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TBE vaccination and the Austrian experience
Vaccine 21 (2003) S1/50–S1/55
TBE vaccination and the Austrian experience Christian Kunz Institute of Virology, University of Vienna, Kinderspitalgasse 15, A-1095 Vienna, Austria
Abstract In the pre-vaccination era, Austria had the highest recorded morbidity of tick-borne encephalitis (TBE) in Europe. The disease accounted for more than 50% of all viral meningoencephalitides in the eastern and southern parts of the country. This prompted us to start a cooperative vaccine development project in 1971 with J. Keppie from the Microbiological Research Establishment, Porton Down, England. After very satisfactory results of field studies, conducted in individuals for whom TBE was classified as occupational disease (forest workers, farmers, etc.), the killed virus vaccine (see chapter by N. Barrett in this issue), was made commercially available by Immuno AG Vienna (now Baxter Health-Care). The vaccine proved to be highly immunogenic and very well tolerated in both adults and children. After completing the series of three vaccinations seroconversion rates of >99% were recorded. In Austria, as in other European countries, TBE is now acquired for the most part during leisure activities. In view of this fact a mass vaccination campaign was initiated in 1981. Subsequently, the vaccination coverage of the Austrian population increased from 6% in 1980 to 86% in 2001, exceeding 90% in some of the high-risk areas. Data annually collected by our surveillance system show that the clinical effectiveness of the vaccine is excellent. Based on the assumption that the whole Austrian population is at risk of infection the calculated rate of protection after three doses of the vaccine is 96–98.7%. Breakthrough disease is rare and affects mainly higher age groups. Since the advent of TBE vaccination only one single case has been observed in the age group up to 20. The increasing vaccination coverage led to a more or less steady decline of TBE, drastically reducing the public health problem that the disease poses in Austria, especially in the provinces, where formerly the highest morbidity rates were observed. For example, in Carinthia, in the years 1973–1982 an average annual incidence of 155 was recorded, compared with only four annual cases in the last 4 years. The Austrian experience shows that containment of a tick-borne viral disease is feasible, provided a well-tolerated and effective vaccine is available that is widely accepted by the general population. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Tick-borne encephalitis; Vaccine; Clinical effectiveness; Austria
1. Introduction The first report about the occurrence of tick-borne encephalitis (TBE) in Austria dates back to 1931 when Schneider described cases of a “meningitis serosa epidemica” of unknown origin [1]. The patients had been hospitalized in the preceding few years in Neunkirchen, the capital of a district situated in a wooded area south of Vienna. Schneider already observed the seasonal incidence of the disease, which regularly occurred in spring and early summer. In 1957, Moritsch and Krausler were able to show that the so-called Schneider’s disease was actually TBE [2]. Three years earlier, a team headed by Dutch virologists had first isolated TBE virus in Austria [3] when an encephalitis of unknown etiology had reached epidemic proportions in Styria and Carinthia [4,5]. In the following years an increasing number of clinical specimens from patients with a suspected viral disease of the central nervous system were sent to us for diagnostic purposes. Subsequently, over the years, the scope E-mail address: [email protected] (C. Kunz).
of the public health importance that TBE poses in Austria became more and more evident. In some years, up to almost 700 hospitalized cases were recorded, although our diagnostic methods were not as efficient as they are today, and sampling was far from complete. Thus, there was considerable underreporting, and it stands to reason that in some years the number of patients with overt disease must have exceeded the 1000 cases mark. In fact, in the pre-vaccination era Austria had the highest recorded morbidity of TBE in Europe. In the eastern and southern parts of Austria, where forests with foci of TBE virus are abundant, TBE accounted for more than 50% of all viral meningoencephalitides. Our attempt at developing a vaccine was initiated by the wish to provide protection at least for those who were most at risk, i.e. people handling infectious virus in the laboratory and professional people working in forests in highly endemic regions. In particular, forest workers became increasingly alarmed as a substantial number of cases with severe sequelae, including some fatalities, had originated from infections while working in tick-infested woods.
0264-410X/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0264-410X(02)00813-7
C. Kunz / Vaccine 21 (2003) S1/50–S1/55
2. The candidate vaccine This prompted us to start a cooperative research project in 1971 with J. Keppie from the Microbiological Research Establishment, Porton Down, England, where facilities for the production of small amounts of vaccines were available. A virus strain isolated from ticks collected about 30 km south of Vienna (Neudörfl) was selected for the production of batches to be used as candidate vaccine. The virus was grown in chick embryo cells, partially purified by hydroxyappatite chromatography and inactivated by formalin, with Al(OH)3 added as adjuvant. At the beginning of 1973, the first small batch of experimental vaccine was ready for human testing. On 25 April my co-worker Hanns Hofmann and I vaccinated each other. Subsequently, a total of 81 volunteers were given two doses 4 weeks apart and a third dose 7–9 months thereafter. The seroconversion rate was highly satisfactory, reaching 95% after the second and 98% after the third dose [6]. In 1974 and 1975, we vaccinated about 30,000 people, mainly forest workers, farmers, and other individuals for whom TBE was classified as occupational disease. One laboratory infection in a vaccinee in 1973 that passed without any signs of disease gave the first hint that the vaccine was protective. Previously, infections contracted while handling infectious virus in our laboratory invariably led to disease. After the vaccine had passed muster, finding a pharmaceutical company that would be willing to produce the vaccine proved to be a difficult task. The main obstacle was that, initially in the Western European countries, TBE was thought to be almost exclusively a public health problem of Austria. Thus, the market appeared to be too small for a financial success and in the 1970s there was little hope that a relatively expensive vaccine produced in the west could be sold in countries beyond the former Iron Curtain.
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9–12 months thereafter, with subsequent booster doses recommended at 3-year intervals. Following vaccination, antibody levels tend to decline individually. Two different cohorts of 339 and 233 randomly selected vaccinees, respectively, were tested with our in-house ELISA 3 or 5 years after having received at least three doses of the TBE vaccine. The ELISA is measured in Vienna units (VIEU) and shows an excellent correlation with our neutralization test [9,10]. Close to 98% of the vaccinees still had antibody levels of >201 VIEU after 3 years and almost 95% after 5 years. This threshold is highly predictive for the presence of protective, neutralizing antibodies [10]. Although it was not a systematic study, and the results were obtained using the routine diagnostic service of the Institute of Virology, this suggests that it may be possible to adjust the booster interval according to the level of protection required in the field. This topic warrants further investigation. In this context, it has to be pointed out that even those vaccinees who lost their antibodies more or less invariably exhibit an IgG response and do not form antibodies of the IgM type. In an unpublished study of the Institute of Virology, University of Vienna, carried out in the years 1996–2001 a total of 180 blood samples were tested from persons who had received a booster dose 10–18 years after their last vaccination. In all but one case (a man 67 years of age) an antibody level of at least 300 VIEU could be detected. Thus, the TBE vaccine induces an immunologic memory that may be long-lasting. Whether or not after vaccination, upon infection, antibodies may sometimes be formed early enough to afford protection from viremia and disease in individuals who had become seronegative, is not known. The vaccine is highly immunogenic. After completing the series of three vaccinations or a booster dose the seroconversion rate was 98% as measured in the hemagglutination inhibition (HI) test and 99.5% in the more sensitive ELISA [11].
3. Immuno decides to produce the vaccine Fortunately, the Austrian company Immuno stepped in and decided to take over the industrial production of the candidate vaccine. In the spring of 1976, the vaccine became commercially available in Austria. In 1979, the quality of the vaccine was further improved by means of continuos flow ultracentrifugation [7]. This method effectively removed impurities derived from chick cells, which probably accounted for systemic reactions such as headache, malaise, and pyrexia initially frequently observed in vaccinees, especially after the first dose was injected [8]. FSME Immun Inject® was the only TBE vaccine available in Austria until the year 2000. All data presented in this article are therefore based on the use of the Austrian vaccine.
5. Adverse events Since 1980 more than 35 million doses of the vaccine have been used in Austria. This extremely high level of acceptance shows that the vaccine is very well tolerated. There have been a few anecdotal reports about neurological disorders, mostly neuritis of varying degree of severity following vaccination [12–15], but a clear causal relationship has not been established in any of these cases. Thus, neurological complications occur extremely rarely, if at all. In this context, it is also worth noting that in a controlled, prospective study the vaccine induced no adverse effects in patients with multiple sclerosis (see Baumhackl et al., this supplement).
4. Immunogenicity of FSME Immun Inject®
6. Initiation of the mass vaccination campaign
The immunization schedule consists of three doses given intramuscularly 2 weeks–3 months apart and a third dose
By 1979 it became obvious that a high vaccination coverage of the professional groups at risk (forest workers,
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farmers, etc.) would not suffice to substantially reduce the morbidity of TBE. In that year 677 cases of hospitalized patients with overt TBE were still recorded. As in other European countries, over the years, with the increasing mobility of the population and the increasing amount of spare time available, TBE has become a disease that is predominantly acquired during leisure activities. Faced with this situation, a mass vaccination campaign was started in 1981 by the Austrian Ministry of Health, the chamber of physicians, and the chamber of pharmacists, which since then each year lasts for about 5–6 months in the first part of the year. During this period the vaccine is made available at a reduced price in pharmacies while doctors charge less than usual for vaccination. Only people with an occupational hazard of infection receive the vaccine free of charge, for the rest of the population only a part of the costs are covered by health insurance. In addition, the public is reminded of the potential risk of acquiring TBE after a tick bite by means of TV spots, radio announcements, and billboards on streets. Due to these measures, the vaccination coverage of the Austrian population increased from 6% in 1980 to 86% in 2001. In Carinthia and Styria, the provinces with the highest morbidity rates before the vaccine became available, 95 and 89%, respectively, of the indigenous population underwent vaccination. These data are based on polls that, with the exception of the years 1998 and 1999, have regularly been conducted after the end of the campaign. The efficacy of the vaccine has already been demonstrated in prelicensure studies in the cohort of 30,000 people at high-risk, vaccinated by us in the years 1973–1976. Not a single case of TBE occurred in this high-risk group of forest workers, farmers, etc. in the following years. According to studies conducted before the advent of vaccination, overt disease is three times more frequent in this group of people than in the rest of the population [16,17]. In the pre-vaccination era, in Carinthia the annual risk of contracting TBE as an occupational hazard was about 1/1000. These field studies were exclusively carried out by members of the Institute of Virology, University of Vienna.
7. Clinical effectiveness of the vaccine After licensure, the vaccine also proved to be effective in the real world, under less ideal conditions. In Austria, those who wish to be vaccinated normally have to buy the vaccine at the pharmacy and take it to the physician of their choice, frequently interrupting the cold chain. Moreover, some physicians still choose the buttocks instead of the deltoid region or the anterolateral aspect (infants) of the thigh for vaccination, thus at least occasionally injecting the vaccine into subcutaneous fat rather than muscle as recommended. Nevertheless, the clinical effectiveness of the vaccine is very satisfactory, as is indicated by the data collected by our surveillance system (Table 1). It can be seen in the table that the calculated rate of protection is 96–98.7% after completing the series of three doses. It will be noted that in the year 2000 the poll, in order to be able to estimate the vaccination coverage, was conducted in a different way than in the previous years 1994–1997. The number 6.5 million includes everybody who has ever been vaccinated against TBE, irrespective of how many doses of the vaccine an individual had received. All Austrian laboratories that perform tests for the diagnosis of TBE cooperate with the Institute of Virology, University of Vienna. Results are reported and sera that are found positive in a commercial test are sent to the Institute for confirmation. In addition, for each TBE patient, information about the clinical form, the history and exact geographic site of the tick bite during the possible incubation period of the disease, as well as about a history of active or passive immunization are gathered by means of a questionnaire. The rate of protection in Table 1 is based on the assumption that the whole Austrian population is at risk, which is certainly not the case, especially in the western parts of Austria. For example, in Vorarlberg, the province bordering Switzerland, only two indigenous cases of TBE have been found thus far. Thus, the rate of protection is actually even higher than shown in the table after completing the whole series of three vaccinations. The two patients in Table 1 who were not fully vaccinated (two doses only) contracted TBE before or around the time when the course of three doses should have been completed. However, it has to
Table 1 TBE in Austria: effectiveness of vaccination Year
1994 1995 1996 1997 2000 2001
No. of cases
172 109 125 99 60 54
Population at risk (×10−3 )
Protection rate (%)
Unvaccinated
Two doses
Three or more doses
Two doses
Three or more doses
2340/165 2110/104 2051/114 2161/93 1250/58 1120/50
390/1 460/1 328/0 390/0
5070/6 5230/4 5421/11 5249/6 6550a /2 6720/4
96.4 95.6 100.0 100.0
98.3 98.4 96.0 97.5 99.3 98.7
160/0
100.0
Assumption: total Austrian population of 7.8 million (census 2001: 8 million) at risk. These figures include eight patients who missed the booster dose after 3 years: >3 years (3), 4 years (2), 6 years (1), 8 years (1), 11 years (1). a Number of doses unknown.
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be pointed out that the level of compliance with undergoing at least the primary three vaccinations is excellent. This probably accounts for the fact that TBE cases with a history of incomplete vaccination are rarely observed in Austria. It must be pointed out that vaccine failures in Table 1 do not only include those 25 patients who developed disease within 3 years after having received the last of at least three doses of the vaccine, i.e. within the recommended interval for revaccination, but also 8 patients who missed the date when a booster dose was due. Considering that by now more than 6.8 million Austrians have been vaccinated, breakthrough disease appears to be rare and tends to occur, for the most part, in higher age groups. In the last 5 years (1997–2001), out of 12 patients who developed TBE in spite of being vaccinated within the 3-year period after the last dose and 5 additional patients who had missed the year for revaccination, 12 were in the age group 60 and over. The youngest patient was 37 years of age. In this context, it is of interest that since the advent of TBE vaccination only one single case of breakthrough TBE has ever been observed in the age group up to 20. It is also noteworthy that the increase of the vaccination coverage in Austria was not accompanied by an increase in the absolute annual numbers of breakthrough disease. This could reflect a benefit from the growing number of booster doses for lowor non-responders after the initial three immunizations in the vaccinated population as is indicated by a study conducted in Sweden. Also, in a small cohort, neutralizing antibodies persisted to a larger extent between booster doses (fourth and fifth dose) than after completing the full course of three initial immunizations [18]. In Table 2, clinical pictures of 805 unvaccinated versus 54 vaccinated patients are compared. The higher percentage of meningoencephalitis in the group with breakthrough disease has to be put into context with the overrepresentation of elderly people in that cohort as is
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Table 2 Clinical forms of TBE in unvaccinated and vaccinated patients Disease
Unvaccinated
Vaccinated
Meningitis Meningoencephalitis Meningoencephalomyelitis Meningoencephaloradiculitis
398 354 23 30
20 31 1 2
(49) (43) (3) (4)
805 (100)
(37) (57) (2) (4)
54 (100)
Values shown in the parentheses are in percentage.
shown above. Only three of the vaccinated patients were under 31 years of age, an age group where meningitis is the dominant clinical form. Generally speaking, the severity of the disease tends to increase with age [19–21]. In Austria, vaccination is recommended for children after 1 year of age and, in highly endemic areas, if the risk of exposure is high, after 6 months of age. In particular, the vaccination program for children at mandatory school age in endemic regions has proven to be a very effective measure for combating the disease, as can be seen in Fig. 1. Whereas in 1971–1981 almost 19% of the patients were 7–14 years of age, in the years 1990–2000 the percentage in this age group has fallen to 2.3%. Moreover, it should be noticed in the figure that in the latter period of time a shift has occurred towards the population close to or at retirement age. Most of these people have lived for many years in endemic areas, where they probably have already experienced many tick bites. They therefore erroneously presume that they are immune and do not avail themselves of the vaccine. The higher actual incidence of TBE in the last 10 years compared with the 1970 in the group beyond 60 years of age (325/265) is of interest because it indicates that the risk of infection in Austria’s forests has certainly not declined over the years.
Fig. 1. Age distribution of TBE in Austria.
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Fig. 2. TBE in Austria and the Czech Republic 1979–2001.
8. Impact of vaccination on the incidence of TBE in Austria The increasing vaccination coverage resulted in a more or less steady decline of the morbidity of TBE in Austria. After the year 1988, fewer than 200 cases and after 1997 fewer than 100 cases were recorded annually. In 1999–2001, with 41, 60 and 54 cases, respectively, the lowest incidence of TBE ever was observed in Austria. The decline was most dramatic in Carinthia, the province which in the pre-vaccination era had the highest morbidity rate. In the years 1973–1982 a total of 1550 cases of TBE were recorded (average annual incidence 155), compared with a total of only 17 cases in the last 4 years. In the year 2000, only two patients were hospitalized with overt TBE, while seven cases were observed in the Tyrol, a low-risk province where the first indigenous case was detected in 1984. The highest incidence of TBE is still seen in Styria, where in the year 2000, 25 of the total of 60 Austrian cases had occurred. However, it has been calculated that vaccination prevented overt disease in about 190 inhabitants of this province in that year. The decline of the disease in Austria is not shared by other European countries. On the contrary, in most other countries a marked increase of TBE has been observed in recent years. This holds especially true for the Czech Republic, Austria’s northern neighbor, where the surveillance of TBE has been excellent for many years. The development of the morbidity rates in these two countries (Fig. 2), from the years 1979 through 2001 is striking and the difference can only be explained by the impact of the high vaccination coverage in Austria. In the Czech Republic, even in high-risk areas such as Southern Bohemia (population 626,000, 234 cases of TBE in the year 2000), only about 10% of the pop-
ulation has undergone vaccination, a situation that existed in Austria at the beginning of the 80s. The Austrian experience shows that this low level of vaccination coverage does not have a marked effect on the incidence of TBE. While Austria has made great and successful strides toward achieving the goal of controlling TBE, no vaccination campaign that would parallel the Austrian example has been conducted elsewhere in Europe. Elimination of the disease is not possible, because nothing has changed in nature. The vector tick Ixodes ricinus is still abundant, as shown also by the increase in cases of Lyme borreliosis during the last two decades. Besides, a small part of the population will always refuse to undergo vaccination. However, if the vaccination program is continued, we are confident that TBE will eventually cease to be a public health problem in Austria. Since no tools are available for interrupting the virus cycle in nature, vaccination will continue to be the mainstay of containment of TBE in all countries where the disease is endemic for many years to come.
References [1] Schneider H. Über epidemische akute “Meningitis serosa”. Wien Klin Wochenschrift 1931;44:350–2. [2] Moritsch H, Krausler J. Die endemische Frühsommer-MeningoEncephalitis im Wiener Becken (Schneidersche Krankheit). Wien Klin Wochenschrift 1957;69:921–6. [3] Verlinde J, van Tongeren HAE, Pattyn SR, Rosenzweig A. Virus meningoencephalitis in Austria. 3. Pathogenic and immunological properties of the virus. Bull WHO 1955;12:565–79. [4] Richling E. Virus-meningoencephalitis in Austria. 1. Epidemiological features. Bull WHO 1955;12:521–34. [5] Grinschgl G. Virus-meningoencephalitis in Austria. 2. Clinical features. Bull WHO 1955;12:535–64.
C. Kunz / Vaccine 21 (2003) S1/50–S1/55 [6] Kunz C, Hofmann H, Stary A. Field studies with a new tick-borne encephalitis (TBE) vaccine. Zentralbl Bakt I Orig A 1976;243:141–4. [7] Heinz FX, Kunz C, Fauma H. Preparation of a highly purified vaccine against tick-borne encephalitis by continuous flow zonal ultracentrifugation. J Med Virol 1980;6:213–21. [8] Kunz C, Heinz FX, Hofmann H. Immunogenicity and reactogenicity of a highly purified vaccine against tick-borne encephalitis. J Med Virol 1980;6:103–9. [9] Hofmann H, Heinz FX, Dippe H. ELISA for IgM and IgG antibodies against tick-borne encephalitis virus: quantification and standardization of results. Zentralbl Bakt 1983;255:448–55. [10] Holzmann H, Kundi M, Stiasny K, Clement J, Mc Kenna P, Kunz C, et al. Correlation between ELISA, hemagglutination inhibition, and neutralization tests after vaccination against tick-borne encephalitis. J Med Virol 1996;48:102–7. [11] Kunz C. Epidemiology of tick-borne encephaltitis and the impact of vaccination on the incidence of disease. In: Eibl MM, Huber C, Peter HH, Wahn V, editors. Proceedings of the Vth Symposium on Immunology. Berlin: Springer; 1996. p. 143–9. [12] Scholz E, Wiethölter H. Postvakzinale Schwerpunktneuritis nach prophylaktischer FSME-Impfung. Dtsch Med Wochenschr 1987;112:544–6. [13] Gold R, Wiethölter H, Rihs I, Löwer J, Kappos L, FrühsommerMeningoenzephaltis-Impfung. Indikation und kritische Beurteilung neurologischer Impfkomplikationen . Dtsch Med Wochenschr 1992; 117:112–6. [14] Goerre S, Kesselring J, Hartmann K, Kuhn M, Reinhart W. Neurological side effects following vaccination of early-summer
[15] [16]
[17]
[18]
[19]
[20]
[21]
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meningoencephalitis. Case report and experiences of the Swiss Center for adverse drug effects. Schweiz Med Wochenschr 1993;123: 654–7. Press R, Solders G. A case report. A vaccine against tick-borne encephalitis caused polyneuritis. Läkartidningen 1999;96:3341–2. Moritsch H, Wencl J. Untersuchungen über die durch Zecken übertragene Frühsommer-Meningo-Encephalitis (tick-borne encephalitis), eine Berufskrankheit der Forstarbeiter in Österreich. In: Proceedings of the XIVth International Congress. Occup Hlth 1963; 62:1746. Groll E, Krausler J, Kunz C, Moritsch H. Untersuchungen über die Morbidität und stille Durchseuchung einer population in einem Endemiegebiet der Frühsommer-Meningo-Encephalitis (tick-borne encephalitis). Arch Ges Virusforsch 1965;15:151–8. Haglund M. Tick-borne encephalitis: prognosis, immunization and virus strain characterization. Ph.D. Thesis. Stockholm: Konge Carolinska Medico Chirurgiska Institutet; 2000. Krausler J. 23 years of TBE in the district of Neunkirchen (Austria). In: Kunz C, editor. Tick-borne encephalitis. In: Proceedings of the International Symposium. Baden/Vienna, Austria. Wien: Facultas; 1979. p. 6–12. Tomazic J, Pikelj F, Schwarz B, Kunze M, Kraigher A, Matjasic M, et al. The clinical features of tick-borne encephalitis in Slovenia. A study of 492 cases in 1994. Antibiot Monitor 1996;12:115– 20. Kaiser R. The clinical and epidemiological profile of tick-borne encephalitis in southern Germany 1994–98: a prospective study of 656 patients. Brain 1999;122:2067–78.
TBE vaccination and the Austrian experience Christian Kunz Institute of Virology, University of Vienna, Kinderspitalgasse 15, A-1095 Vienna, Austria
Abstract In the pre-vaccination era, Austria had the highest recorded morbidity of tick-borne encephalitis (TBE) in Europe. The disease accounted for more than 50% of all viral meningoencephalitides in the eastern and southern parts of the country. This prompted us to start a cooperative vaccine development project in 1971 with J. Keppie from the Microbiological Research Establishment, Porton Down, England. After very satisfactory results of field studies, conducted in individuals for whom TBE was classified as occupational disease (forest workers, farmers, etc.), the killed virus vaccine (see chapter by N. Barrett in this issue), was made commercially available by Immuno AG Vienna (now Baxter Health-Care). The vaccine proved to be highly immunogenic and very well tolerated in both adults and children. After completing the series of three vaccinations seroconversion rates of >99% were recorded. In Austria, as in other European countries, TBE is now acquired for the most part during leisure activities. In view of this fact a mass vaccination campaign was initiated in 1981. Subsequently, the vaccination coverage of the Austrian population increased from 6% in 1980 to 86% in 2001, exceeding 90% in some of the high-risk areas. Data annually collected by our surveillance system show that the clinical effectiveness of the vaccine is excellent. Based on the assumption that the whole Austrian population is at risk of infection the calculated rate of protection after three doses of the vaccine is 96–98.7%. Breakthrough disease is rare and affects mainly higher age groups. Since the advent of TBE vaccination only one single case has been observed in the age group up to 20. The increasing vaccination coverage led to a more or less steady decline of TBE, drastically reducing the public health problem that the disease poses in Austria, especially in the provinces, where formerly the highest morbidity rates were observed. For example, in Carinthia, in the years 1973–1982 an average annual incidence of 155 was recorded, compared with only four annual cases in the last 4 years. The Austrian experience shows that containment of a tick-borne viral disease is feasible, provided a well-tolerated and effective vaccine is available that is widely accepted by the general population. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Tick-borne encephalitis; Vaccine; Clinical effectiveness; Austria
1. Introduction The first report about the occurrence of tick-borne encephalitis (TBE) in Austria dates back to 1931 when Schneider described cases of a “meningitis serosa epidemica” of unknown origin [1]. The patients had been hospitalized in the preceding few years in Neunkirchen, the capital of a district situated in a wooded area south of Vienna. Schneider already observed the seasonal incidence of the disease, which regularly occurred in spring and early summer. In 1957, Moritsch and Krausler were able to show that the so-called Schneider’s disease was actually TBE [2]. Three years earlier, a team headed by Dutch virologists had first isolated TBE virus in Austria [3] when an encephalitis of unknown etiology had reached epidemic proportions in Styria and Carinthia [4,5]. In the following years an increasing number of clinical specimens from patients with a suspected viral disease of the central nervous system were sent to us for diagnostic purposes. Subsequently, over the years, the scope E-mail address: [email protected] (C. Kunz).
of the public health importance that TBE poses in Austria became more and more evident. In some years, up to almost 700 hospitalized cases were recorded, although our diagnostic methods were not as efficient as they are today, and sampling was far from complete. Thus, there was considerable underreporting, and it stands to reason that in some years the number of patients with overt disease must have exceeded the 1000 cases mark. In fact, in the pre-vaccination era Austria had the highest recorded morbidity of TBE in Europe. In the eastern and southern parts of Austria, where forests with foci of TBE virus are abundant, TBE accounted for more than 50% of all viral meningoencephalitides. Our attempt at developing a vaccine was initiated by the wish to provide protection at least for those who were most at risk, i.e. people handling infectious virus in the laboratory and professional people working in forests in highly endemic regions. In particular, forest workers became increasingly alarmed as a substantial number of cases with severe sequelae, including some fatalities, had originated from infections while working in tick-infested woods.
0264-410X/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0264-410X(02)00813-7
C. Kunz / Vaccine 21 (2003) S1/50–S1/55
2. The candidate vaccine This prompted us to start a cooperative research project in 1971 with J. Keppie from the Microbiological Research Establishment, Porton Down, England, where facilities for the production of small amounts of vaccines were available. A virus strain isolated from ticks collected about 30 km south of Vienna (Neudörfl) was selected for the production of batches to be used as candidate vaccine. The virus was grown in chick embryo cells, partially purified by hydroxyappatite chromatography and inactivated by formalin, with Al(OH)3 added as adjuvant. At the beginning of 1973, the first small batch of experimental vaccine was ready for human testing. On 25 April my co-worker Hanns Hofmann and I vaccinated each other. Subsequently, a total of 81 volunteers were given two doses 4 weeks apart and a third dose 7–9 months thereafter. The seroconversion rate was highly satisfactory, reaching 95% after the second and 98% after the third dose [6]. In 1974 and 1975, we vaccinated about 30,000 people, mainly forest workers, farmers, and other individuals for whom TBE was classified as occupational disease. One laboratory infection in a vaccinee in 1973 that passed without any signs of disease gave the first hint that the vaccine was protective. Previously, infections contracted while handling infectious virus in our laboratory invariably led to disease. After the vaccine had passed muster, finding a pharmaceutical company that would be willing to produce the vaccine proved to be a difficult task. The main obstacle was that, initially in the Western European countries, TBE was thought to be almost exclusively a public health problem of Austria. Thus, the market appeared to be too small for a financial success and in the 1970s there was little hope that a relatively expensive vaccine produced in the west could be sold in countries beyond the former Iron Curtain.
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9–12 months thereafter, with subsequent booster doses recommended at 3-year intervals. Following vaccination, antibody levels tend to decline individually. Two different cohorts of 339 and 233 randomly selected vaccinees, respectively, were tested with our in-house ELISA 3 or 5 years after having received at least three doses of the TBE vaccine. The ELISA is measured in Vienna units (VIEU) and shows an excellent correlation with our neutralization test [9,10]. Close to 98% of the vaccinees still had antibody levels of >201 VIEU after 3 years and almost 95% after 5 years. This threshold is highly predictive for the presence of protective, neutralizing antibodies [10]. Although it was not a systematic study, and the results were obtained using the routine diagnostic service of the Institute of Virology, this suggests that it may be possible to adjust the booster interval according to the level of protection required in the field. This topic warrants further investigation. In this context, it has to be pointed out that even those vaccinees who lost their antibodies more or less invariably exhibit an IgG response and do not form antibodies of the IgM type. In an unpublished study of the Institute of Virology, University of Vienna, carried out in the years 1996–2001 a total of 180 blood samples were tested from persons who had received a booster dose 10–18 years after their last vaccination. In all but one case (a man 67 years of age) an antibody level of at least 300 VIEU could be detected. Thus, the TBE vaccine induces an immunologic memory that may be long-lasting. Whether or not after vaccination, upon infection, antibodies may sometimes be formed early enough to afford protection from viremia and disease in individuals who had become seronegative, is not known. The vaccine is highly immunogenic. After completing the series of three vaccinations or a booster dose the seroconversion rate was 98% as measured in the hemagglutination inhibition (HI) test and 99.5% in the more sensitive ELISA [11].
3. Immuno decides to produce the vaccine Fortunately, the Austrian company Immuno stepped in and decided to take over the industrial production of the candidate vaccine. In the spring of 1976, the vaccine became commercially available in Austria. In 1979, the quality of the vaccine was further improved by means of continuos flow ultracentrifugation [7]. This method effectively removed impurities derived from chick cells, which probably accounted for systemic reactions such as headache, malaise, and pyrexia initially frequently observed in vaccinees, especially after the first dose was injected [8]. FSME Immun Inject® was the only TBE vaccine available in Austria until the year 2000. All data presented in this article are therefore based on the use of the Austrian vaccine.
5. Adverse events Since 1980 more than 35 million doses of the vaccine have been used in Austria. This extremely high level of acceptance shows that the vaccine is very well tolerated. There have been a few anecdotal reports about neurological disorders, mostly neuritis of varying degree of severity following vaccination [12–15], but a clear causal relationship has not been established in any of these cases. Thus, neurological complications occur extremely rarely, if at all. In this context, it is also worth noting that in a controlled, prospective study the vaccine induced no adverse effects in patients with multiple sclerosis (see Baumhackl et al., this supplement).
4. Immunogenicity of FSME Immun Inject®
6. Initiation of the mass vaccination campaign
The immunization schedule consists of three doses given intramuscularly 2 weeks–3 months apart and a third dose
By 1979 it became obvious that a high vaccination coverage of the professional groups at risk (forest workers,
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farmers, etc.) would not suffice to substantially reduce the morbidity of TBE. In that year 677 cases of hospitalized patients with overt TBE were still recorded. As in other European countries, over the years, with the increasing mobility of the population and the increasing amount of spare time available, TBE has become a disease that is predominantly acquired during leisure activities. Faced with this situation, a mass vaccination campaign was started in 1981 by the Austrian Ministry of Health, the chamber of physicians, and the chamber of pharmacists, which since then each year lasts for about 5–6 months in the first part of the year. During this period the vaccine is made available at a reduced price in pharmacies while doctors charge less than usual for vaccination. Only people with an occupational hazard of infection receive the vaccine free of charge, for the rest of the population only a part of the costs are covered by health insurance. In addition, the public is reminded of the potential risk of acquiring TBE after a tick bite by means of TV spots, radio announcements, and billboards on streets. Due to these measures, the vaccination coverage of the Austrian population increased from 6% in 1980 to 86% in 2001. In Carinthia and Styria, the provinces with the highest morbidity rates before the vaccine became available, 95 and 89%, respectively, of the indigenous population underwent vaccination. These data are based on polls that, with the exception of the years 1998 and 1999, have regularly been conducted after the end of the campaign. The efficacy of the vaccine has already been demonstrated in prelicensure studies in the cohort of 30,000 people at high-risk, vaccinated by us in the years 1973–1976. Not a single case of TBE occurred in this high-risk group of forest workers, farmers, etc. in the following years. According to studies conducted before the advent of vaccination, overt disease is three times more frequent in this group of people than in the rest of the population [16,17]. In the pre-vaccination era, in Carinthia the annual risk of contracting TBE as an occupational hazard was about 1/1000. These field studies were exclusively carried out by members of the Institute of Virology, University of Vienna.
7. Clinical effectiveness of the vaccine After licensure, the vaccine also proved to be effective in the real world, under less ideal conditions. In Austria, those who wish to be vaccinated normally have to buy the vaccine at the pharmacy and take it to the physician of their choice, frequently interrupting the cold chain. Moreover, some physicians still choose the buttocks instead of the deltoid region or the anterolateral aspect (infants) of the thigh for vaccination, thus at least occasionally injecting the vaccine into subcutaneous fat rather than muscle as recommended. Nevertheless, the clinical effectiveness of the vaccine is very satisfactory, as is indicated by the data collected by our surveillance system (Table 1). It can be seen in the table that the calculated rate of protection is 96–98.7% after completing the series of three doses. It will be noted that in the year 2000 the poll, in order to be able to estimate the vaccination coverage, was conducted in a different way than in the previous years 1994–1997. The number 6.5 million includes everybody who has ever been vaccinated against TBE, irrespective of how many doses of the vaccine an individual had received. All Austrian laboratories that perform tests for the diagnosis of TBE cooperate with the Institute of Virology, University of Vienna. Results are reported and sera that are found positive in a commercial test are sent to the Institute for confirmation. In addition, for each TBE patient, information about the clinical form, the history and exact geographic site of the tick bite during the possible incubation period of the disease, as well as about a history of active or passive immunization are gathered by means of a questionnaire. The rate of protection in Table 1 is based on the assumption that the whole Austrian population is at risk, which is certainly not the case, especially in the western parts of Austria. For example, in Vorarlberg, the province bordering Switzerland, only two indigenous cases of TBE have been found thus far. Thus, the rate of protection is actually even higher than shown in the table after completing the whole series of three vaccinations. The two patients in Table 1 who were not fully vaccinated (two doses only) contracted TBE before or around the time when the course of three doses should have been completed. However, it has to
Table 1 TBE in Austria: effectiveness of vaccination Year
1994 1995 1996 1997 2000 2001
No. of cases
172 109 125 99 60 54
Population at risk (×10−3 )
Protection rate (%)
Unvaccinated
Two doses
Three or more doses
Two doses
Three or more doses
2340/165 2110/104 2051/114 2161/93 1250/58 1120/50
390/1 460/1 328/0 390/0
5070/6 5230/4 5421/11 5249/6 6550a /2 6720/4
96.4 95.6 100.0 100.0
98.3 98.4 96.0 97.5 99.3 98.7
160/0
100.0
Assumption: total Austrian population of 7.8 million (census 2001: 8 million) at risk. These figures include eight patients who missed the booster dose after 3 years: >3 years (3), 4 years (2), 6 years (1), 8 years (1), 11 years (1). a Number of doses unknown.
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be pointed out that the level of compliance with undergoing at least the primary three vaccinations is excellent. This probably accounts for the fact that TBE cases with a history of incomplete vaccination are rarely observed in Austria. It must be pointed out that vaccine failures in Table 1 do not only include those 25 patients who developed disease within 3 years after having received the last of at least three doses of the vaccine, i.e. within the recommended interval for revaccination, but also 8 patients who missed the date when a booster dose was due. Considering that by now more than 6.8 million Austrians have been vaccinated, breakthrough disease appears to be rare and tends to occur, for the most part, in higher age groups. In the last 5 years (1997–2001), out of 12 patients who developed TBE in spite of being vaccinated within the 3-year period after the last dose and 5 additional patients who had missed the year for revaccination, 12 were in the age group 60 and over. The youngest patient was 37 years of age. In this context, it is of interest that since the advent of TBE vaccination only one single case of breakthrough TBE has ever been observed in the age group up to 20. It is also noteworthy that the increase of the vaccination coverage in Austria was not accompanied by an increase in the absolute annual numbers of breakthrough disease. This could reflect a benefit from the growing number of booster doses for lowor non-responders after the initial three immunizations in the vaccinated population as is indicated by a study conducted in Sweden. Also, in a small cohort, neutralizing antibodies persisted to a larger extent between booster doses (fourth and fifth dose) than after completing the full course of three initial immunizations [18]. In Table 2, clinical pictures of 805 unvaccinated versus 54 vaccinated patients are compared. The higher percentage of meningoencephalitis in the group with breakthrough disease has to be put into context with the overrepresentation of elderly people in that cohort as is
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Table 2 Clinical forms of TBE in unvaccinated and vaccinated patients Disease
Unvaccinated
Vaccinated
Meningitis Meningoencephalitis Meningoencephalomyelitis Meningoencephaloradiculitis
398 354 23 30
20 31 1 2
(49) (43) (3) (4)
805 (100)
(37) (57) (2) (4)
54 (100)
Values shown in the parentheses are in percentage.
shown above. Only three of the vaccinated patients were under 31 years of age, an age group where meningitis is the dominant clinical form. Generally speaking, the severity of the disease tends to increase with age [19–21]. In Austria, vaccination is recommended for children after 1 year of age and, in highly endemic areas, if the risk of exposure is high, after 6 months of age. In particular, the vaccination program for children at mandatory school age in endemic regions has proven to be a very effective measure for combating the disease, as can be seen in Fig. 1. Whereas in 1971–1981 almost 19% of the patients were 7–14 years of age, in the years 1990–2000 the percentage in this age group has fallen to 2.3%. Moreover, it should be noticed in the figure that in the latter period of time a shift has occurred towards the population close to or at retirement age. Most of these people have lived for many years in endemic areas, where they probably have already experienced many tick bites. They therefore erroneously presume that they are immune and do not avail themselves of the vaccine. The higher actual incidence of TBE in the last 10 years compared with the 1970 in the group beyond 60 years of age (325/265) is of interest because it indicates that the risk of infection in Austria’s forests has certainly not declined over the years.
Fig. 1. Age distribution of TBE in Austria.
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Fig. 2. TBE in Austria and the Czech Republic 1979–2001.
8. Impact of vaccination on the incidence of TBE in Austria The increasing vaccination coverage resulted in a more or less steady decline of the morbidity of TBE in Austria. After the year 1988, fewer than 200 cases and after 1997 fewer than 100 cases were recorded annually. In 1999–2001, with 41, 60 and 54 cases, respectively, the lowest incidence of TBE ever was observed in Austria. The decline was most dramatic in Carinthia, the province which in the pre-vaccination era had the highest morbidity rate. In the years 1973–1982 a total of 1550 cases of TBE were recorded (average annual incidence 155), compared with a total of only 17 cases in the last 4 years. In the year 2000, only two patients were hospitalized with overt TBE, while seven cases were observed in the Tyrol, a low-risk province where the first indigenous case was detected in 1984. The highest incidence of TBE is still seen in Styria, where in the year 2000, 25 of the total of 60 Austrian cases had occurred. However, it has been calculated that vaccination prevented overt disease in about 190 inhabitants of this province in that year. The decline of the disease in Austria is not shared by other European countries. On the contrary, in most other countries a marked increase of TBE has been observed in recent years. This holds especially true for the Czech Republic, Austria’s northern neighbor, where the surveillance of TBE has been excellent for many years. The development of the morbidity rates in these two countries (Fig. 2), from the years 1979 through 2001 is striking and the difference can only be explained by the impact of the high vaccination coverage in Austria. In the Czech Republic, even in high-risk areas such as Southern Bohemia (population 626,000, 234 cases of TBE in the year 2000), only about 10% of the pop-
ulation has undergone vaccination, a situation that existed in Austria at the beginning of the 80s. The Austrian experience shows that this low level of vaccination coverage does not have a marked effect on the incidence of TBE. While Austria has made great and successful strides toward achieving the goal of controlling TBE, no vaccination campaign that would parallel the Austrian example has been conducted elsewhere in Europe. Elimination of the disease is not possible, because nothing has changed in nature. The vector tick Ixodes ricinus is still abundant, as shown also by the increase in cases of Lyme borreliosis during the last two decades. Besides, a small part of the population will always refuse to undergo vaccination. However, if the vaccination program is continued, we are confident that TBE will eventually cease to be a public health problem in Austria. Since no tools are available for interrupting the virus cycle in nature, vaccination will continue to be the mainstay of containment of TBE in all countries where the disease is endemic for many years to come.
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