaccine against Lyme disease. Clin Infect Dis 2011; 52(Suppl 3):s271 5 113. Barrett PN, Portsmouth D. A novel multivalent OspA vaccine against Lyme borreliosis shows promise in Phase I/II studies 2013. Clin Vaccine Immunol 2014; 21(11):1490 9 114. Gilmore RD Jr, Kappel KJ, Dolan MC, et al. Outer surface protein C (OspC), but not P39, is a protective immunogen against a tick transmitted Borrelia burgdorferi challenge: evidence for a conformational protective epitope in OspC. Infect Immun 1996;64(6):2234 9
• Multivalent OspC vaccine against Lyme borreliosis 115. Earnhart CG, Marconi RT. Construction and analysis of variants of a polyvalent Lyme disease vaccine: approaches for improving the immune response to chimeric vaccinogens. Vaccine 2007;25(17):3419 27 116. Schwan T. Temporal regulation of outer surface proteins of the Lyme disease spirochaete Borrelia burgdorferi. Biochem Soc Trans 2003;31(1):108 12 117. Earnhart CG, Marconi RT. An octavalent lyme disease vaccine induces antibodies that recognize all incorporated OspC type specific sequences. Hum Vaccin 2007; 3(6):281 9 118. Earnhart CG, Buckles EL, Marconi RT. Development of an OspC based tetravalent, recombinant, chimeric vaccinogen that elicits bactericidal antibody against diverse Lyme disease spirochete strains. Vaccine 2007;25(3):466 80 119. Eder G, Barrett N, Crowe B, et al. A candidate OspC Lyme disease vaccine under clinical investigation. Zentralblatt fu¨r Bakteriologie 1999;289(5):688 9 120. Hanson M, Edelman R. Vaccines against Lyme disease. New Gener vaccines 2004;3: 487 98 121. Prybylski D. The cost effectiveness of vaccinating against Lyme disease. Emerg Infect Dis 1999;5(5):727 8
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CHAPTER 5
The burden of tick borne encephalitis in disability adjusted life years (DALYs) for Slovenia
Renata Šmit Maarten J Postma
PLoS One 20a5;a0(a2):e0a44988
93
94 The burden of tick borne encephalitis in disability adjusted life years (DALYs) for Slovenia
Abstract Background : Tick borne encephalitis (TBE) presents an increasing burden in many parts of Europe, Asian Russia, Siberia, Asian former USSR and Far East. Incidence can be considered as one way to express the burden. A more comprehensive measure concerns disability adjusted life years (DALYs), better characterizing the full burden of TBE. TBE burden in DALYs has not yet been estimated, nor has it been specified by the Global Burden of Disease (GBD) studies.
Objective: The purpose of the present study is to estimate the burden of TBE in Slovenia, expressed in DALYs, both from the population and individual perspectives. We discuss the impact of TBE burden on public health and potential strategies to reduce this burden in Slovenia.
Methods : The burden of TBE is estimated by using the updated DALYs' methodology first introduced in the GBD project. The DALYs ᾽ calculations are based on the health outcomes of the natural course of the disease being modelled. Corrections for under reporting and under ascertainment are applied. The impact of uncertainty in parameters in the model was assessed using sensitivity analyses.
Results: From the population perspective, total DALYs amount to 3,450 (167.8 per 100,000 population), while from the individual perspective they amount to 3.1 per case in 2011. Notably, the consequences of TBE present a larger burden than TBE itself.
Conclusions : TBE presents a relatively high burden expressed in DALYs compared with estimates for other infectious diseases from the GBD 2010 study for Slovenia. Raising awareness and increasing vaccination coverage are needed to reduce TBE and its consequences.
Keywords: Tick borne encephalitis (TBE) • burden of TBE • disability adjusted life years (DALYs)
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Introduction Tick borne encephalitis (TBE) presents an increasing public health concern in many parts of Europe and in some Asian countries [1]. TBE is an infectious disease of the central nervous system (CNS) which may lead to long term or permanent neurological sequelae or even death [2 6]. Three genetically closely related TBE virus (TBEV) subtypes (the European, Far Eastern and Siberian) cause TBE [1,7]. These three TBE virus subtypes are usually transmitted by the infected tick genus Ixodes [1]. The virus can also be transmitted through unpasteurized dairy products [8]. All three subtypes are associated with varying courses of the disease and degrees of severity [7]. The European subtype of the virus, which is prevalent in most of Europe (including Slovenia), usually causes disease that follows a biphasic course [7]. This course presents a short lasting acute disease of the first stage with flu like symptoms, starting about two weeks after the tick bite, followed by a few symptom free days with subsequent acute disease of the second stage in the CNS, mostly concerning meningitis, meningoencephalitis and meningoencephalomyelitis [9]. With increasing age, severity of the disease increases [9,10] and mortality rates due to TBE in adults increasing up to 2% [7]. The Far Eastern subtype of the virus is mainly found in Eastern Russia, China, and Japan and the Siberian is found mostly in the Urals, Siberia and Eastern Russian provinces [7]. Both the Far Eastern and Siberian subtypes of the virus cause a monophasic course of the disease [7], characterized by CNS involvement [7]. Disease with the Far Eastern subtype of the virus is usually severe, is frequently associated with encephalitic symptoms and lacks the tendency to develop chronic disease [7]. Mortality rate due to the Far Eastern subtype is between 5 and 35% [7]. Disease from the Siberian subtype of the virus is less severe, but associated with diverse neurological and/or neuropsychiatric symptoms and a tendency to develop chronic or extremely prolonged disease [7]. Mortality rate of the Siberian subtype is between 1 and 3% [7]. Finally, the disease characteristics also depend on the tropism of the TBEV for different regions of the CNS and on the individual immunity of patients [9 11]. TBE is endemic in regions from Alsace Lorraine and Scandinavia to the North eastern parts of China and Northern Japan [1,12 19]. In many parts of Europe, Russia, Siberia and the Far East, the incidence is increasing and new foci have appeared due to increasing mobility, changes in lifestyle, human leisure activities, agricultural practices and effects of climate changes on vectors and reservoir hosts
96 The burden of tick borne encephalitis in disability adjusted life years (DALYs) for Slovenia
[20 24]. In spite of increasing awareness and knowledge of the disease, the incidence of TBE is underestimated [21], mainly due to insufficient routine diagnostics and surveillance [9]. Therefore the full burden of TBE, using corrections for this underestimation, still has to be assessed. Vaccination with safe, efficacious and well tolerated vaccines is the most effective way of preventing TBE [25 28] and reducing its burden. In Slovenia, TBE has been a relevant disease from the public health point of view since 1953 [29]. Slovenia is one of the countries where the European subtype of the virus is prevalent, with a high incidence of TBE and very low vaccination coverage [30,31] despite favourable cost effectiveness [32]. Though the cost effectiveness of vaccination against TBE in Slovenia was evaluated [32] the exact full burden of TBE is also still unknown in this country and needs to be estimated. The burden of TBE is mostly expressed by incidence only [9,30,33]. The burden of the disease can be better evaluated if information on the incidence/prevalence, mortality and sequelae are all combined into a composite measure which can be found in the disability adjusted life years (DALYs) [34]. DALYs reflect lost years of healthy life, as defined by the World Health Organization (WHO) [35]. DALYs, as one criteria, can be used for effective planning and prioritizing of scarce and therefore limited public health resources [34]. The burden of TBE, expressed in DALYs, has not yet been assessed nor has it been specified in the Global Burden of Disease (GBD) studies [36]. The purpose of the present study is to estimate the burden of TBE in Slovenia, expressed in DALYs from both the population and individual perspectives. Furthermore, we discuss strategies to reduce this public health burden in Slovenia. Data used reflect 2011 as the most recent year with data availability. Additionally, we consider the trend in DALYs to analyse how reflective 2011 is for other recent years. Our study can help to guide health policy and action locally as well as provide suggestions globally to mitigate the burden of TBE.
Methods Brief overview of the DALYs ʼ methodology The DALYs ʼ methodology was first introduced by Murray and co workers in the Global Burden of Disease (GBD) project [37] using the following equation:
= + (1)
97 Chapter 5 where YLLs are the number of life years lost due to premature death and YLDs are the number of life years lost due to disability, weighted with a factor between 0 (perfect health) and 1 (death) reflecting the severity of the disability. According to the GBD terminology and the International Classification of Functioning, Disability and Health, [38] the term disability refers to any short term or long term health loss in terms of functional capacity such as mobility, self care, participation in normal activities, pain and discomfort, anxiety and depression and cognition. In the original GBD study in 1990 and further WHO updates [39 47], 3% and 0% discount rates and both presence and absence of age weights in the DALYs’ calculations were used. Discounting means that the value of health is weighted less in the future than in the present due to time preference related to growth in life expectancy [48]. Age weights give less weight to years of healthy life lost at young ages and older ages, with productivity as the main rationale [48]. For the GBD 1990 study, the reference standard life table has a life expectancy at birth of 82.5 years for females and 80.0 years for males [48]. Since the GBD 1990 study was published, there have been intense debates on the key methodological choices used for the DALYs’ calculation, especially regarding the discounting, age weights, disability weights, the years lost per death and the incidence estimates for the YLDs calculation [48 54]. As one outcome of these debates, the new GBD 2010 study, done by Institute of Health Metrics and Evaluation, used a simplified calculation of DALYs without discounting and age weights, and the YLDs are calculated from prevalence estimates rather than incidence estimates [48,55 58]. The GBD 2010 study also involves some modifications of disability weights for the DALYs ʼ calculus and uses a new reference standard life table for the YLLs calculation. The new GBD 2010 reference standard life table has a life expectancy at birth of 86 years for both males and females and expresses an aspiration for high and healthy life expectancy [55]. The GBD studies estimate the global burden of diseases, including communicable, maternal, neonatal, nutritional, non communicable diseases and injuries [48]. In 2008, the European Centre for Disease Prevention and Control urged to develop a new methodology to estimate the burden for communicable diseases in European Member States and EEA/EFTA countries by using a pathogen based approach, taking into account subsequent sequelae and complications associated with infection [59,60]. No age weights or discounting are considered [59].
98 The burden of tick borne encephalitis in disability adjusted life years (DALYs) for Slovenia
Adjustment to correct for under ascertainment and under reporting is applied [59,61]. Under ascertainment refers to cases who do not seek medical care due to mild or absence of symptoms, or who have knowledge that the disease is self limiting [61,62]. Due to under ascertainment, cases will not enter the notification or surveillance system [61,62]. Under reporting refers to cases who seek medical care but are not captured by the surveillance or notification systems because the infection/pathogen is not diagnosed or is misdiagnosed, misclassified or miscounted [61,62]. Further development of this methodology is in progress [60]. Using this methodology to estimate the full burdens of different communicable diseases enables comparisons among these diseases within and between countries to help guide public health policy and action in Europe [59]. In the present study, the updated methodology [60,61,62] will be applied for one individual country.
The DALYs methodology to calculate the burden of TBE On the basis of the natural course of the disease, the following health outcomes of a model were included for the calculation of DALYs [32]: death due to TBE, the acute disease of the second stage with signs of meningitis, meningoencephalitis and/or meningoencephalomyelitis and mild, moderate and severe neurological sequelae. Mild neurological sequelae (emotional liability, tiredness and intermittent headache) can be assumed not to have a significant impact on patients ʼ daily activities, social and working capacity. Moderate neurological sequelae (ataxia of gait, paresis of extremities, cognitive disorders, pronounced dementia or severe deafness) will however affect patients’ daily activities, social and working capacity. In patients with severe neurological sequelae, social life and working capacity can be seriously affected and in a few cases patients need institutional care. In the present study, these neurological sequelae are considered as permanent neurological sequelae. Data in Table 1 were used to calculate the burden for TBE in a straightforward disease burden model programmed in Microsoft Excel. The reported age dependent number of cases with acute disease of the second stage (n ra ) was obtained from the National Institute of Public Health (NIJZ) data [63] and was used as the initial model input. These numbers of cases were corrected for under estimation by a factor γ. This factor γ is the product of a factor β a to correct for under ascertainment and a factor β r to correct for under reporting. Both correction factors β a and β r are calculated based on the schematic presentation of disease progression presented in Fig. 1. [32]. In the
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present study the factor β a was calculated on the basis of targeted specific information. Firstly, the natural course of TBE takes into account that around 90% of symptomatic infections develops acute disease of the first stage with symptoms similar to flu and about one third develops acute disease of the second stage with CNS involvement and the remaining 10% of infections involves more serious disease of the CNS [33,64]. Secondly, all reported cases were assumed to concern patients with acute disease of the second stage with CNS involvement in Slovenia [63].
Fig. 1. Schematic presentation of disease progression, used to estimate the factors βr, βa and consequently γ; with γ (4.5) to correct under estimation of the reported number of cases with the acute disease of the second stage (nra ) resulting from the product of a factor β a (100/40 =
2.5) to correct for under ascertainment and a factor βr (100/55 = 1.8) to correct for under reporting.
Specifically, factor β r was calculated taking into account that 55% of TBE cases are reported; i.e., 45% of TBE cases are assumed misdiagnosed, misclassified or miscounted. The age dependent estimated numbers of cases with acute disease of the second stage (n ea ) were calculated as follows:
= × = × × (2)
The estimated number of cases for mild (n emild ), moderate (n emod ), and severe
(n esev ) permanent neurological sequelae and deaths due to TBE (n ed ) were calculated, using the annual transition probabilities p mild , p mod , p sev and p d of moving from acute disease of the second stage to health outcomes (mild, moderate, severe permanent neurological sequelae and deaths due to TBE, respectively). The age dependent
100 The burden of tick borne encephalitis in disability adjusted life years (DALYs) for Slovenia annual transition probabilities for mild, moderate, and severe permanent neurological sequelae were obtained from national studies [29,65]. The age dependent annual probabilities of deaths due to TBE (p d) were calculated from the NIJZ data [63] and were corrected for under reporting due to under diagnosis by a factor β d. The factor β d for TBE was calculated based on a published study [66] So, the age dependent estimated numbers of cases for mild, moderate, severe permanent neurological sequelae and deaths due to TBE (n ed ) were calculated as follows:
= × (3)
= × (4)
= × (5)
= × × (6)
These estimated numbers of cases for the various health outcomes were subsequently incorporated in the DALYs calculation for TBE. YLLs were calculated by multiplying the estimated age specific numbers of deaths due to TBE (n ed ) with the remaining life expectancy (e) at that age. For life expectancy, the latest GBD 2010 reference standard life table [58] was used.
= × (7)
The YLDs acute for the acute disease of the second stage were calculated by multiplying the estimated number of cases with acute disease of the second stage
(n ea ) with the appropriate disability weights (Dw a) and duration of hospitalization
(l a).
= × × (8)
The YLDs seq for mild, moderate and severe permanent neurological sequelae were calculated by multiplying the estimated number of cases for mild (n emild ), moderate (n emod ) and, severe (n esev ) permanent neurological sequelae with its
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disability weights (Dw mild , Dw mod and Dw sev ) and remaining life expectancies (e mild , emod and esev ).
= × × + × × + × × (9)
The YLDs for all health outcomes (acute disease of the second stage, mild, moderate and severe permanent neurological sequelae) were aggregated to get the total YLDs.
= + (10)
The full burden for TBE is the sum of YLLs and YLDs as follows:
= × + × × + × × + × ×
+ × × (11)
The burden of the disease for one year is presented from the population (total DALYs and DALYs per 100,000 populations) and the individual perspectives (DALYs per case) [62]. Neither discounting nor age weighting was applied in the DALYs calculus.
Data The number of TBE cases for 2011 for age groups from 0 4 years, 5 14 years, 15 24 years, 25 34 years, 35 44 years, 45 54 years 55 64 years, 65 74 years and 75+ years originated from official sources of the NIJZ [63]. In the present study, a maximum age of 105 years was taken, corresponding to the maximum age of 105 years from the GBD 2010 new standard life table. In the present study, the ages of onset for the acute disease of the second stage and mild, moderate and severe permanent neurological sequelae were assumed at the mid points of each age group. We used the new GBD 2010 reference standard life table for the calculation of YLLs, with a life expectancy at birth of 86 years for males and females [58]. An incidence based approach was used to estimate YLDs. In the absence of discounting and age weights, this approach converges to incidence multiplied by estimated duration times with disability weighting for sequelae [67]. In a prevalence based
102 The burden of tick borne encephalitis in disability adjusted life years (DALYs) for Slovenia approach without discounting and age weights, YLDs would follow from prevalence of sequelae times disability weights [67]. As prevalence is approximately incidence times duration, our incidence based YLDs across all ages would approximately equal the prevalence based YLDs, in particular in the absence of discount and age weighting [67]. Notably, when discounting and age weights are applied, the prevalence based YLDs for all ages may be quite different from the incidence based YLDs [67]. As no disability weights for the acute disease of the second stage of TBE exist, age dependent disability weights were derived from the GBD 2004 updated study for Japanese encephalitis [68]. Also, no disability weights for the various levels of TBE related neurological sequelae severities exist, and such disability weights for the mild and moderate and severe permanent neurological sequelae were derived as 1 minus the respective quality weights for each of these sequelae. The quality weights for mild, moderate and severe permanent neurological sequelae were derived from a published study [69]. As mentioned, all base case parameter values are listed in Table 1.
Table 1. Model input parameters for calculating DALYs of TBE: the number of reported cases with acute disease of the second stage for 2011, duration of the acute disease of the second stage, disability weights for the acute disease of the second stage, probabilities of permanent neurological sequelae, disability weights for permanent neurological sequelae and probabilities of death from TBE, inclusive references.
Health Outcomes Base case Range Reference (base case) Acute disease of the second stage Correction factor for 4.5 a 3.5 5.5 b underestimation (γ) Number of all acute cases, by age groups 0 4 5 [63] 5 14 17 [63] 15 24 20 [63] 25 34 19 [63] 35 44 34 [63] 45 54 38 [63] 55 64 65 [63] 65 74 41 [63] 75+ 8 [63] Duration of hospitalization, by
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age groups c 0 14 0.0164 years (6 days) 0.0082 years (3 days) 0.0274 years (10 days) [70] d 15 64 0.0247 years (9 days) 0.0082 years (3 days) 0.1671 years (61 days) d [71] 65 74 0.0274 years (10 days) 0.0082 years (3 days) 0.1205 (44 days) d [71] 75+ 0.0274 years (10 days) 0.0082 years (3 days) 0.1205 (44 days) d [71] Disability weights, by age groups e 0 14 0.616 per life year lived with [68] disability 15 74 0.613 per life year lived with [68] disability 75+ 0.613 per life year lived with [68] disability Permanent neurological sequelae Probability of mild sequelae, by age groups <15 0% [29] >15 10% 10 15.4% f [65] Probability of moderate sequelae, by age groups <5 0% [29] 5 14 1.50% 0 1.5% g [29] >15 46% 22 46% f [65] Probability of severe sequelae, by age groups <5 0% [29] 5 14 0.80% 0 4.1% g [29] >15 2% 2 8.6% f [65] Duration Remaining life expectancy in years Disability weights, all ages h Mild sequelae 0.023 per life year lived with 0 0.1 per life year lived with disability disability Moderate sequelae 0.160 per life year lived with 0.1 0.25 per life year lived with disability disability Severe sequelae 0.629 per life year lived with 0.5 0.7 per life year lived with disability disability Death due to TBE Correction factor for 2i 0 4 j underreporting (βd) Probability of death from TBE 0.4% k Duration Remaining life expectancy in years Disability weights 1 per life year lived with [36] disability a The calculated factor γ (4.5) is a product of factor βa (100/40 = 2.5) and factor βr (100/55=1.8). The factor βa was calculated on the basis of: (i) the natural course of TBE [33,64] and (ii) all reported cases in Slovenia (patients with acute disease of the second stage with CNS involvement).
104 The burden of tick borne encephalitis in disability adjusted life years (DALYs) for Slovenia
The factor βr for TBE in Slovenia is not available, therefore βr (100/55 = 1.8) is calculated taking into account that 55% TBE cases are reported in Slovenia. b The calculated average coefficient of variation (23%) of reported cases during the period 2002 to 2011 [63] was used for calculating the maximum and the minimum values of the factor γ. As it is stated that 97% of all reported cases are hospitalized in 2011 [63], a simplified assumption that all reported cases are hospitalized is used. c The age groups available for duration of hospitalization at 15 to 60 years and >60 years [71] is adapted into a set of age groups of 15 24, 25 34, 35 44, 45 54, 55 64, 65 74 and 75+ years based on official sources of the NIJZ [63]. d The maximum and the minimum values for duration of hospitalization by all age group, were taken from published studies in Slovenia [70,71]. e Disability weights for acute disease of the second stage are not available, therefore the disability weights of Japanese encephalitis from GBD 2004 were updated and subsequently taken into account [68]. f The maximum and minimum values of probabilities for mild, moderate and severe permanent neurological sequelae for those aged 15 years and over were taken from the highest and lowest values from both studies in Slovenia [65] and Lithuania [4]. g The maximum and the minimum values of probabilities for mild, moderate and severe permanent neurological sequelae for under the age of 15 years were taken from both studies in Slovenia [72,73]. h Disability weights for mild, moderate and severe permanent neurological sequelae due to TBE are not available, therefore the disability weights for each of these sequelae as well as their maximum and minimum values were calculated as 1 minus available quality weights. The quality weights for mild, moderate and severe permanent neurological sequelae and their maximum and the minimum values were derived from published data [69]. i The factor βd (100/50 = 2) was calculated taking into account that 50% TBE deaths are reported [66]. j The maximum and minimum values for factor βd is calculated as ± 2 times the base case value. k The probability of death due to TBE was calculated from the average reported deaths due to TBE during the period 2002 to 2011 (1) [63] divided by all reported TBE cases from 2011 (247) [63].
In sensitivity analyses, we tested how the results change with changes in the input parameters’ values. One way and probabilistic sensitivity analyses (PSA) were conducted. With one way sensitivity analyses one parameter was changed while other parameters were kept constant at the base case values. The maximum and minimum values of each parameter were defined by the range from Table 1. The results of one way sensitivity analyses were represented as a tornado diagram for the population perspective. PSA was conducted in the form of simulations using @Risk ® (Palisade Corporation) and 1000 repetitions. Uniform distributions were used between maximum and minimum values as defined by the ranges from Table 1. Results of the PSA were presented using 95% uncertainty cut offs.
Results Base-case analyses Table 2 shows that from the population perspective total DALYs amount to 3,450 or 167.8 per 100,000 population, while from the individual perspective they amount to 3.1 per case. The disease burden is dominated by permanent neurological sequelae (93.9%), followed by the burden of premature death due to TBE (5.6%), while the burden due to the acute disease of the second stage reflects the smallest proportion (0.5%). Within the total permanent neurological sequelae, the burden of moderate
105 Chapter 5 sequelae presents the biggest proportion (77.6%) followed by the burden of severe sequelae (14.0%) and the burden of mild sequelae (2.4%).
Table 2. Calculated DALYs due to TBE for one year from the population perspective (YLLs, YLDs, DALYs and DALYs per 100,000 population) and individual perspective (DALYs per case).
Health outcomes Cases YLLs YLDs DALYs DALYs per DALYs per case 100,000 population Acute disease of the second 1,112 0 17 17 0.015 0.8 stage Permanent neurological sequelae Mild sequelae 101 0 83 83 0.075 4.0 Moderate sequelae 467 0 2,672 2,672 2.403 129.9 Sever sequelae 21 0 484 484 0.435 23.5 Total permanent neurological 3,239 3,239 2.913 157.5 sequelae Death due to TBE 9 194 0 194 0.174 9.4 All health outcomes 194 3,256 3,450 3.1 167.8
Cases = estimated cases. Results in the Table 2 are presented in both disaggregated form (YLLs, YLDs) and aggregated form (DALYs) for one year and are in line with the methodology protocol for calculating the burden of communicable diseases in EU and EEA/EFTA [62]. YLLs = the number of life years lost due to premature death due to TBE at an age of 67 years [30]. YLDs = the number of life years lost due to disability. DALYs = disability adjusted life years. DALYs are calculated as the sum of YLLs and YLDs. DALYs per case are calculated as DALYs divided by the number of estimated cases of acute disease of the second stage. DALYs per 100,000 populations are calculated as DALYs divided by the Slovene population of 2,050,189 people [74] and then multiply by 100,000.
Fig. 2 shows that, from the population perspective, the burden of TBE expressed in DALYs in the age group from 15 to 54 years amounts to 68% of the total burden. The burden in the working age population from 15 to 64 years amounts to 85%. Within working age populations, the burden in the prime aged workers group from 25 to 54 years of age amounts to 53%, followed by the burden in the youth workers group from 15 24 years of age and older workers group from 55 to 64 years (16 17%). The burden expressed as the number of reported cases in the age group from 15 to 54 years amounts to 51% of the total burden and to 72% in the working age population aged 15 to 64 years. The burden in the prime aged workers group amounts to 43%, followed by the burden in the older workers group (21%), while the burden in youth workers group amounts to 8%.
106 The burden of tick borne encephalitis in disability adjusted life years (DALYs) for Slovenia
Fig. 2. Comparison of relative TBE burden expressed in total DALYs from the population perspective with the relative TBE burden expressed by the number of reported cases by age groups. DALYs and reported cases are averages over 2004 2011.
Fig. 3 demonstrates annual data of total DALYs over time, with the peak of 5,279 DALYs in 2006 and the lowest value of 2,572 DALYs in 2010. Long term burden average between 2004 and 2011 amounts to 3,626 DALYs while a short term average between 2009 and 2011 amounts to 3,439 DALYs. Our 2011 estimate can therefore be considered as representative for previous years, despite a slight overall decline during the years.
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Fig. 3. Trend analysis of TBE burden expressed in total DALYs in years 2004 to 2011 from the population perspective.
Sensitivity analyses With one way sensitivity analyses, it was tested which parameters have the greatest influence on the model ʼs results. From Fig. 4, the ordering of parameters according to their influence on DALYs can be seen. The disability weights of moderate permanent neurological sequelae have the greatest influence on estimated DALYs.
108 The burden of tick borne encephalitis in disability adjusted life years (DALYs) for Slovenia
Fig. 4. Tornado diagram of the one way sensitivity analyses of TBE burden expressed in total DALYs from the population perspective.
Results of the probabilistic sensitivity analyses presented in Fig. 5 show a 95% uncertainty interval from 2,394 to 5,774 DALYs. It shows that, for example, with 0.95 likelihood total DALYs are higher than 2,394, whereas DALYs are higher than 2,631 with 0.9 likelihood.
Fig. 5. Cumulative ascending curve of the probabilistic sensitivity analysis of TBE burden expressed in total DALYs from the population perspective, reflecting the likelihood (y axis) of being below a specified total DALYs impact (x axis).
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Discussion DALYs as a composite measure enable the combination of information on incidence, mortality and sequelae associated with TBE infection. Therefore, DALYs provide unique insight into the disease burden [34]. From the population perspective, total DALYs amount to 3,450 (167.8 per 100,000 population) in 2011 in Slovenia, while from the individual perspective they amount to 3.1 per case for that same year. The majority of the estimated burden is centered in adults with potential major impact on productivity losses. 1.5% of TBE burden in the age group from 5 14 years seems low compared to the burden in adults. However, as these are children and disease in children is often considered as of even higher subjective burden than in adults, a greater relative burden of disease may well be conceived than reflected just by the bare percentages. Also, the present study emphasizes the impact of neurological sequelae. These sequelae have significant impact on patients ᾽ quality of life, social and working activities. Cognitive impairments are perhaps one of the most relevant sequelae of TBE and potentially are crucial in the work environment. In the present study, TBE country specific data were used for the DALYs calculation. The study estimates are based on the best evidence the authors could find, however, some data and information were not available for Slovenia, such as disability weights for TBE, both correction factors βd (under reporting of deaths due to TBE) and βr (under reporting of cases of the acute disease of the second stage). In Slovenia, only cases with the acute disease of the second stage with CNS [75] and death due to TBE [63] are routinely reported, DALYs have previously not been used to measure the burden of TBE and application of correction factors for TBE as done in the present study reflects an innovative approach in DALYs’ calculations. The disease burden model developed in the present study could be used as a representative model for TBE DALYs’ calculations for other countries. Cases with asymptomatic infection and symptomatic cases including acute disease of the first stage are not captured by notification or surveillance systems in Slovenia [75] nor by our correction factors, causing potential under estimation of our DALYs’ estimates. Disability weights of mild and severe permanent neurological sequelae, as addressed in the one way sensitivity analyses, appeared to have no crucial impact on DALYs. Additionally, correction for under reporting of deaths due to TBE shows only a slight impact on YLLs in the full disease burden. It is estimated that at the European level (Albania, Austria, Croatia, the Czech Republic, Denmark, Estonia,
110 The burden of tick borne encephalitis in disability adjusted life years (DALYs) for Slovenia
Finland, France, Germany, Hungary, Italy, Latvia, Lithuania, Poland, Russian Federation, Slovak Republic, Slovenia, Sweden, Switzerland) only 30 40% of TBE cases are reported [76], meaning that 60 70% of TBE cases are misdiagnosed, misclassified and miscounted. These figures are derived from varying systems of TBE surveillance and notification and varying diagnostic procedures among these countries in the investigated time period up to 2000 [7]. As TBE has been mandatory notifiable since 1977 in Slovenia [7] and awareness about TBE might increased in the last years, we decided to use a conservative estimate of 55% of TBE cases being reported in Slovenia. Taking into account the proportion of 30 40% of TBE reported cases [76], our total DALYs estimation would obviously still reflect an under estimate. Trend analysis of the TBE burden may be interpreted as showing a slight decrease in DALYs for the time period between 2004 and 2011, likely mainly due to increasing awareness of the disease among the general population. Despite increasing awareness during the last years, vaccination coverage of 13% in terms of persons receiving one or two doses of TBE vaccine was low in 2009 [77]. Notably, vaccination seems far too low in Slovenia for efficient prevention and control of TBE [31]. Still, the trend analysis shows that the estimated burden of 3,450 DALYs for 2011 is likely representative for the national disease burden. In a report of the Dutch National Institute of Public Health & the Environment, burdens are presented as measured in DALYs, incidence and mortality for seven selected infectious diseases (influenza, measles, HIV, campylobacteriosis, infection with enterohaemorrhagic Escherichia coli , salmonellosis and tuberculosis) and compared between some European countries [34]. It was concluded that the relative burden of these diseases expressed in DALYs is different compared to the relative burden expressed just by incidence or mortality data [34]. In a related study [78] explicitly recommend to calculate DALYs also for other infectious diseases in Europe to prioritize interventions. DALYs have previously not been used to measure the burden of TBE. TBE burden, expressed in DALYs is not included in GBD studies, and results of the present study give novel information in that respect. Comparison of the TBE burden expressed in DALYs in the present study to DALYs for other infectious diseases from the GBD 2010 study for Slovenia [79] is possible. However, this comparison should be considered with caution as no GBD disability weights for TBE exist. In the GBD
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2010 study for Slovenia [79], the cluster for communicable, maternal, neonatal and nutritional disorders presents 25,501 DALYs per year. Within this group [79], lower respiratory infections present the highest burden with 7,545 DALYs amounting to 29.6%, followed by diarrheal diseases with 1,225 DALYs (4.8%), otitis media with 954 DALYs (3.7%), upper respiratory infections with 951 DALYs (3.7%), tuberculosis with 776 DALYs (3%) and HIV/AIDS with 547 DALYs (2.1%). The potential proportion of our estimated TBE burden in this cluster amounts to 13.5%, demonstrating a relatively high burden in Slovenia. Thus, the present study can serve as an informative estimation of the TBE ᾿s national burden and the importance of the TBE on population's health in Slovenia. TBE can be considered to have a high impact on public health and to present a challenge for more efficient health policies and actions to reduce TBE in Slovenia. Such action may lead to huge population health benefits on national scales. Austria is the only European country where an extended vaccination campaign was launched in 1981. In Austria, vaccination is free of charge only for people with an occupational risk of TBE, while for the rest of the Austrian population a part of the costs are still covered by health insurance [9,80]. Vaccination coverage of persons receiving at least one dose of vaccine increased from 6% at the beginning of the programme to 88% in 2006, with 58% being regularly vaccinated within the recommended schedule [27]. This has led to drastic reductions in TBE in all age groups [27]. In the years between 2000 and 2006, about 2800 cases were prevented in Austria [27]. TBE is endemic in Slovenia, one of the countries with the highest incidence worldwide [30]. In Slovenia, vaccination is recommended for the general population from the age of one. TBE vaccine is free of charge only for those who are potentially exposed during fieldwork while the rest of the population has to pay for the vaccination [81,82]. Furthermore, because of limited public health resources in Slovenia, it was recommended [30] to provide only selective access to free of charge vaccination for specific age groups in specific regions. The findings of the present study may suggest the need to prioritize prevention of TBE disease further and reallocation of limited public health resources in Slovenia, for example, for an extended TBE vaccination for all groups, ages and regions, potentially free of charge or at a reduced price. It has been shown before that extended TBE vaccination can be beneficial from an economic perspective [80]. Extended vaccination may result in
112 The burden of tick borne encephalitis in disability adjusted life years (DALYs) for Slovenia major health benefits to the population as a whole as well as cost savings to the health care system.
Conclusions TBE presents a relatively high burden in Slovenia, expressed in DALYs both from the population and individual perspectives. Public health impact may justify relocation of scarce budgets to better control TBE. In particular, continued awareness raising and corresponding increased vaccination coverage is needed to reduce TBE and its consequences in Slovenia. Author Contributions Conceived and designed the study: RŠ, MJP. Performed the study: RŠ. Contributed analysis tools: RŠ, MJP. Analysed data and interpreted results: RŠ. Wrote the manuscript: RŠ, MJP. Conceived and designed disease burden model: RŠ.
Financial & competing interests disclosure Prof Maarten J Postma received grants and honoraria from various pharmaceutical companies. However, all grants and honoraria are fully unrelated to the specific topic of this paper. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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55. Murray CJ, Ezzati M, Flaxman AD, Lim S, Lozano R, Michaud C, et al. GBD 2010: design, definitions, and metrics. 2013;380: 2063 2066. 56. Murray CJ, Ezzati M, Flaxman AD, Lim S, Lozano R, Michaud C, et al. GBD 2010: a multi investigator collaboration for global comparative descriptive epidemiology. 2013;380: 2055 2058. 57. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. Disability adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. 2013;380: 2197 2223. 58. Murray CJ, Ezzati M, Flaxman AD, Lim S, Lozano R, Michaud C, et al. Comprehensive Systematic Analysis of Global Epidemiology: Definitions, Methods, Simplification of DALYs, and Comparative Results from the Global Burden of Disease 2010 Study. 2010: 2063 2066. 59. Mangen MJ, Plass D, Havelaar AH, Gibbons CL, Cassini A, Mühlberger N, et al. The pathogen and incidence based DALY approach: an appropriated methodology for estimating the burden of infectious diseases. 2013;8: e79740. 60. Kretzschmar M, Mangen MJ, Pinheiro P, Jahn B, Fevre EM, Longhi S, et al. New methodology for estimating the burden of infectious diseases in Europe. 2012;9: e1001205. 61. Gibbons CL, Mangen MJ, Plass D, Havelaar AH, Brooke RJ, Kramarz P, et al. Measuring underreporting and under ascertainment in infectious disease datasets: a comparison of methods. BMC Public Health. 2014;14: 147. 62. Mangen M, Gibbons C, Kretzschmar M, de Wit A, Havelaar A, van Lier A, et al. Current and future Burden of Communicable Diseases in the European Union and EEA/EFTA countries (BCoDE). Methodology protocol; 2011. 63. Nacionalni institut za javno zdravje (NIJZ). Epidemiolosko spremljanje nalezljivih bolezni v Sloveniji. 2014. Available: http://www.ivz.si/. Accessed February 2014. 64. Jereb M, Karner P, Muzlovič I, Jurca T. Severe tick borne encephalitis in Slovenia in the years 2001–2005: Time for a mass vaccination campaign? Wien Klin Wochenschr. 2006;118: 765 768. 65. Radšel Medvešček A, Marolt Gomišček M, Povše Trojan M, Gajšek Zima M, Cvetko B. Late sequelae after tick borne meningoencephalitis in patients treated at the Hospital for Infectious Diseases, University Medical Centre of Ljubljana during the period 1974–1975. In: Vesenjak Hirjan J, editor. Arboviruses in the Mediterranean countries. In: Anonymous Zbl Bakt Suppl. 9. Stuttgart, New York: Gustav Fischer Verlag.; 1980. pp. 281 284. 66. Kelly TA, O'Lorcain P, Moran J, Garvey P, McKeown P, Connell J, et al. Underreporting of viral encephalitis and viral meningitis, Ireland, 2005 2008. Emerg Infect Dis. 2013;19: 1428 1436. 67. World Health Organization (WHO). Disability weights, discounting and age weighting of DALYs. Available:
117 Chapter 5 http://www.who.int/healthinfo/global_burden_disease/daly_disability_weight/en/. Accessed: February 2014. 68. World Health Organization (WHO). Global Burden of Disease 2004 update: Disability weights for diseases and conditions. Available: http://www.who.int/healthinfo/global_burden_disease/tools_national/en/index.html/. Accessed February 2014. 69. Livartowski A, Boucher J, Detournay B, Reinert P. Cost effectiveness evaluation of vaccination against Haemophilus influenzae invasive diseases in France. Vaccine. 1996;14: 495 500. 70. Logar M, Arnez M, Kolbl J, Avsic Zupanc T, Strle F. Comparison of the epidemiological and clinical features of tick borne encephalitis in children and adults. Infection. 2000;28: 74 77. 71. Logar M, Bogovič P, Cerar D, Avšič Županc T, Strle F. Tick borne encephalitis in Slovenia from 2000 to 2004: comparison of the course in adult and elderly patients. Wien Klin Wochenschr. 2006;118: 702 707. 72. Rakar R. Tick borne meningoencephalitis. In: Lesnicar J, ed. Bedjanic symposion on tick borne meningoencephalitis. Dobrna: Infektoloska Sekcija SZD: 37 41. 73. Lesnicar G, Poljak M, Seme K, Lesnicar J. Pediatric tick borne encephalitis in 371 cases from an endemic region in Slovenia, 1959 to 2000. Pediatr Infect Dis J. 2003;22: 612 617. 74. Statistical Office of the Republic of Slovenia. Population by large and 5 year age groups and sex, statistical regions, Slovenia, half yearly. Available: http://www.stat.si. Accessed February 2014. 75. European Centre for Disease Prevention and Control (ECDC). Epidemiological situation of tick borne encephalitis in the European Union and European Free Trade Association countries. Stockholm: ECDC; 2012. Available at: http://ecdc.europa.eu/en/publications/Publications/TBE in EU EFTA.pdf. Accessed: March 2015. 76. International Scientific Working Group on Tick Borne Encephalitis (ISW TBE). ECDC presentation Tick borne diseases: ECDC initiatives. Available: http://www.tbe info.com/tbe.aspx. Accessed April 2015.2015. 77. Kunze U. TBE–awareness and protection: the impact of epidemiology, changing lifestyle, and environmental factors. 2010;160: 252 255. 78. van Lier EA, Havelaar AH, Nanda A. The burden of infectious diseases in Europe: a pilot study. Euro Surveill. 2007;12: E3 4. 79. Institute for Health Metrics and Evaluation (IHME). GBD Database. Seattle, WA: IHME, University of Washington, 2014. Available: http://www.healthdata.org/search gbd data?s=Slovenia. Accessed April 2015.
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80. Kunz C. TBE vaccination and the Austrian experience. Vaccine. 2003;21: S50 S55. 81. Nacionalni institut za javno zdravje (NIJZ). Navodila za izvajanje Programa cepljenja in zaščite z zdravili za leto 2013. Available: Accessed February 2014. 82. Nacionalni institut za javno zdravje (NIJZ). Priporocila za cepljenje proti klopnemu meningoencefalitisu za zdravnike cepitelje. Available: http://www.img.ivz.si/. Accessed February 2014.
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CHAPTER 6
Cost effectiveness of tick borne encephalitis vaccination in Slovenian adults
Renata Šmit
Vaccine 2012;30(44):6301 6
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122 Cost effectiveness of tick borne encephalitis vaccination in Slovenian adults
Abstract Background: Slovenia is an endemic country with a high incidence rate of tick borne encephalitis (TBE) and low vaccination coverage. TBE causes high costs for the health care insurances as well as the society due to hospitalization and frequent long term or permanent neurological sequelae. Vaccination is effective and a safe prophylaxis against TBE.
Objective: The purpose of this study was to evaluate the incremental cost effectiveness ratio (ICER) between vaccination and no vaccination in Slovenia. The results are shown as cost per quality adjusted life year (QALY) gained from the view of the health care payer and the society.
Methods: Based on the natural course of the disease, the Markov model was used for comparing the economic and health outcomes of vaccinated and unvaccinated groups from 18 to 80 years of age.
Results: The incremental cost effectiveness ratio from the current Slovenian vaccination programme for FSME Immun® compared to no vaccination amounts to €15,128 per QALY gained and for Encepur® €20,099 per QALY gained from the view of the health care payer. From the view of the society vaccination is cost saving, mainly due to avoiding the high indirect costs.
Conclusions: According to the cost effectiveness threshold as proposed by the Slovenian Health Council, the current Slovenian vaccination programme against TBE is cost effective from the health care payer’s perspective and also economical from the society’s perspective.
Keywords: Tick borne encephalitis • cost effectiveness • adults • Slovenia
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Introduction Slovenia is within Europe one of the countries with the highestrate of incidence of tick borne encephalitis (TBE) and low vaccination coverage [1]. In different parts of Europe, the incidence of the disease is increasing and new foci are emerging [2,3]. The risk of infection is related to increases of mobility in the endemic area, changing lifestyles and climate changes [2,3]. TBE causes high costs for the health care insurances as well as the society due to hospitalization and frequent long term or permanent neurological sequelae [3,4]. Therefore it is worthwhile to find the most effective way of preventing TBE. Wearing suitable clothes and shoes, using repellents and avoiding tick infested areas, is one of the ways to prevent the disease [1]. However, the most effective protection is vaccination against TBE [1,5,6]. In Slovenia there are currently two vaccines against TBE in use: FSME Immun® and Encepur® [7]. Both vaccines are safe, effective and well tolerated [4,6,8]. Seeing that these two TBE vaccines can be used interchangeably [4,9], both vaccines were taken into account in the present study. A cost benefit study on TBE vaccination was done [10]. However, cost effectiveness studies on TBE immunization in Slovenia are clearly needed so that TBE vaccination could be included into the national immunization programmes [1]. The purpose of this study was to evaluate the incremental cost effectiveness ratio between a vaccinated and no vaccinated group from 18 to 80 years of age from the view of the health care payer and the society.
Methods Natural course of disease The Eastern subtype virus is characterized by a monophasic course of the disease, while the Western subtype virus usually causes a biphasic course of the disease [11]. According to the WHO [6] only one third of the infected develops the typical biphasic course of the disease. Clinical acute signs of the disease (meningitis, meningoencephalitis, meningoencephalomyelits) appear suddenly [6,12,13] and most of the patients with these signs need hospitalization [6,12]. However, the consequences of the disease affect the quality of life and sometimes change the individual’s life style [13]. In the Slovenian region, Radšel Medvešček et al. [14] categorized the sequelae into three groups: minor complaints (10%),
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Fig. 1. Natural course of TBE. major complaints (46%), and difficulties associated with resuming previous levels of activity (2%). Therefore these permanent sequelae were used in the current study and were classified according to Bohr et al. [12] as mild, moderate and severe. Some reports suggest that there is an abortive form of TBE [15]. This suggestion relies more on data for Eastern TBE than on data for Western TBE [15]. Mortality in adults due to the disease is 1–2% [2]. The natural course of the disease is shown in Fig. 1.
Model On the basis of the natural course of the disease (Fig. 1) a Markov model in TreeAge Pro 2011 (TreeAge Software Inc., Williamstown, MA, USA) was developed. This model was chosen because it is the most widely used technique in health economics for the evaluation of cost effectiveness [16]. In the present study, the model was used to compare the economic and health outcomes of vaccinated and unvaccinated groups between the age of 18 and 80 years (i.e. a time horizon of 62 years). The whole life cycle of both groups was included. A cycle length of 1 year was used. During each cycle, patients who do not die due to other causes, develop TBE, which may lead to either permanent neurological sequelae, or recovery or death due to TBE. Permanent neurological sequelae were divided into mild, moderate and
125 Chapter 6 severe, depending on their impact on the patient’s quality of life. Patients moved through these health states based on annual transition probabilities. Each health state is associated with costs and quality weights. Costs and quality weights of the second stage (i.e. hospitalization) were used as prior costs for starting the Markov process. According to Bohr et al. [12] mild sequelae (emotional liability, tiredness, and headache intermittent) do not have a significant impact on patients’ quality of life, while moderate sequelae (ataxia of gait, paresis of extremities, pronounced dementia or severe deafness) affect patients’ quality of life, their daily activities, social and working capacity. In patients with severe sequelae, social life and working capacity are seriously affected and in a few cases patients need institutional care. The results were shown as the cost per quality adjusted life year (QALY) gained due to vaccination from the view of the health care payer and the society. QALY takes into account both the quantity and quality of life. The Markov six state model is shown in Fig. 2, while the input data for the model are presented in Table 1.
Fig. 2. Markov model with six health states. The mild, moderate and severe sequelae are all permanent. Death occurs from the disease as well as from other causes.
Vaccination The current Slovenian immunization programme recommends 3 doses of vaccine (0, 1–3, 9–12 months) plus first booster after three years and following boosters every five years [32]. For individuals aged over 60 years vaccinated with FSME Immun® and for individuals aged over 50 years vaccinated with Encepur®, a 3 year interval is recommended [32].
126 Cost effectiveness of tick borne encephalitis vaccination in Slovenian adults
On the basis of this recommendation vaccination with FSME Immun ® and Encepur® were used in the present study: Vaccination with FSME Immun®: at the age of 18, three doses of vaccine during the first year plus the first booster after three years at the age of 21, following boosters every five years till the age of 61 and then every three years till the age of 80 years. Vaccination with Encepur®: at the age of 18, three doses of vaccine during the first year plus the first booster after three years at the age of 21, following boosters every five years till the age of 51 and then every three years till the age of 80 years. The efficacy of 98.7% for both vaccines was used in the present study [23].
Costs The costs were calculated from the published data by the Slovenian Health Insurance for the year 2012 [24]. The study was carried out from the perspective of a health care payer covering the direct costs, as well as from the perspective of the society, where also indirect costs were taken into account. In direct costs, the costs of the general practitioner (GP) and physician specialist visits as well as the costs of hospitalization were included. Indirect costs were costs due to loss of productivity and they included the costs due to absence from work. The average costs of hospitalization were calculated from the Disease Related Groups (DRG) weights [26]. Due to the lack of data for the DRG weight for mechanical ventilation and the number of check ups at the GP as well as the physician specialists of patients with neurological sequelae, an estimate was provided by an expert [27] and used in the study The weighted average cost of hospitalization was calculated from costs of hospitalization and the probabilities of patients who need hospitalization. The average costs of mild and moderate sequelae were calculated from the costs of several check ups at the GP and physician specialists (neurologist, psychiatrist, infectologist). The percentage of patients with paresis, (in the moderate sequelae group) amounts to 3.8% [21]. Here the cost of visiting the out patient physiotherapy treatments was also taken into account. The average costs of the severe sequelae were calculated as the price of one day in a single room institutional care [25]. Adults (aged 18–60) being treated in the hospital are absent from work for 9 days and seniors (aged >60) 10 das [21] throughout the whole year. Patients with
127 Chapter 6 mild sequelae are not absent from work [12,17], 80% of patients with moderate sequelae are absent from work for 4 h per day throughout the whole year and the remaining of patients are absent from work 8 h a day [10,12,17]. Days of productivity were valued at the average daily wage which was in €2011 8.18 per hour [28]. The price of both TBE vaccines, as published by the health insurance [7] were used. The price for FSME Immun® was €20 and for Encepur® €24 [7].
Table 1. Input data for the Markov model: probability of contracting the disease, by age groups and costs both were calculated from data found in the references, while other variables were directly used from the references.
Input variable Base case Range Reference (base case) Risk of exposure 70 % [18] Probability of contracting disease, by age groups 0.0150 % 0.0354 % a 18 24 0.0168 % [19, 20] 25 34 0.0153 % [19, 20] 35 44 0.0151 % [19, 20] 45 54 0.0275 % [19, 20] 55 64 0.0339 % [19, 20] 65 74 0.0354 % [19, 20] 75 + 0.0150 % [19, 20] Probability of health outcome Permanent mild neurological sequelae 10 % 10 % 15.4 % b [14] Permanent moderate neurological sequelae 46 % 22 % 46 % b [14] Permanent severe neurological sequelae 2 % 2 % 8.6 % b [14] Recovered & Immune residual Probability of death from disease, by age groups 18 ≤60 0 [21] >60 2.3 % 1.84 % 2.76 % c [21] Probability of dying due to other reasons, by age 0.063 % 5.814 % d [22] Vaccination Vaccination with FSME Immun® Age at vaccination with 3 doses of vaccine 18 Age at vaccination with first booster of vaccine 21 Five years booster interval from the age 21 till the age of 61 Three years booster interval from the age 61 till the age of 80 Vaccination with Encepur®
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Age at vaccination with 3 doses of vaccine 18 Age at vaccination with first booster of vaccine 21 Five years booster interval from the age 21 till the age of 51 Three years booster interval from the age 51 till the age of 80 Efficacy for both vaccines 98.7 % 97.98 % 99.09 [23] % Duration of efficacy for both vaccines lifetime Costs of vaccine per dose Price for FSME Immun® Adults €20 [7] Price for Encepur® Adults €24 [7] Administration cost for both vaccines €2 [24] Cost of FSME Immun® €22 €18 26 e Cost of Encepur® €26 €21 31 e Direct costs per year Weighted average cost of hospitalization, by age groups 18 ≤60 €6,457 >60 €6,876 Permanent mild neurological sequelae €70 €56 84 e [24] Permanent moderate neurological sequelae €122 €98 146 e [24] Permanent severe neurological sequelae €28,952 €23,162 34,742 e [25] Costs of hospitalization per year Medical unit €5,187 [21, 26] Intensive care €14,899 [21, 26] Mechanical ventilation €47,878 [21, 27] Probability of patients who need hospitalization, by age groups Medical unit 80.8 % Intensive care 18 ≤60 5.3 % [21] >60 10.8 % [21] Mechanical ventilation [21] 18 ≤60 1.6 % [21] >60 1.5 % [21] Indirect costs per year, based on absence from work Hospitalization, by age groups 18 ≤60 €632 [28] >60 €702 [28] Permanent mild neurological sequelae 0 Permanent moderate neurological sequelae €15,383 €12,306 [28] 18,460 e Permanent severe neurological sequelae €25,638 € 20,510 [28]
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30,766 e Duration of hospitalization, by age groups 18 ≤60 9 days [21] >60 10 days [21] Quality weights 6 Susceptible 1 [29] Hospitalization 0.19 [30] Permanent mild neurological sequelae 0.977 0.90 – 1 [29] Permanent moderate neurological sequelae 0.84 0.75 0.90 [30] Permanent severe neurological sequelae 0.371 0.30 0.50 [29] Discount rate (costs & quality weights) 5 % 0 5 % g [31] a Maximum value is the highest probability for contracting the disease and minimum value is the lowest probability for contracting the disease. b Maximum and minimum values of probability for mild, moderate and severe sequelae in the present study was taken from the highest and lowest values from both studies in Slovenia [14] and Lithuania [17]. c Maximum and minimum values of probability of death from disease are calculated as ±20% of the base case value. d See Supplementary material [22]. e Maximum and minimum values of costs are calculated as ±20% of the base case values and rounded up. f Quality weights for calculating QUALY were obtained from published studies [29,30]. Value 1 represents perfect mental and physical health (susceptible) and value 0 represents death [29]. g Maximum values of discount rate (costs & quality weights) are base case values. Minimum values of discount rate are 5% of the base case value.
Table 2. Incremental cost per QALY gained from the view of the health care payer, when vaccination is compared with no vaccination.
Outcome Vaccination with No Vaccination with No FSME Immun®. vaccination Encepur®. vaccination Cost ( €) 49.10 15.86 60.02 15.86 Incremental cost ( €) per person a 33.23 44.15 Expected QALY per person 7.953 7.951 7.953 7.951 Incremental QALY per person a 0.002 0.002 Incremental cost ( €) per QALY gained 15,128 20,099
a Each incremental value compares the values of the vaccinated group with FSME Immun® or Encepur® with the values of the no vaccinated group. Costs and outcomes discounted at 5% [31].
130 Cost effectiveness of tick borne encephalitis vaccination in Slovenian adults
Table 3. Incremental cost per QALY gained from the view of the society, when vaccination is compared with no vaccination.
Outcome Vaccination with No Vaccination with No FSME Immun®. vaccination Encepur®. vaccination Cost ( €) 51.03 164.10 61.95 164.10 Incremental cost ( €) per person a 113.05 102.13 Expected QALY per person 7.953 7.951 7.953 7.951 Incremental QALY per person a 0.002 0.002 Incremental cost ( €) per QALY gained 51,462 46,491 a Each incremental value compares the values of the vaccinated group with FSME Immun® or Encepur® with the values of the no vaccinated group. Costs and outcomes discounted at 5% [31].
Base-case analysis Costs and health outcomes were discounted at a 5% annual rate as recommended and used by different European countries [31]. The results were shown as the incremental cost effectiveness ratio (ICER) from the view of the health care payer and the society. The ICER which is calculated as the difference in the cost of vaccination and no vaccination, divided by the difference in the QALY produced by vaccination and no vaccination.
Sensitivity analysis With sensitivity analysis it was tested how the result may change with changes in the input parameter’s values. One way sensitivity and probabilistic analysis (PSA) were performed. Both analyses were performed on vaccination with FSME Immun® and Encepur® compared to no vaccination. A threshold value of €30,000 per QALY gained (as proposed by the Slovenian Health Council [33], was set. The results of the one way sensitivity analysis of both vaccines were presented from the health care payer’s point of view. PSA was performed in the form of Monte Carlo simulation; the number of samples was 10,000. Uniform distribution was used, except for vaccine efficacy where triangular distribution was used and maximum and minimum values of parameters for the distribution were defined by range from Table 1. The results of a PSA were represented by using cost effectiveness acceptability curves from the view of the health care payer.
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Results Base-case analysis Table 2 shows that vaccination with FSME Immun® or Encepur®, if compared to no vaccination, was associated with a greater benefit in terms of QALY. Vaccination with both vaccines can be considered cost effective if the threshold value of €30,000 per QALY gained (as proposed by Slovenian Health Council, [33]) is taken into account. Vaccination with FSME Immun® was less costly compared to vaccination with Encepur®, both vaccines showed identical benefit in terms of QALY. Table 3 shows that vaccination with both vaccines is less costly as well as more effective than no vaccination (i.e. dominant).
Sensitivity analysis One-way sensitivity analysis With the one way sensitivity analysis it was tested which parameters have the greatest influence on the model’s results. Results of the one way sensitivity analysis are shown graphically in Fig. 3.
132 Cost effectiveness of tick borne encephalitis vaccination in Slovenian adults
Fig. 3. The one way sensitivity analysis for vaccination for both vaccines from the view of the health care payer. ICER presents the cost per quality adjusted life year (QALY) gained. The quality weights are relative values according to the health state in terms of the psychological aspect and functional handicap. Value 1 represents perfect mental and physical health and value 0 represents death [29]. Costs and outcomes are discounted at 5% [31].
From the view of the health care payer, ICER at the base case for FSME Immun® is €15,128 per QALY gained and for Encepur® €20,099 per QALY gained. Vaccination at the base case for FSME Immun ® and Encepur® is cost effective if the threshold value of €30,000 per QALY gained (as proposed by Slovenian Health Council, [33]) is taken into account. Parameters which are the key drivers of the model’s results for vaccination with FSME Immun® and Encepur® are: probability of moderate sequelae, probability of severe sequelae, probability of contracting TBE, discount rate (costs and quality weights), quality weights of moderate sequelae, cost for FSME Immun® and Encepur®. Even if parameter values change within a fixed range, vaccination is still cost effective (i.e. an ICER is below €30,000 per QALY gained).
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Only at a minimum probability value for the moderate sequelae the ICER for vaccination with Encepur® is €35,595 per QALY gained and at a maximum probability value for the severe sequelae, vaccination is cost saving. When costs and benefit were not discounted, the ICER is €1846 per QALY gained for FSME Immun® and €4183 per QALY gained for Encepur®. At a maximum value of both vaccine costs, vaccination is still cost effective, the ICER value does not exceed €30,000 per QALY gained.
Cost-effectiveness acceptability curves Results of the cost effectiveness acceptability curves show that for a willingness to pay (WTP) value of €20,000 per QALY gained, a vaccination with FSME Immun® has a 99.3% chance of being cost effective, while a vaccination with Encepur® has a 97.7% chance of being cost effective.
Discussion The results show that, from the health care payer’s perspective, vaccination for adults under the current Slovenian immunization programme is cost effective if the threshold of €30,000 per QALY gained (as proposed, [33]) is taken into account. The ICER at the base case for FSME Immun® is €15,128 per QALY gained and for Encepur® €20,099 per QALY gained. From the society’s perspective vaccination is cost saving, mainly due to avoiding the high indirect costs. With the one way and probabilistic sensitivity analyses the parameter values within a given range were changed. ICER values of these parameters do not exceed the threshold value of €30,000 per QALY gained from the health care payer’s and society’s perspective. Only at a minimum probability value for the moderate sequelae at vaccination with Encepur®, yields an ICER of €35,595 per QALY gained. That is in accordance with the Slovenian Health Council’s definition, which stipulates that it is partly cost effective (an ICER is below €45,000 per QALY gained and above €30,000 per QALY gained [33]. At a maximum probability value for the severe sequelae, vaccination is cost saving. For TBE there are no recent cost effectiveness evaluations [6]. An estimate for Austria (Schwarz, 1993) suggests that the TBE vaccine may be cost effective, at least in countries where TBE is widespread and highly endemic [6]. In Sweden the cost effectiveness ratio for immunization was estimated to be 1.68, if hypothetically 75% of cases were averted by a vaccination rate of 42% for the
134 Cost effectiveness of tick borne encephalitis vaccination in Slovenian adults
Stockholm population [34]. The limitation of the present study is that it was focused only on the adult population. Only the adult population was taken into account because with increasing age the clinical course of the disease is more severe and the elderly are very active and mobile, putting them at higher risk for contracting TBE [2]. Although Čižman et al. found severe TBE that required treatment in an intensive care unit for 7 (5.2%) of 133 children who were hospitalized between 1993 and 1998 [35], it was stated in 2003 that the disease at children is mild with favourable health outcomes [36]. Therefore children were not included in the present work as well as the fact that in 2009, the proportion of sick children under 15 years of age accounted for 8.9% [19]. Grkič Vitek et al. in 2011 stated the trend in Slovenia shows a decrease of morbidity at children [1]. The second limitation is that this study does not take into account the first stage of the disease with symptoms of headache, fever, and vomiting. People often mistake the symptoms as a result of infection with TBE with flu. Mostly they do not even visit a GP. Also an abortive form of TBE is not included in this study because it does not exist in Slovenia [15]. The third limitation is that vaccination adverse effects were not taken into account. The reason is that only common adverse effects were reported, but none were serious or life threatening [37]. The economic burden of tick borne encephalitis in Slovenia is in preparation (Šmit et al.). Both vaccines are safe, effective and well tolerated by humans [4,6,8]. Vaccination is effective and a safe prophylaxis against TBE. Increasing vaccination coverage rate will reduce the number of patients and the consequences which follow.
Conclusions According to the cost effectiveness threshold as proposed by the Slovenian Health Council, vaccination under the current Slovenian immunization programme against TBE is cost effective for adults from the health care payer’s perspective. In terms of the society, vaccination brings economic savings.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.vaccine.2012.07.083.
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References 1. Grgič Vitek M, Klavs I. High burden of tick borne encephalitis in Slovenia –challenge for vaccination policy. Vaccine 2011;29(32):5178–83. 2. Kunze U, Baumhackl U, Bretschneider R, Chmelik V, Grubeck Loebenstein B, Haglund M, et al. The Golden Agers and Tick borne encephalitis Conference report and position paper of the International Scientific Working Group on Tick borne encephalitis. Wien Med Wochenschr 2005;155(11–12): 289–94. 3. Donoso Mantke O, Schadler R, Niedrig M. A survey on cases of tick borne encephalitis in European countries. Euro Surveill 2008;13(17):18848. 4. Vaccines against tick borne encephalitis. The WHO Position Paper. Draft 13th March 2011. Available from: http://www.who.int/immunization/sage/ previous april2011/en/index.html/ [accessed 10.09.11]. 5. Lindquist L, Vapalahti O. Tick borne encephalitis. Lancet 2008;371(9627): 1861–71. 6. Kollaritsch H, Krasilnikov V, Holzmann H, Karganova G, Barrett A, Suss J, et al. Background Document on Vaccines and Vaccination against Tickborne Encephalitis (TBE). Available from: http://www.who.int/immunization/ sage/previous april2011/en/index.html/ [accessed 10.09.11]. 7. Health Insurance Institute of Slovenia. Central database of drugs. Available from: http://www.cbz.si/ [last accessed 02.07.12]. 8. Demicheli V, Debalini MG, Rivetti A. Vaccines for preventing tick borne encephalitis. Cochrane Database Syst Rev 2009;(1):CD000977. 9. Broker M, Schondorf. Are tick borne encephalitis vaccines interchangeable? Exp Rev Vaccines 2006;5(4):461–6. 10. Desjeux G, Galoisy Guibal L, Colin C. Cost benefit analysis of vaccination against tick borne encephalitis among French troops. Pharmacoeconomics 2005;23(9):913–26. 11. Dumpis U, Crook D, Oksi J. Tick borne encephalitis. Clin Infect Dis 1999;28(4):882–90. 12. Kaiser R. The clinical and epidemiological profile of tick borne encephalitis in southern Germany 1994–98: a prospective study of 656 patients. Brain 1999;122(Pt 11):2067–78. 13. Haglund M, Gunther G. Tick borne encephalitis – pathogenesis, clinical course and long term follow up. Vaccine 2003;21(Suppl. 1):S11–8. 14. Radšel Medvešček A, Marolt Gomišček M, Povˇse Trojan M, Gajšek Zima M, Cvetko B. Late sequelae after tick borne meningoencephalitis in patients treated at the Hospital for Infectious Diseases, University Medical Centre of Ljubljana during the period 1974–1975. In: Vesenjak Hirjan J, editor. Arboviruses in the Mediterranean countries. Zbl Bakt Suppl. 9. Stuttgart, New York: Gustav Fischer Verlag; 1980. p. 281–4. 15. Lotrič Furlan S, Avšič Zupanc T, Strle F. Is an isolated initial phase of a tick borne encephalitis a common event? Clin Infect Dis 2000;30(6):987–8.
136 Cost effectiveness of tick borne encephalitis vaccination in Slovenian adults
16. Cesar Sato R, Desiree Moraes Z. Markov models in health care. Einstein 2010;8(3 Pt. 1):376–9. 17. Mickiene A, Laiskonis A, Gunther G, Vene S, Lundkvist A, Lindquist L. Tickborne encephalitis in an area of high endemicity in Lithuania: disease severity and long term prognosis. Clin Infect Dis 2002;35(6):650–8. 18. Jereb M, Karner P, Muzlovic I, Jurca T. Severe tick borne encephalitis in Slovenia in the years 2001–2005: time for a mass vaccination campaign? Wien Klin Wochenschr 2006;118(23–24):765–8. 19. Institute of Public Health of the Republic Slovenia. Epidemiological surveillance of communicable diseases in Slovenia 2009. Available from: http://www.ivz.si/ Mp.aspx?ni=105&pi=5& 5 id=788& 5 PageIndex=0& 5 groupId=219& 5 news Category=& 5 action=ShowNewsFull&pl=105 5.0/ [accessed 04.02.11]. 20. Statistical Office of the Republic Slovenia. Population by large and 5 year age groups and sex, statistical regions, Slovenia, annually. Available from: http:// pxweb.stat.si/pxweb/Dialog/varval.asp?ma=05C2002E&ti=&path=./Database/Demographi cs/05 population/10 Number Population/10 05C20 Population stat regije/&lang=1/ [accessed 11.08.12]. 21. Logar M, Bogovic P, Cerar D, Avsic Zupanc T, Strle F. Tick borne encephalitis in Slovenia from 2000 to 2004: comparison of the course in adult and elderly patients. Wien Klin Wochenschr 2006;118(21–22):702–7. 22. Kalin K. Personal communication. Life table for 2009, both sexes were included. Statistical Office of the Republic Slovenia. 23. Heinz FX, Holzmann H, Essl A, Kundi M. Field effectiveness of vaccination against tick borne encephalitis. Vaccine 2007;25(43):7559–67. 24. Health Insurance Institute of Slovenia. Prices of health services valid from 1 st Jan 2012. Available from: http://www.zzzs.si/zzzs/pao/izvajalci.nsf/Vcenikpov [accessed 01.01.12]. 25. Varstveno delovni center Nova gorica. Enota Stara Gora. The price of one day in a single room institutional care valid from 1st Sept 2011. Available from: http://www.vdcng.si/ [accessed 30.09.11]. 26. Institute of Public Health of the Republic Slovenia. Disease Related Groups (DRG) 2009. Available from: http://www.ivz.si/podatkovne zbirke/ [accessed 04.02.11]. 27. Strle F. Personal communication. Estimation of the DRG weight for mechanical ventilation, the number of check ups at the GP and the physician specialists from patients with neurological sequelae. Department of Infectious Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia. 28. Statistical Office of the Republic Slovenia. Average monthly earnings. Available from: http://www.stat.si/eng/indikatorji.asp?ID=29 [accessed 11.02.12].
137 Chapter 6
29. Livartowski A, Boucher J, Detournay B, Reinert P. Cost effectiveness evaluation of vaccination against Haemophilus influenzae invasive diseases in France. Vaccine 1996;14(6):495–500. 30. Korves CT, Goldie SJ, Murray MB. Cost effectiveness of alternative bloodscreening strategies for West Nile Virus in the United States. PLoS Med 2006;3(2):e21. 31. Pharmacoeconomic Guidelines Around The World. Available from: http://www.ispor.org/PEguidelines/index.asp [accessed 17.07.12]. 32. Institute of Public Health of the Republic Slovenia. Recommendations for vaccination against TBE. Available from: http://www.ivz.si/cepljenje navodila priporocila/ [accessed 23.06.12]. 33. Ministry of Health of the Republic Slovenia. Postopek ocenjevanja in vključevanja novih ali spremenjenih zdravstvenih programov in drugih novosti pri metodah dela v programme zdravstvene dejavnosti v Republiki Sloveniji [dated 24th November 2009]. Available from: http://www.mz.gov.si/ fileadmin/mz.gov.si/pageuploads/ZS IN RSK/zapisniki 2009/Postopek uvodni del NOVI.pdf [accessed 23.06.12]. 34. Haglund M, Forsgren M, Gudrun L, Lindquist L. A 10 year follow up study of tick borne encephalitis in the Stockholm area and a review of the literature: need for a vaccination strategy. Scand J Infect Dis 1996;28: 217–24. 35. ˇCiˇzman M, Rakar R, Zakotnik B, Pokorn M, Arnež M. Severe forms of tick borne encephalitis in children. Wien Klin Wochenschr 1999;111:484–7. 36. Lesnicar G, Poljak M, Seme K, Lesnicar J. Pediatric tick borne encephalitis in 371 cases from an endemic region in Slovenia, 1959 to 2000. Pediatr Infect Dis J 2003;22(7):612–7. 37. Institute of Public Health of the Republic Slovenia. Side effects associated with vaccination in Slovenia. Available from: http://www.ivz.si/Mp.aspx?ni=106&pi=5& 5 id=378& 5 PageIndex=0& 5 groupId=220& 5 newsCategory=& 5 action=ShowNewsFull&pl=106 5.0 [accessed 23.06.12].
138 Cost effectiveness of tick borne encephalitis vaccination in Slovenian adults
Supplementary material
Table 4. Life table by age (from the age 18 till the age of 80) for 2009 [22].
Both sexes Probability of Number of Number of Number of Total number Life dying persons death person years of person expectancy surviving years x qx lx dx Lx Tx ex 18 0.00063 99541 62 99510 6115849 61.4 19 0.00042 99479 42 99458 6016339 60.5 20 0.00052 99437 52 99411 5916882 59.5 21 0.00068 99385 67 99351 5817471 58.5 22 0.00071 99318 71 99282 5718120 57.6 23 0.00045 99247 44 99225 5618838 56.6 24 0.00047 99202 47 99179 5519613 55.6 25 0.00046 99156 46 99133 5420434 54.7 26 0.00048 99110 47 99087 5321301 53.7 27 0.00053 99063 52 99037 5222214 52.7 28 0.00061 99011 60 98980 5123177 51.7 29 0.00076 98950 75 98913 5024197 50.8 30 0.00063 98875 62 98844 4925284 49.8 31 0.00064 98813 63 98781 4826440 48.8 32 0.00054 98750 53 98723 4727659 47.9 33 0.00039 98696 38 98677 4628935 46.9 34 0.00088 98658 87 98615 4530258 45.9 35 0.00073 98572 72 98536 4431643 45.0 36 0.00096 98500 95 98452 4333107 44.0 37 0.00091 98405 89 98360 4234655 43.0 38 0.00073 98316 72 98280 4136294 42.1 39 0.00122 98244 119 98184 4038015 41.1 40 0.00142 98124 139 98055 3939830 40.2 41 0.00115 97985 112 97929 3841776 39.2 42 0.00158 97873 155 97795 3743847 38.3 43 0.00223 97718 218 97609 3646051 37.3 44 0.00154 97500 150 97425 3548442 36.4 45 0.00182 97350 178 97261 3451017 35.4 46 0.00268 97173 261 97042 3353755 34.5 47 0.00271 96912 262 96781 3256713 33.6 48 0.00330 96649 319 96490 3159933 32.7 49 0.00316 96330 304 96178 3063443 31.8 50 0.00400 96026 384 95834 2967264 30.9 51 0.00349 95642 334 95475 2871430 30.0 52 0.00432 95308 412 95102 2775955 29.1 53 0.00473 94896 449 94672 2680853 28.3 54 0.00611 94447 577 94159 2586182 27.4 55 0.00648 93870 609 93566 2492023 26.5 56 0.00648 93262 604 92960 2398457 25.7 57 0.00702 92658 651 92332 2305497 24.9 58 0.00718 92007 661 91676 2213165 24.1 59 0.00819 91346 748 90972 2121489 23.2 60 0.00838 90598 759 90219 2030517 22.4 61 0.00950 89839 853 89413 1940298 21.6
139 Chapter 6
62 0.01143 88986 1017 88477 1850885 20.8 63 0.01046 87969 920 87509 1762408 20.0 64 0.01118 87048 973 86562 1674899 19.2 65 0.01367 86075 1176 85487 1588338 18.5 66 0.01397 84899 1186 84306 1502851 17.7 67 0.01640 83713 1373 83026 1418545 16.9 68 0.01684 82340 1386 81647 1335519 16.2 69 0.01744 80954 1412 80248 1253872 15.5 70 0.01927 79542 1533 78776 1173624 14.8 71 0.02036 78009 1588 77215 1094849 14.0 72 0.02462 76421 1881 75480 1017634 13.3 73 0.02594 74539 1933 73573 942154 12.6 74 0.02949 72606 2141 71536 868581 12.0 75 0.03377 70465 2380 69275 797045 11.3 76 0.03667 68085 2497 66837 727770 10.7 77 0.03732 65588 2448 64365 660933 10.1 78 0.04574 63141 2888 61697 596568 9.4 79 0.04973 60253 2996 58755 534872 8.9 80 0.05814 57257 3329 55592 476117 8.3
140
ANNEX 6.1
Some details on Cost effectiveness of tick borne encephalitis vaccination in Slovenian adults
Renata Šmit
Based on Vaccine 2013;31(23):2602
141
142 Some details on Cost effectiveness of tick borne encephalitis vaccination in Slovenian adults
Triggered by specific comments [1], Annex 6.1 provides some more details on my original study “Cost effectiveness of tick borne encephalitis vaccination in Slovenian adults” [2]. The values of QALYs and costs are calculated accordance to the Markov model by using the formula for discounting
1 + and the time dependent values can be used as follows:
− _ (1)
− + (2) where the startAge was 18 and in accordance with the proposed methodology [3] formula (2) was used. If formula (1) is used, the expected QALYs are approximately 19 years, if formula (2) is used, the expected QALYs are 7.953 years. Taking into account the 5% discount rate, the “present values” are automatically moved and set at the age of 0 years. Additionally, the half cycle correction [4] reduces these values to half of the values (of QALYs and costs) at 18 years and the values further decrease from the age of 0 to the age of 18. This explains why the input costs at 0 years are €33 and €13.71 by the age of 18, which of course influences the total outcome of €49.10 for the costs from 18 to 80 years of age. Life expectancy (LE) is an indicator of how long a person can expect to live on average, given prevailing mortality rates [5], and can be calculated from life tables while the calculation of QALYs should include the product of the utilities [6]. Seeing that these utilities are included in Table 1 (see Ref. [2]), the approximately 19 years for the QALYs as mentioned by Kos and Locatelli [1] could not have been evaluated only from the supplementary material file (Table 4, included in Ref. [2]), but must have included the utilities mentioned in Table 1 as well (see Ref. [2]). The same explanations are valid for the vaccine Encepur®.
143 Annex 6.1
The incremental cost effectiveness ratio (ICER = incremental cost per QALY gained) values of €15,128 per QALY gained for FSME Immun® and €20,099 per QALY gained for Encepur® from the standpoint of the health care payer are in accordance with the above explanations.
References 1. Kos M, Locatelli I. Limitations of the study “Cost effectiveness of tickborne encephalitis vaccination in Slovenian adults”. Vaccine 2013;31(23): 2601. 2. Šmit R. Cost effectiveness of tick borne encephalitis vaccination in Slovenian adults. Vaccine 2012;30(44):6301–6. 3. Muennig P, Franks P, Gold M. The cost effectiveness of health insurance. Am J Prev Med 2005;28(1):59–64. 4. Sonnenberg FA, Beck JR. Markov models in medical decision making: a practical guide. Med Decis Making 1993;13(4):322–38. 5. Australian Institute of Health and Welfare (AIHW). Life expectancy. Available from: http://www.aihw.gov.au/life expectancy/ [accessed 30.01.2013]. 6. Naglie G, Krahn MD, Naimark D, Redelmeier DA, Detsky AS. Primer on medical decision analysis. Part 3. Estimating probabilities and utilities. Med Decis Making 1997;17:136–41.
Abbreviation: QALY(s), quality adjusted life year(s).
144
ANNEX 6.2
Further details on Cost effectiveness of tick borne encephalitis vaccination in Slovenian adults
Renata Šmit
Based on Vaccine 2014; 32(11):1227 8
145
146 Further details on Cost effectiveness of tick borne encephalitis vaccination in Slovenian adults
Annex 6.2 provides some further details on the model and formulas used in my original study [1]. Also, it provides the platform to exhibit some policy impact of the original paper so far. Below, I start off with the latter aspect, before switching to details of the model.
Policy Impact Based on the original article [1] as well as its model, the County Council of Sornland in Sweden decided about vaccination against tick borne encephalitis (TBE) [2]. The abstract of the original article [1] was also included in their protocol. The results of the original article [1] were acknowledged by the Central European Vaccination Awareness Group [3] as well as by Italian researchers [4] and positively accepted at a congress in China [5]. The purpose of the original article [1] was to evaluate the incremental cost effectiveness ratio (ICER) for TBE in Slovenian adults. An elaborate explanation follows.
Modelling & Formulas used Markov modelling basics Markov models, named after the Russian mathematician Andrey Andreyevich Markov (1856–1922), are used widespread in different scientific disciplines [6]. According to Sonnenberg and Beck [7] the use of the Markov models for determining prognosis in medical application was described by Pauker and Beck in 1983. The basis for the original article [1] was this Markov model and the data in Table 1 of the original article [1] were fed into the TreeAge Pro2011. The window used for the calculations in the model was from the age of 18 to 80 years. A Markov cycle of 1 year was chosen. The assumption was made that all subjects start in the susceptible (well) state. The initial probability of 1 (100% of the cohort began at the susceptible state) below the branch of this state was assigned and was used by TreeAge Pro 2011 only once during the Markov process, to determine where the individuals should spend the first cycle ( stage = 0) of the process. Below the branch of the following state (mild sequelae, moderate sequelae, severe sequelae, death due to TBE, recovered and immune) the initial probability of 0 was entered. All costs and quality weights at the stage = 0 were equal to the susceptible (well) state since the entire cohort started the cycle in this state. Patients moved through health states based on annual transition probabilities. During each cycle, patients who do not die due to other causes, develop
147 Annex 6.2
TBE, which may lead to either permanent neurological sequelae, or recovery or death due to TBE. Costs and quality weights were assigned to the specific health state.
Half cycle correction Counting the number of subjects only at the beginning or at the end of the cycle will lead to errors [7]. In reality transitions in a state occur continuously throughout each cycle, therefore the assumption is made that state transitions occur on average, halfway through each cycle [7]. In the original article [1] this half cycle correction in the model was used. The under and overestimations were thereby balanced.
Formulae In the original article [1] the time dependent value
Age−f( stage+startAge) was included in the formula for discounting
1 +
as the potency, i.e. where: cost = input costs for the specific health state (included in Table 1 [1]) utility = quality weights for each health state (included in Table 1 [1]) rate = 5% discount rate for costs and utilities (included in Table 1 [1]) stage = cycle counter starting with zero startAge = 18 This methodology was proposed by Muennig et al. [8].
148 Further details on Cost effectiveness of tick borne encephalitis vaccination in Slovenian adults
Expected quality adjusted life years (QALYs) or effectiveness related to the above formulae
Table 1. The expected QALYs per person vaccinated with FSME Immun® from the view of the health care payer for two age groups.
Outcome Age group 18 80 Age group 1 80 aExpected QALYs per person 7.953 18.8
QALYs outcomes discounted at 5%. Half cycle correction is applied. a The total effectiveness accumulated over all cycles.
Age as time dependent value, indicates that the expected QALYs for the age group of 18–80 are 7.953 years and 18.8 for the group of 1–80. It shows that there is a difference in the QALYs between the age groups of 18–80 and 1–80 what means that Age as time dependent value shows the impact of TBE better. That is because children who have TBE but no permanent neurological sequelae are included in the age group of 1–80.
Perspective of a newborn child The perspective of a newborn child for TBE regarding vaccination and the number of reported cases are also included in reports of the Institute of Public Health of the Republic of Slovenia [9,10]. TBE affects people of all ages and the severity of the disease increases with age [3]. Although there is a continuous debate about the use of discount rates in general [11] the 5% discount rate was used. This discount rate moved the “present values” to the age of 0 years. However that does not imply that the model runs from a newborn child perspective.
The first year of vaccination (stage = 0) related to the above formulae
Table 2. Costs during the first year of vaccination ( stage = 0) for adults when vaccinated with FSME Immun® from the view of the health care payer.
Outcome Age group 18 80 aCosts ( €) at the _stage = 0 13.71
a The first year of vaccination = stage = 0 at the age of 18.
149 Annex 6.2
During the first year of vaccination at the stage = 0 the probability is 1 only for the susceptible (well) state, and the costs are D 13.71 with the half cycle correction and 5% discount rate and with the Age as time dependent value. The first year of vaccination ( stage = 0) is at the age of 18 and applies to healthy persons who are vaccinated with 3 doses of the vaccine FSME Immun®. These people do not have any sequelae and therefore no other costs are included (Table 2). The same reasoning is valid for vaccination with Encepur® [1]. The ICER is the ratio between the costs of vaccination and no vaccination divided by the difference in QALYs produced by vaccination and no vaccination. The ICER is the same regardless of the intermediate results because the slope of the line that connects vaccination and no vaccination remains the same. Taking all the above scientific explanations as well as the international acceptance of the original article [1] into account, it is proved that the methodology and outcomes of the original article [1] are correct and rest on firm scientific arguments.
References 1. Šmit R. Cost effectiveness of tick borne encephalitis vaccination in Slovenian adults. Vaccine 2012;30(44):6301–6. 2. Ola Engman K, Kallings Larsson C, Feldman I, Available from: http://www. landstingetsormland.se/PageFiles/37448/(9)%20H%C3%A4lsoekonomisk% 20analys%20av%20allm%C3%A4n%20TBE vaccinering%20av%20inv%C3% A5narna%20i%20S%C3%B6rmland.pdf [accessed 18.08.13] Halsoekonomisk analys av allman TBE vaccinering av inv ˙anarna I Sormland; 2013. 3. Zavadska D, Anca I, Andre F, Bakir M, Chlibek R, Čižman M, et al. Recommendations for tick borne encephalitis vaccination from the Central European Vaccination Awareness Group (CEVAG). Hum Vaccin Immunother 2013;9(January (2)):362–74. 4. Amicizia D, Domnich A, Panatto D, Luigi Lai P, Luisa Cristina M, Avio U, et al. Epidemiology of tick borne encephalitis (TBE) in Europe and its prevention by available vaccines. Hum Vaccin Immunother 2013;9(February (5)):1163–71. 5. Šmit R. Vaccination against tick borne encephalitis to reduce the burden of the disease in Slovenia. In: Proceedings: BIT’s 3rd Annual World Congress of Microbes 2013. 2013. p. 101. 6. Geisler PB, Available from: http://cdn.intechopen.com/pdfs/14042/InTech Automating first and second order monte carlo simulations for markov models in treeage pro.pdf [accessed 18.08.13] Automating first and second order Monte Carlo simulations for Markov models in TreeAge Pro; 2013.
150 Further details on Cost effectiveness of tick borne encephalitis vaccination in Slovenian adults
7. Sonnenberg FA, Beck JR. Markov models in medical decision making: a practical guide. Med Decis Making 1993;13(4):322–38. 8. Muennig P, Franks P, Gold M. The cost effectiveness of health insurance. Am J Prev Med 2005;28(1):59–64. 9. Institute of Public Health of the Republic of Slovenia, Available from http://www.ivz.si/Mp.aspx?ni=78&pi=6& 6 id=357& 6 PageIndex=0& 6 groupId= 2& 6 newsCategory=IVZ+kategorija& 6 action=ShowNewsFull&pl=78 6.0[accessed 18.08.13] Analysis of the implementation of vaccination in Slovenia;2013. 10. Institute of Public Health of the Republic of Slovenia, Available from http://www.ivz.si/Mp.aspx?ni=78&pi=6& 6 id=788& 6 PageIndex=0& 6 groupId= 2& 6 newsCategory=IVZ+kategorija& 6 action=ShowNewsFull&pl=78 6.0 [accessed 18.08.13] Epidemiological surveillance of communicable diseases in Slovenia; 2013. 11. Bos JM, Postma MJ, Annemans L. Discounting health effects in pharmacoeconomic evaluations: current controversies. Pharmacoeconomics 2005;23(7):639–49.
151 Annex 6.2
152
CHAPTER 7
Discussion and Conclusions
153
154 Discussion and Conclusions
Discussion TBDs are a global public health concern. In Chapter 3, it has been discussed that TBE endemic belt extends from Alsace Lorraine and Scandinavia to the North Eastern parts of China and Northern Japan, however endemic areas are further expanding to new and nonendemic areas. Comparing the number of TBE reported cases between 1976 and 1989 with those in period from 1990 to 2007, increases in TBE reported cases over 300% in Europe, including Russia, is seen. Comparing the number of TBE reported cases between 1991 and 2000 with those between 2001 and 2010, increases in TBE reported cases in Sweden, Finland and Norway by approximately 100% is seen and in the Czech Republic, Germany, Switerland and Poland by approximately 144%. TBE reported cases decreased by 65% in Estonia, Latvia, Lithuania while in Russia by 42%. In period from 2005 to 2009, countries with the highest national incidence of TBE reported cases per 100,000 population are Slovenia (14.07), Estonia (11,10), Lithuania (10,59), Latvia (8,76). Russia has areas with high TBE incidence in terms of reported cases but there are also nonendemic areas (Chapter 3). At the European level, TBE presents a high burden that is not fully recognized. It is believed that the incidence of the TBE is under estimated likely due to under diagnosis. Safe, efficient, and well tolerated TBE vaccines are available, however, they are likely underused to efficiently reduce the TBE burden (Chapter 3). Western European vaccines are used for all persons aged ≥1 years. The primary series with both vaccines consists of three doses. The second dose should be given 1 3 months after the first dose and the third dose 5 12 months after the second (for Encepur® the third dose is administered 9 12 months after the second dose). ʿAccelerate ʾ or ʿrapid ʾ schedules for both vaccines can be used mainly for travellers and military forces. The second dose beeing given 14 days after the first dose and the third dose 5 12 months after the second (for Encepur® 9 12 months after the second) for ʿaccelerate ʾ protection. ʿRapid ʾ schedule requires the second dose being given 7 days after the first, the third dose after 21 days and the fourth dose after the third dose for Encepur®. The first booster dose with Western European vaccines is recommended 3 years after the primary series and subsequent boosters at intervals of 3 5 years. In persons aged ≥50 years, 3 year booster intervals are recommended, while application with FSME Immun® for persons aged ≥60 years, booster intervals of 5 years are recommended. In Switzerland intervals of ≤10 years are used (Chapter 3). Russian vaccines are used for persons aged ≥3 years. The primary series of vaccination with Russian vaccines
155 Chapter 7 consists of three doses. The second dose should be given 1–7 months (for Encevir® 5 7 months) after the first dose and the third dose 12 months after the second. ʿRapid ʾ schedule with Encevir® requires the second double dose being given 1 2 months after the first dose, the third double dose 1 3 months after the second double dose, and the fourth dose 6 12 months after the third double dose. The first booster with Russian vaccines is given 3 years after the primary series of vaccination and subsequent boosters are recommended subsequently every three years (Chapter 3). Efficacy of all TBE vaccines is based on induction of neutralizing antibodies. After three doses, all TBE vaccines suggest protection in 90 100% of vaccinated. Very low rate of waning of protection after the booster following three doses of vaccination with both Western European vaccines is shown. It was shown that after booster dose protection against TBE persists for at least 6 8 years. After 8 years after booster, the protection against TBE with seroprotection rate of 87% was shown. The field effectiveness of both Western European vaccines is about 99% in regularly vaccinated persons for all age groups. All TBE vaccines are safe, potential side effects of TBE vaccines are common (Chapter 3). Factors such as vaccination schedule in terms of number of doses and timing of doses, duration of protection all have impact on result of cost effectiveness analysis. In the case of vaccination against TBE, extended vaccination interval can improve compliance as well it reduces costs of TBE vaccination programme, leading in more favourable cost effectiveness ratio (Chapter 3). Studies on cost effectiveness of TBE vaccines can help make decision on inclusion/or expansion of the vaccination into the national vaccination programme to increase vaccination to reduce disease burden. Therefore, more attention directed towards cost effectiveness evaluations that can help to establish an efficient prevention policy to reduce TBE burden at the European level is needed (Chapter 3). In Chapter 6, the first study on cost effectiveness of vaccination against TBE was performed, using a Markov model. This study was conducted for Slovenia, one of the countries with the highest TBE incidence worldwide and low vaccination coverage. The results of Chapter 6 show that the ICER for vaccination with both Western European vaccines amounts to about €15,000 20,000 per QALY gained for adults from the view of healthcare payer. The results of PSA using CEAC indicate that at WTP value of €20,000 per QALY gained, a vaccination with both vaccines has a 99.3 97.7% probability of being cost effective for adults from the view of healthcare payer. Based on Slovenian threshold of €30,000 per QALY gained, vaccination
156 Discussion and Conclusions against TBE is cost effective from the healthcare payer’s perspective. From the view of society, vaccination saves costs, mainly due to avoiding the high indirect costs that include the costs due to absence from work. In Chapter 6, a novel Markov model for evaluating cost effectiveness of TBE vaccination was developed. The model compared costs and health outcomes in vaccinated and no vaccinated groups from 18 to 80 years of age. The susceptible, mild, moderate and severe permanent neurological sequelae, death due to TBE, recovered and immune are health states that were included in the model (Chapter 6). Each health state was assigned costs and quality weights, both discounted at a 5% annual rate (Chapter 4). Costs and quality weights of the second stage (i.e. hospitalization) were used as prior for starting the Markov process (Chapter 6). A Markov cycle length of one year was used and patients moved through these health states based on annual transition probabilities (Chapter 6). Annexes to Chapter 6 provide details on the model. In Chapter 6, it has been discussed that the limitation of the study on cost effectiveness of TBE vaccination is that the study was focused only on the adult population. Severity of the disease increases with age and the elderly are very active and mobile, putting them at higher risk for contracting the disease. Although Čižman et al. found severe TBE in children that required treatment in an intensive care unit, it was stated in 2003 that TBE in children is mild with favourable health outcomes. Therefore, children were not included in this study. Next, under estimation of TBE reported cases were not included in cost effectiveness analysis. If a factor of 4.5 to correct under estimation of TBE reported cases from Chapter 5 were used in cost effectiveness analysis, vaccination against TBE would be even more cost effective. Next, the first stage of the disease with symptoms of headache, fever, and vomiting was not taken into account, because people often mistake these symptoms with flu and mostly they do not even visit a GP. In addition, an abortive form of TBE is not included in the study because it likely does not exist in Slovenia. Lastly, adverse effects due to vaccination were not taken into account because no serious or life threatening adverse events were reported. Previously, only cost benefit of vaccination against TBE among French troops, using a decision tree was published in 2005 (Chapter 3), showing that the TBE vaccination programme for French troops should not be implemented, because the net benefit is negative. The Markov model and the methodology as done in Chapter 6
157 Chapter 7 are an innovative approach for evaluating cost effectiveness of TBE vaccines. This study (Chapter 6) made a breakthrough in the field of health economics of TBE, in particular in cost effectiveness of vaccination. The importance and recognition of the study (Chapter 6) can be seen considering its impact first, in Sweden in Sörmland County, where the County Council used the same Markov model in cost effectiveness analysis for a decision about TBE vaccination. Next, in Finland, the study on cost effectiveness, using the Markov model was performed and Tick borne encephalitis vaccination working group made a recommendation about vaccination against TBE. Following, in Estonia, the study on cost effectiveness of TBE vaccination, using also the Markov model, was performed (Chapter 2). Next to the study on cost effectiveness of TBE vaccination (Chapter 6), TBE burden in DALYs, including correction for under estimation of TBE reported cases and correction for under reporting of death due to TBE were applied for the first time in TBE DALYs calculations (Chapter 5). Therefore, the full TBE burden is estimated for the first time (Chapter 5) This study was also performed for Slovenia. The result of Chapter 5 indicates that the number of TBE cases with the acute disease of the second stage with CNS is 4.5 times higher than official reported cases. TBE burden expressed in DALYs is high compared with estimates for other infectious diseases from GBD 2010 study for Slovenia. Chapter 5 shows that from the population perspective, total DALYs amount to 3,450 (167.8 per 100,000 population), while from the individual perspective they amount to 3.1 per case in 2011. Results of the PSA show a 95% uncertainty interval from 2,394 to 5,774 DALYs, indicating that for example with 0.95 likelihood total DALYs are higher than 2,394 while with 0.9 likelihood total DALYs are higher than 2,631. Next, DALYs give a composite assessment of TBE's burden, seeing that TBE burden is dominated by neurological sequelae. In Chapter 5, a novel disease burden model was developed for the DALYs calculations. Death due to TBE, the acute disease of the second stage with CNS and mild, moderate and severe permanent neurological sequelae were health states that were included in this model. The acute disease of the second stage was corrected for under estimation by a factor γ that is a product of a factor β a to correct for under ascertainment and a factor β r to correct for under reporting. Death due to TBE was corrected for under reporting by a factor β d. No discounting or age weighting was applied in the DALYs calculations.
158 Discussion and Conclusions
In Chapter 5 it has been discussed that disability weights for TBE do not exist because both correction factors β d and βr were not available for Slovenia. Only cases with the acute disease of the second stage and death due to TBE are routinely reported in Slovenia. However, cases with asymptomatic infection and symptomatic cases including acute disease of the first stage are not captured by notification or surveillance systems in Slovenia nor by correction factors, causing potential under estimation of TBE DALYs’ estimate. Therefore, the TBE DALYs estimation in Chapter 5 represents an under estimate. From previous studies, it has been seen that the burden of TBE was expressed only by incidence or mortality data (Chapter 3). In Chapter 5, TBE burden in DALYs, including correction for TBE under estimation was evaluated for the first time. This study presents a novelty in the field of TBE health economics. The disease burden model, calculation of correction factors for TBE and their application as done in Chapter 5 reflect an innovative approach in DALYs calculations. Factor of 4.5 to correct under estimation (Chapter 5) could be reasonable for the wider region. The burden of TBE has not been specified by the Global Burden of Disease studies. Therefore, results of Chapter 5 give novel knowledge in that respect and provide unique insight into the disease burden. The unique model and methodology as done in Chapter 5 could be used as a representative model for TBE DALYs’ calculations for other countries. The study presented in Chapter 5 could help to guide public health policy and action in Europe to reduce TBE burden. In addition, it provides suggestion globally for potential inclusion of TBE into the Global Burden of Disease studies. Based on findings of Chapter 5, it may be suggested that there is a need to prioritise diseases and reallocate limited public health resources for an extended vaccination against TBE for whole population of all ages and all regions, potentially free of charge or at a reduced price in Slovenia. In Austria, it has been shown that extended TBE vaccination leads to substantial reductions in TBE in all age groups and therefore it can contribute to health and economic benefits. TBE is the most important flavivirus infection of the central nervous system in Europe, while LB is the most commonly reported TBDs worldwide (Chapter 2). In Chapter 4, it has been discussed that LB is endemic in many part of Europe, Asia and North America, however its endemic areas are expanding. The European Centre for Disease Prevention and Control indicates that all persons who are exposed to risk of
159 Chapter 7 being bitten by a tick are at risk of becoming infected with B. burgdorferi [1]. In the USA, the number of reported cases of LB has increased from 10,000 cases in 1992 to about 30,000 in 2009 [2]. New estimates show that about 300,000 cases are reported annually, meaning by 10 times more than previous thoughts (Chapter 4). In many European countries, the number of reported cases of LB has increased since 1990 (Chapter 4). For example in Slovenia, the number of reported cases of LB has increased from 4,123 cases in 2005 to 6,938 cases in 2013 [3]. In Denmark, the number of cases of neuroborreliosis has increased from 41 cases in 2002 to 104 cases in 2006. In 2009, 61 cases have been reported in Denmark. In Norway, the number of reported cases of disseminated and late borreliossis has increased from 75 cases in 1995 to 273 cases in 2009 (EpiNorthData, 2011) [2]. The incidence of LB is likely under estimated, mainly due to under diagnosis. LB is a multi system bacterial infection. A red colored skin rash called erythema mygrans that characterizes an early Lyme disease is not always present or recognized by patients, thus patients or their doctors may not be aware of being sick from LB. Therefore, many of patients may have gone undiagnosed for many years, which may lead to long term sequelae and patients’ disability. These patients can be unable to return to their jobs. Vaccination could be the most effective protection against LB infection, it can thereby avoid the complications associated with progressive LB disease (Chapter 4). Vaccination against LB can be beneficial to all persons of all ages exposed to risk of being bitten by a tick being at risk of becoming infected with B. burgdorferi. A major obstacle to developing LB vaccines is antigenic variation of the LB spirochetes, along with differences between LB strains in Europe and the USA. Several borrelia outer membrane proteins have been evaluated as potential LB vaccine candidates such as OspA, OspC, OspB, DbpA, BBK32, RevA. OspA borrelia outer membrane protein is the most investigated protein and therefore a promising vaccine candidate against LB (Chapter 4). In 1990, two monovalent recombinant OspA vaccines against LB were developed only for use in the USA. Mechanism of action of OspA vaccines in producing antibodies that bind B. burfdorferi in the tick gut, block transmission of spirochetes to the human, and consequently prevent borrelia infection in tick. In 1998, a monovalent recombinant adjuvanted OspA vaccine was licensed for adults. Phase III safety and efficacy trial demonstrated that this vaccine reduced new infections in vaccinated by 76% after three doses, meaning that 24% of fully vaccinated adults could still get sick from Lyme disease. No significant adverse events
160 Discussion and Conclusions were reported. Despite promising outcomes from clinical trials with both vaccines, in 2002, the manufacturer voluntarily withdrew the monovalent adjuvant OspA vaccine, because it was unjustly considered that this vaccine might cause arthritis. The second monovalent non adjuvant OspA vaccine, showing good safety profile, and efficacy of 92% after three doses, was never applied for license. Currently, human vaccine against LB is not available. However, huge efforts are orientated towards development of novel, improved vaccines against LB (Chapter 4). For example, vaccines against LB based on multivalent OspA are in the clinical phase of development. Phase I and II demonstrated that this vaccine is safe, well tolerable, and highly immunogenic. After three doses, 91 100% of vaccinated achieve antibody response for protection against LB. These potential novel vaccines could effectively protect individuals against LB globally (Chapter 4). Efficacious of OspA vaccines is depended upon anti OspA antibodies titres. Repeated doses of OspA vaccines for long term protection are needed. However, the duration of protection with OspA vaccines is not known yet (Chapter 4). There is a need for novel approaches to making LB vaccines more effective. For example, multiple borrelia outer membrane proteins, tick proteins or a combination of borrelia and tick (saliva) proteins could be potential vaccine candidates for development an effective Lyme vaccine (Chapter 4). These appeoaches might not only prevent LB, but also could prevent transmission of arthropod borne pathogens in general [4]. Vaccines, combining multiple Borrelia antigents, showed higher efficacy compared to vaccination based on single or double proteins, in mice [4]. Potential anti tick vaccine based on tick salivary gland proteins obtained from Ixodes ricinus could inhibit feeding and transmission of multiple pathogens (bacteria, virus protozoa) [5]. Studies in mice showed that potential anti tick vaccine could prevent multiple European TBDs such as LB, TBE, babesiosis. This vaccine would prevent transmission of pathogens to humans, animals or wildlife to reduce the incidence of TBDs in humans. Therefore, potential anti tick vaccine would be highly cost effective public health intervention [5]. Three studies on cost effectiveness of vaccination with the monovalent adjuvant OspA vaccine against LB have been done only for the USA in the period between 1999 and 2002. Methodologically, in one study a decision tree and in the other two a Markov model was used (Chapter 4). Results of these studies indicate favourable cost effectiveness for LB vaccination (Chapter 4).
161 Chapter 7
Human vaccine against LB has never been developed for application in Europe. However, potential novel multivalent OspA vaccine manufactured by Baxter to protect individuals against LB in the USA, Europe and Asia has completed the I and II phase of clinical development. This potential novel, improved vaccine likely has not yet entered into the III phase of clinical development (ClinicalTrial.gov). Therefore, studies on cost effectiveness of vaccination against LB have not yet been performed for Europe (Chapter 4). Further study on cost effectiveness of vaccination with the potential novel vaccine against LB, using a Markov model developed based on the natural course of the disease could be performed. It is expected that vaccination with the novel vaccine could be cost effective from the societal view mainly due to long term consequences, high socioeconomic costs and lost productivity costs. Therefore, vaccination against LB could be health and economically beneficial to society. TBDs are infectious diseases in which pathogen (virus, bacterium, protozoa, fungi) transmits from a vertebrate host like birds, rodents, or other larger animals to a person during tick feeding (Chapter 1). Therefore, dynamic transmission model for TBE and LB could be developed, considering vertebrate host tick pathogen human interaction. The simple dynamic transmission model for TBE and LB should consider tick pathogen human interaction, consisting of compartments that represent human population and compartments that represent tick population, taking into account transmission of pathogen from an infected tick to potentially susceptible human. In the model, effects of vaccination and increasing vaccination coverage over the time can be incorporated to explore the impact on transmission and disease burden. This potential model could help to understand transmission of pathogen for control of the disease and to evaluate cost effectiveness of vaccination. Widespread use of vaccines against TBE or LB could prevent transmission and thus result in a degree of herd immunity, may lead to more favourable cost effectiveness ratios. Intensive interactions between human, animals and ecosystem are likely the driving force for increasing TBDs burdens worldwide. TBDs burdens are not fully known. Improved diagnosis and surveillance of diseases could provide better overall epidemiological picture and true TBDs burdens. Human population, wildlife and domestic animals as well as tick populations are increasing, people are travelling, global environmental changes allow pathogens to adapt to new environment.
162 Discussion and Conclusions
Pathogens and ticks are spreading to new areas and expanding globally. TBDs’s global spread has the potential to impair public health systems [2]. My thesis promotes the importance of TBDs on public health. Effectively transfer information, new insight, and knowledge presented in this thesis to endemic and non endemic countries and spread internationally with the aim for effective prevention and control of diseases could be relevant. Currently, only TBE vaccination is available which is likely underused but if properly implemented in countries to reach a sufficiently high coverage of having the potential for favourable (cost )effectiveness of vaccination to reduce transmission would leading to reduction of TBE’ burden, and improving population health.
Conclusions TBDs reflect an increasing burden and public health threat worldwide. Vaccination could be the most effective intervention to protect individuals of all ages against TBDs. In the USA, no vaccines against TBDs exist. Vaccines against TBE are available, however they are likely underused in Europe. Vaccines against LB are still in the phase of development. Cost effectiveness of TBE vaccination applying the Markov model show favourable cost effectivenes of vaccination. DALYs provide comprehensive insight into the disease burden. Therefore, more efficient vaccination policy and recommendations for prevention and control of TBE has to be considered on European level that can help to increase vaccination and to reduce TBE. Increasing awareness and knowledge of what causes TBDs and their consequences in endemic as well as nonendemic countries among general population, children and their parents, travellers, healthcare practitioners, professionals working outdoors and their employers through educational programmes, social media and prevention campaigns are needed. In addition, increasing awareness regarding preventive measures against TBDs and their implementation is essential in reducing TBDs. More research funding related to TBDs is needed, and continued efforts especially in development of safe, efficient vaccines for LB and other TBDs to prevent these diseases and their disabling consequences are also needed. Also health economics research for TBDs, in particular for TBE and LB are urgently needed that can help to establish more efficient policy for prevention and control of these diseases to reduce the diseases’ burden, leading to health benefits for the population as a whole.
163 Chapter 7
References 1. European Centre for Disease Prevention and Control (ECDC). Factsheet for health professionals. Available from www.ecdc.europa.eu/ [Accessed: June 2016] 2. Institute of Medicine (IOM). 2011. Critical needs and gaps in understanding prevention, amelioration, and resolution of Lyme and other tick borne diseases: the short term and long term outcomes. Washington (DC): The National Academies Press. Available from: www.iom.edu/ [Accessed: August 2015] 3. Nacionalni inštitut za javno zdravje (NIJZ). Epidemiološko spremljanje nalezljivih bolezni v Sloveniji. www.nijz.si/ [Accessed: June 2016] 4. Schuijt TJ, Hovius JW, van der Poll T, van Dam AP, Fikrig E. Lyme borreliosis vaccination: the facts, the challenge, the future. Trend Parasitol 2011 Jan;27(1):40 7. 5. Sprong H, Trentelman J, Seemann I, et al. ANTIDotE: anti tick vaccines to prevent tick borne diseases in Europe. Parasit Vectors 2014;21:7–77.
164
SUMMARY
Worldwide, tick borne diseases (TBDs) reflect an increasing burden and public health threat. Reducing TBDs’ burden is a grand public health challenge. The aim of this doctoral thesis is to evaluate health economics of TBDs, with focus on tick borne encephalitis (TBE) and Lyme borreliosis (LB), and to evaluate their impact on public health. In particular, I aim to develop models based on the natural course of these diseases for assessing the costs and health outcomes and cost effectiveness of vaccination. Currently, scarcity of health economics studies presents an important knowledge gap in the field of TBE and LB. This thesis adds novel insights and makes an important contribution to the field of health economics and cost effectiveness evaluations of TBE and LB. Findings presented in this thesis can help to develop better guidance for more efficient prevention and control of these diseases, travel recommendations, occupational health policies, likely leading to reduction of diseases’ burdens, and improving population health. With Chapter 1 presenting above introductory issues, Chapter 2 provides an overview of TBDs, focus on vaccines and cost effectiveness of vaccination, being based on one of the published papers in Expert Reviews of Vaccines (Chapters 3 and 4 being the others). Chapter 3 provides an overview of TBE. TBE presents a high burden in Europe. Vaccines against TBE, that are generally well tolerated, effective and safe, are likely under used and therefore lack to efficiently prevent and control the disease and reduce its burden at population levels. The first study on the cost effectiveness of TBE vaccination was performed for Slovenia, a high endemic country (Chapter 6). We argue that more attention needs to be oriented towards health economics for TBE at the European level. This can help to formulate efficient policies for prevention of TBE, increase vaccination coverage and thus reduce TBE in Europe. Rising awareness about TBE and the benefits of vaccination in endemic as well as non endemic countries within the general population is needed. Chapter 4 provides an overview of LB. LB is a multi system disease with an increasing burden worldwide. Early and appropriate antibiotics therapy is crucial to prevent persistent infection that may be followed by post treatment Lyme disease syndrome. Currently, there is no human LB vaccine available. However, in Europe
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huge efforts are oriented towards development of novel LB vaccines, aiming to improve on the previous generation that never became successful. The potential novel multivalent OspA vaccine candidates are already in the clinical phase of development for prevention against LB globally. Anti tick vaccines based on tick proteins for prevention against multiple TBDs, including LB, could be a highly cost effective public intervention in Europe. Continued efforts in research of all aspects on LB are needed In Chapter 5 the burden of TBE expressed in DALYs was estimated for the first time, using a disease burden model. This novel model was developed based on the natural course of the disease. Corrections for under estimation were included in the DALYs calculations to show the full burden of TBE. The findings of Chapter 5 indicate that TBE in Slovenia presents relatively high burdens of disease in comparison with other infectious diseases in Slovenia. The potential strategies to reduce this burden were discussed in Chapter 5 as well. In Chapter 6, the first study on cost effectiveness of vaccination against TBE was performed, using a Markov model. This novel Markov model was developed based on the natural course of the disease. The findings of Chapter 6 indicate that vaccination against TBE is cost effective for adults from the health care payer's perspective in Slovenia. From the view of society, vaccination saves costs. Annexes to Chapter 6 provide details of the model. Notably, the model has subsequently been used in other settings. Chapter 7 summarizes principal findings of this thesis, outlines appraisal of methods, compares methodology and findings with previous work, presents the thesis its original contributions to the scientific knowledge and its implications and provides a framework for further research. Finally, conclusions of this thesis are provided.
166
SAMENVATTING
Teken gerelateerde ziekten (TGZn) presenteren tegenwoordig wereldwijd een toenemend probleem. Reductie van TGZn is een enorme uitdaging voor de volksgezondheid. Doelen van dit proefschrift betreffen de evaluatie van de gezondheidseconomische aspecten van TGZn, met een focus op encephalitis en Lyme borreliosis (LB), en beschouwing van de impact op de volksgezondheid. In het bijzonder, beoog ik modellen te ontwikkelen voor de progressie van ziekte, te koppelen aan kosten, gezondheidsverlies en kosten effectiviteit van (potentiële) vaccins. De huidige schaarste aan gezondheidseconomische studies is een belangrijke leemte in onze kennis en dit proefschrift draagt bij deze leemte deels op te vullen met nieuwe inzichten in de “health economics” en kosten effectiviteit bij de preventie van encephalitis en LB. Bevindingen kunnen helpen richting te geven aan meer efficiënte en doelgerichte preventie en controle van TGZ, reisadviezen en bedrijfsgezondheid, mogelijk resulterend in reductie van ziekte en verder verbeteren van de volksgezondheid. Nadat Hoofdstuk 1 bovenstaande inleidende zaken bespreekt, geeft Hoofdstuk 2 een overzicht van TGZ, beschikbare en te ontwikkelen vaccins en kosten effectiviteit gebaseerd op één van de onderliggende publicaties in Expert Reviews of Vaccines (Hoofdstuk 3 en 4 zijn de anderen). Hoofdstuk gaat in op de details van de TGZ encephalitis (TGE), onderhand een groot probleem in Europe. Vaccins tegen encephalitis zijn goed verdraagbaar, effectief en veilig en het gebruik is veel lager dan optimaal en mogelijk. Daardoor worden kansen op goede preventie en controle van ziekte gemist. De eerste studie inzake de kosten effectiviteit van TGE vaccinatie werd op Slovenië gericht, een hoog endemisch land (Hoofdstuk 6). Wij betogen dat er meer aandacht nodig is voor “health economics” van TGE op Europees niveau. Hierdoor zou meer efficiënt preventiebeleid ontwikkeld kunnen worden, inclusief verhoging van de dekkingsgraad, resulterend in gezondheidswinst voor de bevolking. Toenemende “awareness” over TGE en de waarde van vaccins is nodig, zowel in hoog als laag endemische landen.
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Hoofdstuk 4 geeft een overzicht voor LB. LB is een ‘multi systeem’ ziekte met eveneens een toenemende problematiek wereldwijd. Vroegtijdige en adequate toediening van antibiotica is cruciaal ter preventie van persistente infectie en post therapie Lyme syndroom. Er is nog geen humaan LB vaccin beschikbaar, wel zijn er diverse initiatieven voortbouwend op een eerdere generatie LB vaccins die nooit succesvol werden. De potentieel nieuwe multivalente OspA vaccine kandidaten zijn reeds in de klinische fase van ontwikkeling. Potentiële geïntegreerde anti teken vaccins gebaseerd op teken proteïnes ter bescherming tegen diverse TGZn, inclusief LB, kunnen uiterst kosten effectief zijn in Europa. Voortdurende inspanningen een dergelijk vaccin te ontwikkelen zijn vereist. In Hoofdstuk 5 werd de ziektelast van TGE in Slovenië geschat en uitgedrukt in DALYs op basis van een expliciet ziektelast model. Correcties warden uitgevoerd voor onder rapportage om de volledige impact van TGE te vangen. De bevindingen van Hoofdstuk 5 suggereren dat TGE in Slovenië een forse ziektelast veroorzaakt, ook in vergelijking met andere infectieziekten. Mogelijke strategieën om de ziektelast in DALYs te verlagen warden eveneens in dit hoofdstuk besproken. In Hoofdstuk 6 werd de eerste studie naar de kosten effectiviteit van vaccinatie tegen TGE gepresenteerd, gebruik makend van een innovatief Markov model voor de ziekteprogressie. De bevindingen van dit hoofdstuk suggereren dat TGE kosten effectief is voor volwassenen in Slovenië vanuit het gezondheidszorg perspectief. Vanuit maatschappelijk perspectief is vaccinatie zelfs kostenbesparend. Annexes bij dit hoofdstuk geven verdere details van het model. Opvallend is dat hetzelfde model later in andere “settings” en landen eveneens gebruikt is. Hoofdstuk 7 vat de belangrijkste bevindingen van het proefschrift samen, weegt de gebruikte methoden, vergelijkt de methodologie met werk van anderen en geeft aan hoe dit proefschrift bijdraagt aan de ontwikkeling van wetenschappelijke kennis in dit specifieke gebied. Tenslotte, worden de conclusies en verder werk voor de toekomst uitgelegd.
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BIBLIOGRAPHY
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169
ACKNOWLDGEMENTS
My passion for my research gave me the strength to overcome all challenges encountered over a six year period working on my PhD project on tick borne diseases.
My gratitude goes to my first supervisor Prof. Marteen J Postma for his precious support of my PhD study.
Dear Professor Postma, No words can describe the happiness I felt when you accepted to supervise my PhD project, which has resulted in this unique PhD thesis. Thank you for giving me the opportunity to lead as well as to design, develop and realize my ideas and research. Thank you for offering financial support in the form of research/ teaching appointment at the unit of PharmacoTherapy, Epidemiology & Economics of the Groningen Research Institute of Pharmacy (GRIP) to work on an international collaborative project beyond my PhD work.
Dear Professor Poelstra, I am truly grateful that you accepted to be my second supervisor and for the support of my PhD study.
Dear Professor Rudolf, I am sincerely thankful that you make sure that the process of my thesis submission to Hora Finita and my PhD ceremony went smoothly.
My sincere thanks also go to members of my reading committee: Professor Frijlink , Professor Friedrich , and Professor McIntosh, I am grateful for their insightful comments and approval of my thesis.
I am grateful that I trained and educated at the esteemed Research Institute SHARE (Science in Healthy Ageing and healthcaRE) of the University Medical Center Groningen, Faculty of Medical Science, University of Groningen. My sincere thanks
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go to Renate Kroese for support with SHARE related questions and Truus van Ittersum for support with thesis related questions.
I am grateful to be part of the group of exceptional researchers at the Groningen Research Institute of Pharmacy (GRIP). Special thanks go to Jannie Schoonveld for her kindness and for support with administrative issues. I thank my dear colleagues Auliya, Bert, Bianca, Christiaan, Dianna, Didik, Eva, Evgeni, Fabian, Jelena, Job, Jos, Jugo, Jurjen, Koen, Lan, Lusi, Maarten Bijlsma, Marcy, Najmiatul, Neily, Pepijn, Pieter, Thea, Ury, Qi for their friendship, the interesting discussions, as well as for all the fun we have had in Groningen and at the international congresses.
I thank Job van Boven and Pieter de Boer to be my paranymphs and for their support before and during the ceremony.
The most, I would like to thank my beloved mother, father and sister for giving me continuous support and love through all my life.
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RESEARCH INSTITUTE SHARE
This thesis is published within the Research Institute SHARE (Science in Healthy Ageing and healthcaRE) of the University Medical Center Groningen / University of Groningen. Further information regarding the institute and its research can be obtained from our internetsite: http://www.share.umcg.nl/
More recent theses can be found in the list below. ((co ) supervisors are between brackets)
2016
Darvishian M Real world influenza vaccine effectiveness; new designs and methods to adjust for confounding and bias (prof E Hak, prof ER van den Heuvel)
Berm EJJ Optimizing treatment with psychotropic agents through precision drug therapy; it is not about the mean (prof B Wilffert, prof E Hak, dr JG Maring)
Fugel H-J Economics of stratified medicine (prof MJ Postma, dr M Nuijten, dr K Redekop)
Salavati M Assessing gross motor function, functional skills, and caregiver assistance in children with cerebral palsy (CP) and cerebral palsy impairment (CPI) (prof CP van der Schans, prof B Steenbergen, dr A Waninge, dr EAA Rameckers)
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Wierike SCM te ‘The’ pathway towards the elite level in Dutch basketball; a multidimensional and longitudinal study on the development of talented youth basketball players (prof C Visscher, dr MT Elferink Gemser)
Jacobs JJWM General practitioner on an island. How research and innovation help to improve primary care (prof R Sanderman, prof T van der Molen)
Küpers LK The first 1000 days and beyond (prof H Snieder, prof RP Stolk, dr E Corpeleijn)
Kuiper JS The importance of social relationships in the process of cognitive ageing (prof RC Oude Voshaar, prof RP Stolk, dr N Smidt)
Göhner, C Placental particles in pregnancy and preeclampsia (prof SA Scherjon,prof E Schleuβner, dr MM Faas, dr T Plösch)
Vries AJ de Patellar tendinopathy; causes, consequences and the use of orthoses (prof RL Diercks, dr I van den Akker Scheek, dr J Zwerver, dr H van der Worp)
Holland B van Promotion of sustainable employment; occupational health in the meat processing industry (prof MF Reneman, prof S Brouwer, dr R Soer, dr MR de Boer) 13.04.2016 EXPAND
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Otter TA Monitoring endurance athletes; a multidisciplinary approach (prof KAPM Lemmink, prof RL Diercks, dr MS Brink)
Bielderman JH Active ageing and quality of life; community dwelling older adults in deprived neighbourhoods (prof CP van der Schans, dr MHG de Greef, dr GH Schout)
Bijlsma MJ Age period cohort methodology; confounding by birth in cardiovascular pharmacoepidemiology (prof E Hak, prof S Vansteelandt, dr F Janssen)
Dingemans EAA Working after retirement; determinants and conzequences of bridge employment (prof CJIM Henkens, dr ir H van Solinge)
Jonge L de Data quality and methodology in studies on maternal medication use in relation to congenital anomalies (prof IM van Langen, prof LTW de Jong van den Berg, dr MK Bakker)
Vries FM de Statin treatment in type 2 diabetes patients (prof E Hak, prof P Denig, prof MJ Postma)
For more 2016 and earlier theses visit our website.
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CURRICULUM VITAE
Renata Šmit holds a Master of Science degree in the field of Pharmacy from the University of Ljubljana, Slovenia and has a Master of Business Administration (MBA) degree from the University of Clemson, USA. Renata was employed several years at a subsidiary of the international pharmaceutical company Sanofi in Ljubljana. Her involvement was especially important in the analysis of development opportunity assessment of several projects connected with different diseases and their treatment. Her contributions were instrumental in defining the strategies and monitoring performance. She developed and wrote her PhD project proposal that gained funding under the “Innovative scheme for the co financing of PhD studies ” from the European Union and the Ministry of Education, Science and Culture of the Republic of Slovenia. She was pursuing her doctoral degree in the Netherlands at the University of Groningen at the Department of Pharmacy & Institute of Healthy Aging & healthcaRE (SHARE) under the supervision of Prof. Maarten J Postma and Prof. Klaas Poelstra. Her PhD thesis titled Health Economics of Tick Borne Diseases focuses on health and economic aspects of tick borne encephalitis and Lyme borreliosis and their impact on public health. In particular, she developed models based on the natural course of the disease for assessing the costs and health outcomes and cost effectiveness of vaccination. During her PhD education and training program she completed several courses and attended international congresses and conferences where she gave oral and poster presentations of her research. She serves as a reviewer and editorial author of international journals Expert Review of Vaccines and Vaccine . Renata will earn her PhD degree from the University of Groningen in November 18, 2016. Renata’s work in progress refers to cost effectiveness of vaccination with the novel vaccine against Lyme borreliosis. She has designed and developed a Markov model based on the natural course of the disease for the evaluation of cost effectiveness of vaccination. Contact: Renata Šmit renata_smit@t 2.net
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