Field effectiveness of vaccination against tick-borne encephalitis
Introduction
Tick-borne encephalitis (TBE) virus is one of the major human pathogenic flaviviruses, a group of about 70 viruses that also includes the mosquito-borne yellow fever, dengue, Japanese encephalitis and West Nile viruses [1], [2]. TBE virus circulates in endemic regions of many countries of Central, Southern, Northern, and Eastern Europe as well as Central and Eastern Asia including Northern Japan and Northern China [1], [3], [4]. Based on sequence comparisons, three subtypes can be differentiated – designated European, Siberian, and Far Eastern subtypes – that are antigenically closely related [5], [6] and transmitted by the ticks Ixodes ricinus (European subtype) and Ixodes persulcatus (Asian subtypes) [4], [7]. Consistent with the overlap of distribution areas for I. ricinus and I. persulcatus in North-Eastern Europe, European and Asian subtype viruses have both been isolated in the Baltics and Finland [8], [9], [10].
About 3000 hospitalized cases of TBE are recorded annually in Europe [11] and between about 5500 and 10,000 in Russia [12], [13]. After the acute phase of the disease, a significant proportion of the patients (up to 46%) suffers from neurological sequelae for a certain period of time or even life-long [14]. In Europe, the lethality as a consequence of TBE lies between 1 and 2% [14] but has been reported to reach 20–40% in the Far East [7]. It has to be considered, however, that these comparisons were not made under standardized conditions and may be biased by differences in the rates of laboratory diagnosis and hospitalization of less severe cases. They thus cannot be ascribed solely to the higher pathogenicity of Far-Eastern strains without further scrutiny and data analysis.
Starting with the development of a formalin-inactivated TBE vaccine in 1973 and its further purification [15], [16], [17], [18], [19], highly purified inactivated vaccines are now available in Europe from two manufacturers: Baxter (formerly Immuno), designated ‘FSME Immun™’ [15], [16], [18], using an Austrian isolate (strain Neudoerfl), and Novartis (formerly Chiron, formerly Behring), designated ‘Encepur™’, using a German isolate (strain Karlsruhe) [20], [21]. Both of the manufacturing strains belong to the European subtype [5]. In Austria, FSME Immun™ has been in use since 1976, and Encepur™ was introduced in 1999; in this country, these vaccines are currently used at a ratio of ca. 90 to 10, respectively (Institute for Medical Statistics Austria; www.imshealth.at).
Human vaccines are usually licensed and controlled on the basis of seroconversion data, using different assays for measuring the formation of specific antibodies. In the case of TBE virus and other flaviviruses, there is abundant evidence from animal studies that the presence of virus-neutralizing antibodies in serum provides an excellent correlate for protection against virus challenge [22], [23], [24], [25], [26], [27], [28], [29]. Nevertheless, the final proof for the success of vaccines depends on the evaluation of their effectiveness in the field. In terms of this field effectiveness, a wide range has been observed for different inactivated vaccines, from 50 to 80% for influenza vaccines [30] to more than 90% for hepatitis B vaccines [31], [32] and hepatitis A vaccines [33], [34]. The vaccine most closely related to the TBE vaccine investigated here is the inactivated Japanese encephalitis vaccine, which proved to have an effectiveness of 91% under field conditions [35].
With respect to TBE, Austria is an exceptional example because vaccination coverage has been steadily increasing since the 1970s, when the first vaccine (a precursor of the current vaccines [15], [16], [18]) became available. Today, 88% of the total population in Austria have been vaccinated at least once, with 58% being regularly vaccinated within the officially recommended vaccination schedule. This is in sharp contrast to neighbouring countries with comparable TBE virus endemicity such as Germany and the Czech Republic, where vaccination coverage has reached only 13 and 11%, respectively.
In this work, we have analyzed the field effectiveness of TBE vaccination (i.e. prevention of laboratory-diagnosed cases of TBE virus infections with neurological symptoms causing hospitalization) in Austria for the years 2000–2006 in different age groups and groups with different vaccination histories. The study is based on (1) the annual numbers of hospitalized TBE cases confirmed by laboratory diagnosis, (2) the vaccination history of these cases, (3) the annual population figures in Austria, and (4) the TBE vaccination coverage data in the different groups collected by representative inquiries involving 8500 to 10,000 individuals annually (see Section 2). Our analysis reveals an extraordinarily high degree of protection by TBE vaccination in Austria in the range of 99% which does not exhibit significant differences between age groups. Protection is equally high in the months following the first two vaccinations—i.e. before the third shot of the basic vaccination schedule, but is somewhat lower in persons with an irregular history of vaccination that lies outside the recommended regular scheme. The data presented confirm the excellent protection record of TBE vaccination under field conditions which – when compared to that of other vaccines – is among the best achievable by active immunization against viral diseases [15], [30], [31], [32], [33], [34], [35].
Section snippets
TBE vaccination
Like in other European countries, two TBE vaccines are commercially available in Austria, FSME-Immun™ manufactured by Baxter [15] and Encepur™ manufactured by Novartis [21]. Both vaccines are highly purified formalin-inactivated whole virus vaccines adjuvanted with aluminium hydroxide and can be used interchangeably. According to the Institute of Medical Statistics Austria (www.imshealth.at), the market coverage in Austria for the Baxter and Novartis vaccines in 2000 was about 95 and 5%,
Vaccination status of the Austrian population
The percentages of people in Austria in the categories: (1) unvaccinated, (2) regularly vaccinated, (3) vaccinated with two doses only of the basic immunization schedule, and (4) irregularly vaccinated were determined by means of representative inquiries conducted annually (see Section 2). The results generated through these inquiries are displayed in Fig. 1 for the years 2000–2006 with respect to the total Austrian population. For the purposes of this study, these data were further dissected
Discussion
It was the objective of this study to evaluate the field effectiveness of TBE vaccination in Austria for the years 2000–2006 by making use of the documentation systems for clinical cases of TBE, their vaccination histories and the vaccination status of the Austrian population as determined by representative inquiries. When all age groups are included, our analysis reveals an overall effectiveness of about 99% in persons that had followed the recommended vaccination schedule, with a possible
Acknowledgements
The authors are grateful for the excellent technical assistance of Silvia Röhnke and Jutta Hutecek, to Karin Stiasny for figure design, and to Karin Stiasny and Christian Kunz for critically reading the manuscript (all at the Institute of Virology, Medical University of Vienna, Austria). We also thank Egon Marth and Elisabeth Daghofer (Institute of Hygiene, Medical University of Graz) as well as Manfred Dierich and Gernot Walder (Institute of Hygiene, Medical University of Innsbruck) for their
References (51)
Epidemiology and ecology of TBE relevant to the production of effective vaccines
Vaccine
(2003)- et al.
Molecular epidemiology of tick-borne encephalitis virus: cross-protection between European and Far Eastern subtypes
Vaccine
(1992) - et al.
Tick-borne flaviviruses
Adv Virus Res
(2003) - et al.
Main features of tick-borne encephalitis eco-epidemiology in Russia
Zentralbl Bakteriol
(1999) - et al.
Tick-borne encephalitis—pathogenesis, clinical course and long-term follow-up
Vaccine
(2003) - et al.
History of TBE vaccines
Vaccine
(2003) TBE vaccination and the Austrian experience
Vaccine
(2003)- et al.
A randomized phase II study of a new tick-borne encephalitis vaccine using three different doses and two immunization regimens
Vaccine
(1992) - et al.
Report on a WHO consultation on immunological endpoints for evaluation of new Japanese encephalitis vaccines, WHO, Geneva, September 2–3, 2004
Vaccine
(2005) Impact of hepatitis B vaccination on hepatitis B disease and nucleic acid testing in high-prevalence populations
J Clin Virol
(2006)
Effectiveness of hepatitis A vaccine in a former frequently affected community: 9 years’ followup after the Monroe field trial of VAQTA
Vaccine
Diagnosis of tick-borne encephalitis
Vaccine
Evidence that climate change has caused ‘emergence’ of tick-borne diseases in Europe?
Int J Med Microbiol
Insufficient protection for healthy elderly adults by tetanus and TBE vaccines
Vaccine
Immunity and ageing in man
Exp Gerontol
Tick-borne encephalitis (TBE) in Germany and clinical course of the disease
Int J Med Microbiol
Severe forms of tick-borne meningoencephalitis in Slovenia
J Infect
Immunogenicity and safety of a booster vaccination against tick-borne encephalitis more than 3 years following the last immunisation
Vaccine
Persistence of protective immunity following vaccination against tick-borne encephalitis—longer than expected?
Vaccine
Persistence of antibodies after vaccination against tick-borne encephalitis
Int J Med Microbiol
Flaviviruses
Flaviviridae: the viruses and their replication
Tick-borne encephalitis
Clin Infect Dis
Sequence analysis and genetic classification of tick-borne encephalitis viruses from Europe and Asia
J Gen Virol
Characterization of tick-borne encephalitis virus from Estonia
J Med Virol
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