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Persistence of antibodies after vaccination against tick-borne encephalitis
ARTICLE IN PRESS
International Journal of Medical Microbiology 296 (2006) S1, 202–207 www.elsevier.de/ijmm
MINI-REVIEW
Persistence of antibodies after vaccination against tick-borne encephalitis Pamela Rendi-Wagnera, Olaf Zentb,, Wolfgang Jilgc, Annelie Plentzc, Jiri Berand, Herwig Kollaritscha a
Department of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Austria Chiron Vaccines, Emil-von-Behring-Str. 76, D-35041 Marburg, Germany c University of Regensburg, Germany d Department of Infectious Diseases, University Hospital, Hradec Kralove, Czech Republic b
Abstract Active vaccination against the tick-borne encephalitis (TBE) virus has successfully been implemented in endemic countries for many years. However, little was known about persistency of antibodies after completion of the primary vaccination and/or TBE booster immunization. Five recently performed serological follow-up studies in adults have now revealed that the persistence of protective immunity following at least one booster immunization was longer than expected. Notably, studies which analyzed different age groups indicate differences between younger adults aged 18–49 years and older adults aged X50 years with respect to TBE antibody persistence and the immune response following a subsequent booster dose. To summarize, the serological studies included in this analysis generally support a reconsideration of current TBE booster recommendations and a prolongation of booster intervals at least in younger adults. r 2006 Elsevier GmbH. All rights reserved. Keywords: Tick-borne encephalitis; Vaccine; Booster immunization; Immunity
Introduction Active vaccination appears to be the most effective means of prevention of tick-borne encephalitis (Barret et al., 2004). Thus, TBE vaccination strategies have successfully been implemented in many European countries, where TBE is endemic. The development and recent licensure of improved TBE vaccine formulations has rendered it necessary to re-evaluate recommendations for booster intervals, which have been unchanged for many years. Noticeably, little is known about persistence of antibodies after primary vaccination and/or TBE booster immunizations: Only a few serological studies have been published during the last Corresponding author. Tel.: +49 6421 39 4759; fax: +49 6421 39 4667. E-mail address: [email protected] (O. Zent).
1438-4221/$ - see front matter r 2006 Elsevier GmbH. All rights reserved. doi:10.1016/j.ijmm.2006.01.030
years; and these shall be reviewed in this article. In this context, the persistence of TBE antibodies when using different immunization schedules for primary TBE immunization is of particular interest.
TBE immunization schedules for primary immunization There are two different immunization schedules registered for primary immunization against TBE for the widely used European TBE vaccines (i.e. licensed versions of Encepurs, Chiron Behring GmbH & Co KG, Germany, and FSME-IMMUNs, Baxter AG, Austria) (Table 1). The conventional immunization schedule consists of three immunizations (Table 2), which for licensed
ARTICLE IN PRESS P. Rendi-Wagner et al. / International Journal of Medical Microbiology 296 (2006) S1, 202–207
Table 1.
203
Pharmaceutical composition of widely used TBE vaccines Encepurs Adults (since 2001)
Encepurs Children (since 2001)
FSME-IMMUNs 0.5 ml (adults) (since 2001)
FSME-IMMUNs 0.25 ml junior (since 2001)
Antigen details Strain Passages Production Amount of antigen
K-23 PCEC PCEC 1.5 mg
K-23 PCEC PCEC 0.75 mg
Neudoerfl PCEC PCEC 2.4 mg
Neudoerfl PCEC PCEC 1.2 mg
Excipients Adjuvant Preservative Stabilizer
Al(OH)3 No Sucrose
Al(OH)3 No Sucrose
Al(OH)3 No HSA
Al(OH)3 No HSA
Age limit Shelf life Adjusted
X12 years 24 months 0.5 ml
o12 years 24 months 0.25 ml
X16 years 24 months 0.5 ml
o16 years 24 months 0.25 ml
Note: pooled data from national SPCs. HSA: human serum albumin. PCEC: primary chicken embryonic cells.
versions of Encepurs are administered on day 0 (1st dose), after 1–3 months (2nd dose), followed by a 3rd dose 9–12 months later for completion of the primary immunization course (Zent et al., 2005). For the licensed versions of FSME-IMMUNs, immunizations are to be administered for persons aged X16 years on day 0 (1st dose), after 21 days to 3 months (2nd dose), followed by the 3rd dose 5–12 months later for completion of the primary immunization course. For persons aged o16 years primary immunization consists of vaccinations given on day 0 (1st dose), after 1–3 months (2nd dose), followed by the 3rd dose 9–12 months later (Barret et al., 2004; Anonymous, 2005). The rapid immunization schedule registered for the licensed versions of the TBE vaccine Encepurs consists of three immunizations, on days 0, 7, and 21 for primary immunization (Harabacz et al., 1992; Zent et al., 2005). It is intended for people who require immunity at short notice, e.g. travellers from non-endemic areas travelling to TBE endemic areas or when the tick season has already started. The recommended rapid immunization schedule for the licensed versions of the FSMEIMMUNs vaccine consists of immunizations on days 0 and 14 followed by the 3rd dose 5–12 months (persons aged X16 years) or 9–12 months (persons aged o16 years) later for completion of primary immunization (Barret et al., 2004; Anonymous, 2005).
Booster intervals Until recently, recommended intervals for booster immunizations remained unchanged for many years.
Regular booster doses were recommended every 3 years when using the conventional immunization schedule. For the immunization according to the rapid schedule, it was recommended to administer the 1st booster dose as early as 12–18 months after completion of the primary immunization. Subsequent booster doses were recommended every 3 years. However, recent study results which are discussed below about the persistence of TBE antibodies post-immunization led the Austrian Immunization Board to change their recommendation as follows: Regular boosters are now recommended every 5 years for subjects o60 years, except for the administration of the 1st booster which remains unchanged (see Table 2). For subjects aged 60 years or older it is also recommended to maintain 3-year intervals for regular booster immunizations (Anonymous, 2004).
Serological studies for the persistence of TBE antibodies Conventional schedule No data which are based on prospective serological follow-up studies have been published to date, although such studies might have been performed. At least one historical, so far unpublished, prospective serological follow-up study is known: It refers to a previously licensed version of Encepurs and was conducted from 1991 to 1994. The study revealed the persistence of TBE antibodies (as measured by ELISA) in 85% of the study subjects at 3.5 years after completion of primary immunization (data on file, Chiron Vaccines).
ARTICLE IN PRESS 204
Table 2.
P. Rendi-Wagner et al. / International Journal of Medical Microbiology 296 (2006) S1, 202–207
TBE immunization schedules for primary and booster immunization
Registered schedules for TBE immunization Conventional schedules FSME-IMMUNs 0.5 ml (Adults)/0.25 ml juniorb
Encepurs Adults/children Rapid schedules FSME-IMMUNs 0.5 ml (Adults)/0.25 ml juniorb
Encepurs Adults/children
Primary immunization
1st booster dose
Subsequent booster dosesa
(n ¼ 3 doses)
(n ¼ 4th dose)
(nX5 doses)
1st: day 0 2nd: 21 days/1b–3 months
After 3 years
Every 5 years for people aged o60 yr Every 3 years for people aged X60 yr
After 3 years
Every 5 years for people aged o60 yr Every 3 years for people aged X60 yr
After 3 years
Every 5 years for people aged o60 yrs Every 3 years for people aged X60 yrs
After 12–18 months
Every 5 years for people aged o60 yrs Every 3 years for people aged X60 yrs
3rd: 5–12 months/9–12 monthsb after 2nd dose 1st: day 0 2nd: 1–3 months 3rd: 9–12 months after 2nd dose 1st: day 0 2nd: day 14 3rd: 5–12 months/9–12 monthsb after 2nd dose 1st: day 0 2nd: day 7 3rd: day 21
Note: pooled data from national SPCs. a According to recommendations of the Austrian Immunization Board. b Relates to FSME-IMMUNs 0.25 ml junior.
A few retrospective studies for the evaluation of the TBE antibody status in previously vaccinated subjects have been published. Historically, data were published in the late 1980s and 1990s and referred to previous versions of the TBE vaccine FSME-IMMUNs (Kunz, 1989, 1996). More recently, five studies have been performed which are summarized as follows:
Study A In this retrospective, mono-center phase IV study conducted in Austria in 2002, the TBE antibody status (measured by a neutralization test (NT) as described elsewhere (Zent et al., 2003) and two different ELISA methods) was evaluated in subjects with a complete primary TBE immunization (and possible additional booster immunizations) at least 3 years after completion of the primary or booster immunization (Rendi–Wagner et al., 2004a, b). Subjects were stratified into two age groups (adults: 18–49 years and elderly X50 years of age) and according to the time interval between study entry and the last TBE immunization (3–5, 6–7, X8 years). On study, the subjects also received a booster dose with the marketed TBE vaccine Encepurs adults. A total of 430 volunteers (male: 37%; female: 63%) all of whom were previously immunized with marketed versions of FSME-IMMUNs participated in the trial.
The mean number of previous TBE vaccine doses received was 5.5 for the younger adults and 5.8 for the elderly, the mean number of years since the last TBE immunization was 6.672.7 years and 5.672.9 years, respectively. Comparison of demographic characteristics did not reveal any clinically relevant differences for the different strata, except for age. All subjects had previously been immunized with marketed versions of FSME-IMMUNs and received a subsequent TBE immunization with the marketed TBE vaccine Encepurs adults. As tested by NT, the baseline geometric mean titers (GMTs) of all subgroups were 144 and 44 for the 18–49 year olds and the X50 year olds, respectively. Approximately 95% of the subjects had NT titer levels X10. The majority of subjects was also TBE seropositive by both ELISA methods. Only 1% of the subjects aged 18–49 years, and 6% of the subjects aged X50 years were negative or borderline in ELISA. When analyzing the study population by age groups, it was evident that subjects X50 years had significantly lower titers compared to the younger adults, and this was noted for all time intervals. Notably, the data also indicate differences in both the baseline titers and the kinetics of the immune response after a subsequent booster dose in subjects who had just received primary immunization (n ¼ 3 doses) versus subjects with nX4 previous TBE immunizations. Following a single booster dose, the GMT at 3 weeks post-immunization
ARTICLE IN PRESS P. Rendi-Wagner et al. / International Journal of Medical Microbiology 296 (2006) S1, 202–207
(as measured by NT) was 331 and 142 for the 18–49 year olds and the X50 year olds, respectively. The results of this study generally initiated discussion in Austria about reconsideration (prolongation) of TBE booster intervals. Furthermore, this study clearly showed that it is not necessary to re-start primary immunization when booster intervals are exceeded, provided that the primary TBE immunization has been completed.
Study B In this retrospective study conducted between 2000 and 2002 in the Czech Republic, TBE antibody levels (as measured by ELISA) were investigated in subjects with an incomplete or complete primary TBE immunization (partly including subjects who had already received booster doses) prior to an additional TBE vaccination (Pazdiora and Janusˇ ka, 2004). Subjects were stratified into two age groups (younger and older adults) and according to the number of previous TBE immunizations (n ¼ 2, 3, 4, 5, and 6 doses). All subjects had previously been immunized with marketed versions of FSME-IMMUNs and received a subsequent TBE immunization with the marketed version of Encepurs. The proportion of the 143 study participants with high pre-immunization TBE antibody levels (4126 VIE U/ml as measured by the Immunozym-ELISA) ranged between 71% and 100% for younger adults (14–27 years) and 33–91% for older adults (aged 55–72 years). Notably, the lower proportions were noted prior to the 3rd and 4th dose. Post-immunization TBE antibody levels 4126 VIE U/ml were noted in 100% of the younger adults and ranged between 93% and 100% for the elderly. The authors concluded that the study results support the combined use of the two different TBE vaccines, which were used in this study, for completion of the primary immunization course and/or booster immunization. However, the authors also considered it necessary to further evaluate the 3-year interval for booster immunizations.
Study C In this serological survey, the TBE antibody status in 47 subjects with a history of 3–8 TBE vaccine doses was evaluated (Kind, 2004). Hence, the majority of subjects had already received more than 3 doses in the past. The interval to the latest TBE immunization ranged from 3 to 11 years. Forty-six of 47 subjects (98%) tested TBE positive (no detailed information about the diagnostic test method provided). The author concluded therefore that regular TBE booster immunizations every 3 years are probably not justified.
205
Rapid schedule Recently, two prospective serological follow-up studies were published and shall be reviewed as follows:
Study D In this prospective study conducted from 2001 to 2003 in Germany, the persistence of neutralizing TBE antibodies was investigated at 1 and 2 years after the 1st booster dose (Zent et al., 2004). Furthermore, the TBE antibody status as measured by ELISA (Enzygnosts Anti-TBE virus) was evaluated. The 191 study participants (aged 20–52 years) had received their 1st booster dose (Encepurs adults) in a previous study which was performed at 12–18 months after completion of the primary TBE immunization. At 1 and 2 years after the 1st booster dose, TBE antibodies measured by an NT as described elsewhere (Zent et al., 2003) had remained at a high level: As tested by NT, the GMT was 462 and 400, respectively, and more than 99% of the subjects still had NT titer levels X10. Similarly, 98% of the subjects tested positive in ELISA. Based on these study results, the authors concluded that a subsequent booster dose after 3 years is not justified in the TBE IgG positive subjects. In this context, a general reconsideration of TBE booster intervals has been proposed.
Study E In this prospective study conducted from 1999 to 2002 in the Czech Republic, the persistence of TBE antibodies (as measured by ELISA) was investigated 3 years after the 1st booster dose (Beran et al., 2004). The 148 study participants (aged 18–63 years) had received the 1st booster dose (with the historical version of the TBE vaccine Encepurs) in a previous study 15 months after completion of the primary TBE immunization. In the context of this serological follow-up, the study participants also received the 2nd booster dose with the marketed TBE vaccine Encepurs adults. As measured by ELISA (Enzygnosts Anti-TBE virus), all 148 subjects were still seropositive prior to the 2nd booster dose; the baseline GMTs were 149 and 71 U/ml for the 18–49 year olds and the X50 year olds, respectively. The 2nd booster immunization resulted in an increase of TBE antibodies (419 and 286 U/ml, respectively) as measured 30 (+10) days following the 2nd booster dose. Based on these study results, the authors concluded that this TBE vaccine may be used to effectively boost adults previously immunized with the former version of the vaccine.
ARTICLE IN PRESS 206
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Discussion and conclusions All serological studies which are briefly summarized in this article clearly showed that persistence of TBE antibodies following the administration of at least 4 vaccine doses is much longer than expected so far. Studies A and B also indicate a more rapid decline of antibodies in subjects with a history of just 3 vaccine doses as compared to those with at least 4 vaccine doses. These results were noted independently of the kind of TBE vaccine administered and the immunization schedules used for either primary or booster immunization. Of particular interest is study A, which analyzed subjects with overrun booster intervals separately. Generally, a good immune response following a single booster dose was noted in this study and this was independent from the time interval elapsed since the latest TBE immunization. Serological data from the studies A, B, and E, which were stratified and analyzed by age groups, clearly indicate differences in the immune response between younger adults aged 18–49 years and older adults aged X50 years. In this context, it could be demonstrated that not only the persistence of TBE immunity is compromised in the elderly, but also that the postbooster immune response is of lower magnitude than in younger adults. Considering the usage of different test methods for TBE antibody determination (i.e. NT, various ELISA tests) in individual studies, it is difficult to compare the serological data directly between each of the 5 studies. Determination of TBE antibodies by NT is the method of choice for assessment of protective immunity. However, practical implications based on the complicated procedure for performance of NTs resulted in the widespread use of various TBE ELISAs for assessment of antibody status. IgG antibodies as measured by ELISA can be regarded as indicators for the presence of neutralizing TBE antibodies, nonetheless, there are obvious limitations when using ELISA methods, e.g. due to cross-reactivity with other flaviviruses (Holzmann et al., 1996). A case report in a subject in whom re-vaccination was rejected on the basis of a positive ELISA test and who subsequently experienced TBE and died from its complications (Kaiser, 1999; Kaiser et al., 1999) stresses the importance of neutralizing TBE antibodies for assessment of protective immunity. The results about the persistence of TBE antibodies generally correlate with risk factors identified in (the few) patients who experienced vaccine failures following TBE vaccination as analyzed on a regular basis by the Austrian Immunization Board (Kollaritsch, pers. comm.): Although the current data are inconclusive, it appears that risk factors for vaccine failures include advanced age (X60 years), a limited number of vaccina-
tions (o4 doses) and exceeded intervals between primary immunization and the 1st booster dose. Similarly, the serological follow-up studies indicate that the TBE immunity is compromised in the elderly and that there is a more rapid decline of antibodies in subjects who received only 3 immunizations. Thus, the results from serological follow-up studies generally support the recent recommendation of the Austrian Immunization Board to prolong the booster intervals following the 1st booster immunization (n ¼ 4 doses) just for the younger adults from 3 to 5 years. To conclude, the recently published data can be regarded as encouraging with respect to a general reconsideration of TBE booster intervals. However, further serological long-term studies with the currently licensed TBE vaccines for different age groups and all immunization schedules used for primary immunization are recommended to build up a solid basis for future TBE booster recommendations.
References Anonymous, 2004. Impfplan 2004 O¨sterreich. Empfehlungen des Obersten Sanita¨tsrates (Impfausschuss) vom 4. November 2003. www.bmgf.gv.at. Anonymous, 2005. Fachinformation (Zusammenfassung der Produkteigenschaften/SPC), FSME-IMMUN Erwachsene, Baxter Deutschland GmbH, Heidelberg, February 2005. Barret, P.N., Dorner, F., Ehrlich, H., Plotkin, S.A., 2004. Tick-borne encephalitis vaccine. In: Plotkin, S.A., Orenstein, W.A. (Eds.), Vaccines. W.B. Saunders Company, London, pp. 1039–1055. Beran, J., Douda, P., Gniel, D., Zent, O., 2004. Long-term immunity after vaccination against tick-borne encephalitis with Encepur using the rapid vaccination schedule. Int. J. Med. Microbiol. Suppl. 37, 130–133. Harabacz, I., Bock, H., Ju¨ngst, Ch., Klockmann, U., Praus, M., Weber, R., 1992. A randomized phase II study of new tick-borne encephalitis vaccine using three different doses and two immunization regimen. Vaccine 10, 145–150. Holzmann, H., Kundi, M., Stiasny, K., Clement, J., McKenna, P., Kunz, C., Heinz, F.X., 1996. Correlation between ELISA, hemagglutination inhibition, and neutralization test after vaccination against tick-borne encephalitis. J. Med. Virol. 48, 102–107. Kaiser, R., 1999. Impfung gegen FSME – fraglicher Nutzen der Antiko¨rperbestimmung zur U¨berpru¨fung der Immunita¨tslage. Dt. Med. Wschr. 124, 542. Kaiser, R., Neumann-Haefelin, D., Hartmann, J., Stunder, W.A., 1999. Impfung gegen FSME: Wie lange ha¨lt der Impfschutz und was bringt die Antiko¨rperbestimmung zur U¨berpru¨fung der Immunita¨tslage? Z. Allg. Med. 75, 373–374. Kind, A., 2004. Wie viele Auffrischimpfungen sind notwendig gegen die Zeckenencephalitis FSME (Fru¨hsommermeningoencephalitis)? Schweiz. A¨rztezeitung 85, 844–848. Kunz, C., 1989. Erfahrungen mit einem modernen Impfstoff am Beispiel der FSME-Impfung in O¨sterrreich. In: Stickl,
ARTICLE IN PRESS P. Rendi-Wagner et al. / International Journal of Medical Microbiology 296 (2006) S1, 202–207
H.A., Kunz, C. (Eds.), Moderne Impfungen. Springer, Berlin, pp. 15–25. Kunz, C., 1996. Epidemiology of tick-borne encephalitis and the impact of vaccination on the incidence of disease. In: Eible, M.M., Huber, C., Peter, H.H., Wahn, V. (Eds.), Proceedings of the Fifth Symposium on Immunology. Springer, Berlin, pp. 143–149. Pazdiora, P., Janusˇ ka, J., 2004. Dynamics of antibody formation after vaccination against tick-borne encephalitis. Epidemiol. Mikrobiol. Imunol. 1, 17–21 (in Czech). Rendi-Wagner, P., Kundi, M., Zent, O., Dvorak, G., Jaehnig, P., Holzmann, H., Mikolasek, A., Kollaritsch, H., 2004a. Protective immunity following vaccination against tickborne encephalitis: antibody persistence longer than expected? Vaccine 22, 2743–2749. Rendi-Wagner, P., Kundi, M., Zent, O., Banzhoff, A., Jaehnig, P., Stemberger, R., Dvorak, G., Grumbeck, E.,
207
Laaber, B., Kollaritsch, H., 2004b. Immunogenicity and safety of a booster vaccination against tick-borne encephalitis more than 3 years following the last immunization. Vaccine 23, 427–434. Zent, O., Banzhoff, A., Hilbert, A.K., Meriste, S., Sluzewski, W., Wittermann, Ch., 2003. Safety, immunogenicity and tolerability of a new pediatric tick-borne encephalitis (TBE) vaccine, free of protein-derived stabilizer. Vaccine 21, 3584–3592. Zent, O., Plentz, A., Schwarz, T.F., Fru¨hwein, N., Kuhr, H.B., Broeker, M., Banzhoff, A., Jilg, W., 2004. TBE immunization according to the rapid immunization schedule: are 3-year booster intervals really necessary? Vaccine 23, 312–315. Zent, O., Hennig, R., Banzhoff, A., Broeker, M., 2005. Protection against tick-borne encephalitis (TBE) with a new vaccine formulation – free of protein-derived stabilizers. J. Travel. Med. 12, 85–93.
International Journal of Medical Microbiology 296 (2006) S1, 202–207 www.elsevier.de/ijmm
MINI-REVIEW
Persistence of antibodies after vaccination against tick-borne encephalitis Pamela Rendi-Wagnera, Olaf Zentb,, Wolfgang Jilgc, Annelie Plentzc, Jiri Berand, Herwig Kollaritscha a
Department of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Austria Chiron Vaccines, Emil-von-Behring-Str. 76, D-35041 Marburg, Germany c University of Regensburg, Germany d Department of Infectious Diseases, University Hospital, Hradec Kralove, Czech Republic b
Abstract Active vaccination against the tick-borne encephalitis (TBE) virus has successfully been implemented in endemic countries for many years. However, little was known about persistency of antibodies after completion of the primary vaccination and/or TBE booster immunization. Five recently performed serological follow-up studies in adults have now revealed that the persistence of protective immunity following at least one booster immunization was longer than expected. Notably, studies which analyzed different age groups indicate differences between younger adults aged 18–49 years and older adults aged X50 years with respect to TBE antibody persistence and the immune response following a subsequent booster dose. To summarize, the serological studies included in this analysis generally support a reconsideration of current TBE booster recommendations and a prolongation of booster intervals at least in younger adults. r 2006 Elsevier GmbH. All rights reserved. Keywords: Tick-borne encephalitis; Vaccine; Booster immunization; Immunity
Introduction Active vaccination appears to be the most effective means of prevention of tick-borne encephalitis (Barret et al., 2004). Thus, TBE vaccination strategies have successfully been implemented in many European countries, where TBE is endemic. The development and recent licensure of improved TBE vaccine formulations has rendered it necessary to re-evaluate recommendations for booster intervals, which have been unchanged for many years. Noticeably, little is known about persistence of antibodies after primary vaccination and/or TBE booster immunizations: Only a few serological studies have been published during the last Corresponding author. Tel.: +49 6421 39 4759; fax: +49 6421 39 4667. E-mail address: [email protected] (O. Zent).
1438-4221/$ - see front matter r 2006 Elsevier GmbH. All rights reserved. doi:10.1016/j.ijmm.2006.01.030
years; and these shall be reviewed in this article. In this context, the persistence of TBE antibodies when using different immunization schedules for primary TBE immunization is of particular interest.
TBE immunization schedules for primary immunization There are two different immunization schedules registered for primary immunization against TBE for the widely used European TBE vaccines (i.e. licensed versions of Encepurs, Chiron Behring GmbH & Co KG, Germany, and FSME-IMMUNs, Baxter AG, Austria) (Table 1). The conventional immunization schedule consists of three immunizations (Table 2), which for licensed
ARTICLE IN PRESS P. Rendi-Wagner et al. / International Journal of Medical Microbiology 296 (2006) S1, 202–207
Table 1.
203
Pharmaceutical composition of widely used TBE vaccines Encepurs Adults (since 2001)
Encepurs Children (since 2001)
FSME-IMMUNs 0.5 ml (adults) (since 2001)
FSME-IMMUNs 0.25 ml junior (since 2001)
Antigen details Strain Passages Production Amount of antigen
K-23 PCEC PCEC 1.5 mg
K-23 PCEC PCEC 0.75 mg
Neudoerfl PCEC PCEC 2.4 mg
Neudoerfl PCEC PCEC 1.2 mg
Excipients Adjuvant Preservative Stabilizer
Al(OH)3 No Sucrose
Al(OH)3 No Sucrose
Al(OH)3 No HSA
Al(OH)3 No HSA
Age limit Shelf life Adjusted
X12 years 24 months 0.5 ml
o12 years 24 months 0.25 ml
X16 years 24 months 0.5 ml
o16 years 24 months 0.25 ml
Note: pooled data from national SPCs. HSA: human serum albumin. PCEC: primary chicken embryonic cells.
versions of Encepurs are administered on day 0 (1st dose), after 1–3 months (2nd dose), followed by a 3rd dose 9–12 months later for completion of the primary immunization course (Zent et al., 2005). For the licensed versions of FSME-IMMUNs, immunizations are to be administered for persons aged X16 years on day 0 (1st dose), after 21 days to 3 months (2nd dose), followed by the 3rd dose 5–12 months later for completion of the primary immunization course. For persons aged o16 years primary immunization consists of vaccinations given on day 0 (1st dose), after 1–3 months (2nd dose), followed by the 3rd dose 9–12 months later (Barret et al., 2004; Anonymous, 2005). The rapid immunization schedule registered for the licensed versions of the TBE vaccine Encepurs consists of three immunizations, on days 0, 7, and 21 for primary immunization (Harabacz et al., 1992; Zent et al., 2005). It is intended for people who require immunity at short notice, e.g. travellers from non-endemic areas travelling to TBE endemic areas or when the tick season has already started. The recommended rapid immunization schedule for the licensed versions of the FSMEIMMUNs vaccine consists of immunizations on days 0 and 14 followed by the 3rd dose 5–12 months (persons aged X16 years) or 9–12 months (persons aged o16 years) later for completion of primary immunization (Barret et al., 2004; Anonymous, 2005).
Booster intervals Until recently, recommended intervals for booster immunizations remained unchanged for many years.
Regular booster doses were recommended every 3 years when using the conventional immunization schedule. For the immunization according to the rapid schedule, it was recommended to administer the 1st booster dose as early as 12–18 months after completion of the primary immunization. Subsequent booster doses were recommended every 3 years. However, recent study results which are discussed below about the persistence of TBE antibodies post-immunization led the Austrian Immunization Board to change their recommendation as follows: Regular boosters are now recommended every 5 years for subjects o60 years, except for the administration of the 1st booster which remains unchanged (see Table 2). For subjects aged 60 years or older it is also recommended to maintain 3-year intervals for regular booster immunizations (Anonymous, 2004).
Serological studies for the persistence of TBE antibodies Conventional schedule No data which are based on prospective serological follow-up studies have been published to date, although such studies might have been performed. At least one historical, so far unpublished, prospective serological follow-up study is known: It refers to a previously licensed version of Encepurs and was conducted from 1991 to 1994. The study revealed the persistence of TBE antibodies (as measured by ELISA) in 85% of the study subjects at 3.5 years after completion of primary immunization (data on file, Chiron Vaccines).
ARTICLE IN PRESS 204
Table 2.
P. Rendi-Wagner et al. / International Journal of Medical Microbiology 296 (2006) S1, 202–207
TBE immunization schedules for primary and booster immunization
Registered schedules for TBE immunization Conventional schedules FSME-IMMUNs 0.5 ml (Adults)/0.25 ml juniorb
Encepurs Adults/children Rapid schedules FSME-IMMUNs 0.5 ml (Adults)/0.25 ml juniorb
Encepurs Adults/children
Primary immunization
1st booster dose
Subsequent booster dosesa
(n ¼ 3 doses)
(n ¼ 4th dose)
(nX5 doses)
1st: day 0 2nd: 21 days/1b–3 months
After 3 years
Every 5 years for people aged o60 yr Every 3 years for people aged X60 yr
After 3 years
Every 5 years for people aged o60 yr Every 3 years for people aged X60 yr
After 3 years
Every 5 years for people aged o60 yrs Every 3 years for people aged X60 yrs
After 12–18 months
Every 5 years for people aged o60 yrs Every 3 years for people aged X60 yrs
3rd: 5–12 months/9–12 monthsb after 2nd dose 1st: day 0 2nd: 1–3 months 3rd: 9–12 months after 2nd dose 1st: day 0 2nd: day 14 3rd: 5–12 months/9–12 monthsb after 2nd dose 1st: day 0 2nd: day 7 3rd: day 21
Note: pooled data from national SPCs. a According to recommendations of the Austrian Immunization Board. b Relates to FSME-IMMUNs 0.25 ml junior.
A few retrospective studies for the evaluation of the TBE antibody status in previously vaccinated subjects have been published. Historically, data were published in the late 1980s and 1990s and referred to previous versions of the TBE vaccine FSME-IMMUNs (Kunz, 1989, 1996). More recently, five studies have been performed which are summarized as follows:
Study A In this retrospective, mono-center phase IV study conducted in Austria in 2002, the TBE antibody status (measured by a neutralization test (NT) as described elsewhere (Zent et al., 2003) and two different ELISA methods) was evaluated in subjects with a complete primary TBE immunization (and possible additional booster immunizations) at least 3 years after completion of the primary or booster immunization (Rendi–Wagner et al., 2004a, b). Subjects were stratified into two age groups (adults: 18–49 years and elderly X50 years of age) and according to the time interval between study entry and the last TBE immunization (3–5, 6–7, X8 years). On study, the subjects also received a booster dose with the marketed TBE vaccine Encepurs adults. A total of 430 volunteers (male: 37%; female: 63%) all of whom were previously immunized with marketed versions of FSME-IMMUNs participated in the trial.
The mean number of previous TBE vaccine doses received was 5.5 for the younger adults and 5.8 for the elderly, the mean number of years since the last TBE immunization was 6.672.7 years and 5.672.9 years, respectively. Comparison of demographic characteristics did not reveal any clinically relevant differences for the different strata, except for age. All subjects had previously been immunized with marketed versions of FSME-IMMUNs and received a subsequent TBE immunization with the marketed TBE vaccine Encepurs adults. As tested by NT, the baseline geometric mean titers (GMTs) of all subgroups were 144 and 44 for the 18–49 year olds and the X50 year olds, respectively. Approximately 95% of the subjects had NT titer levels X10. The majority of subjects was also TBE seropositive by both ELISA methods. Only 1% of the subjects aged 18–49 years, and 6% of the subjects aged X50 years were negative or borderline in ELISA. When analyzing the study population by age groups, it was evident that subjects X50 years had significantly lower titers compared to the younger adults, and this was noted for all time intervals. Notably, the data also indicate differences in both the baseline titers and the kinetics of the immune response after a subsequent booster dose in subjects who had just received primary immunization (n ¼ 3 doses) versus subjects with nX4 previous TBE immunizations. Following a single booster dose, the GMT at 3 weeks post-immunization
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(as measured by NT) was 331 and 142 for the 18–49 year olds and the X50 year olds, respectively. The results of this study generally initiated discussion in Austria about reconsideration (prolongation) of TBE booster intervals. Furthermore, this study clearly showed that it is not necessary to re-start primary immunization when booster intervals are exceeded, provided that the primary TBE immunization has been completed.
Study B In this retrospective study conducted between 2000 and 2002 in the Czech Republic, TBE antibody levels (as measured by ELISA) were investigated in subjects with an incomplete or complete primary TBE immunization (partly including subjects who had already received booster doses) prior to an additional TBE vaccination (Pazdiora and Janusˇ ka, 2004). Subjects were stratified into two age groups (younger and older adults) and according to the number of previous TBE immunizations (n ¼ 2, 3, 4, 5, and 6 doses). All subjects had previously been immunized with marketed versions of FSME-IMMUNs and received a subsequent TBE immunization with the marketed version of Encepurs. The proportion of the 143 study participants with high pre-immunization TBE antibody levels (4126 VIE U/ml as measured by the Immunozym-ELISA) ranged between 71% and 100% for younger adults (14–27 years) and 33–91% for older adults (aged 55–72 years). Notably, the lower proportions were noted prior to the 3rd and 4th dose. Post-immunization TBE antibody levels 4126 VIE U/ml were noted in 100% of the younger adults and ranged between 93% and 100% for the elderly. The authors concluded that the study results support the combined use of the two different TBE vaccines, which were used in this study, for completion of the primary immunization course and/or booster immunization. However, the authors also considered it necessary to further evaluate the 3-year interval for booster immunizations.
Study C In this serological survey, the TBE antibody status in 47 subjects with a history of 3–8 TBE vaccine doses was evaluated (Kind, 2004). Hence, the majority of subjects had already received more than 3 doses in the past. The interval to the latest TBE immunization ranged from 3 to 11 years. Forty-six of 47 subjects (98%) tested TBE positive (no detailed information about the diagnostic test method provided). The author concluded therefore that regular TBE booster immunizations every 3 years are probably not justified.
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Rapid schedule Recently, two prospective serological follow-up studies were published and shall be reviewed as follows:
Study D In this prospective study conducted from 2001 to 2003 in Germany, the persistence of neutralizing TBE antibodies was investigated at 1 and 2 years after the 1st booster dose (Zent et al., 2004). Furthermore, the TBE antibody status as measured by ELISA (Enzygnosts Anti-TBE virus) was evaluated. The 191 study participants (aged 20–52 years) had received their 1st booster dose (Encepurs adults) in a previous study which was performed at 12–18 months after completion of the primary TBE immunization. At 1 and 2 years after the 1st booster dose, TBE antibodies measured by an NT as described elsewhere (Zent et al., 2003) had remained at a high level: As tested by NT, the GMT was 462 and 400, respectively, and more than 99% of the subjects still had NT titer levels X10. Similarly, 98% of the subjects tested positive in ELISA. Based on these study results, the authors concluded that a subsequent booster dose after 3 years is not justified in the TBE IgG positive subjects. In this context, a general reconsideration of TBE booster intervals has been proposed.
Study E In this prospective study conducted from 1999 to 2002 in the Czech Republic, the persistence of TBE antibodies (as measured by ELISA) was investigated 3 years after the 1st booster dose (Beran et al., 2004). The 148 study participants (aged 18–63 years) had received the 1st booster dose (with the historical version of the TBE vaccine Encepurs) in a previous study 15 months after completion of the primary TBE immunization. In the context of this serological follow-up, the study participants also received the 2nd booster dose with the marketed TBE vaccine Encepurs adults. As measured by ELISA (Enzygnosts Anti-TBE virus), all 148 subjects were still seropositive prior to the 2nd booster dose; the baseline GMTs were 149 and 71 U/ml for the 18–49 year olds and the X50 year olds, respectively. The 2nd booster immunization resulted in an increase of TBE antibodies (419 and 286 U/ml, respectively) as measured 30 (+10) days following the 2nd booster dose. Based on these study results, the authors concluded that this TBE vaccine may be used to effectively boost adults previously immunized with the former version of the vaccine.
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Discussion and conclusions All serological studies which are briefly summarized in this article clearly showed that persistence of TBE antibodies following the administration of at least 4 vaccine doses is much longer than expected so far. Studies A and B also indicate a more rapid decline of antibodies in subjects with a history of just 3 vaccine doses as compared to those with at least 4 vaccine doses. These results were noted independently of the kind of TBE vaccine administered and the immunization schedules used for either primary or booster immunization. Of particular interest is study A, which analyzed subjects with overrun booster intervals separately. Generally, a good immune response following a single booster dose was noted in this study and this was independent from the time interval elapsed since the latest TBE immunization. Serological data from the studies A, B, and E, which were stratified and analyzed by age groups, clearly indicate differences in the immune response between younger adults aged 18–49 years and older adults aged X50 years. In this context, it could be demonstrated that not only the persistence of TBE immunity is compromised in the elderly, but also that the postbooster immune response is of lower magnitude than in younger adults. Considering the usage of different test methods for TBE antibody determination (i.e. NT, various ELISA tests) in individual studies, it is difficult to compare the serological data directly between each of the 5 studies. Determination of TBE antibodies by NT is the method of choice for assessment of protective immunity. However, practical implications based on the complicated procedure for performance of NTs resulted in the widespread use of various TBE ELISAs for assessment of antibody status. IgG antibodies as measured by ELISA can be regarded as indicators for the presence of neutralizing TBE antibodies, nonetheless, there are obvious limitations when using ELISA methods, e.g. due to cross-reactivity with other flaviviruses (Holzmann et al., 1996). A case report in a subject in whom re-vaccination was rejected on the basis of a positive ELISA test and who subsequently experienced TBE and died from its complications (Kaiser, 1999; Kaiser et al., 1999) stresses the importance of neutralizing TBE antibodies for assessment of protective immunity. The results about the persistence of TBE antibodies generally correlate with risk factors identified in (the few) patients who experienced vaccine failures following TBE vaccination as analyzed on a regular basis by the Austrian Immunization Board (Kollaritsch, pers. comm.): Although the current data are inconclusive, it appears that risk factors for vaccine failures include advanced age (X60 years), a limited number of vaccina-
tions (o4 doses) and exceeded intervals between primary immunization and the 1st booster dose. Similarly, the serological follow-up studies indicate that the TBE immunity is compromised in the elderly and that there is a more rapid decline of antibodies in subjects who received only 3 immunizations. Thus, the results from serological follow-up studies generally support the recent recommendation of the Austrian Immunization Board to prolong the booster intervals following the 1st booster immunization (n ¼ 4 doses) just for the younger adults from 3 to 5 years. To conclude, the recently published data can be regarded as encouraging with respect to a general reconsideration of TBE booster intervals. However, further serological long-term studies with the currently licensed TBE vaccines for different age groups and all immunization schedules used for primary immunization are recommended to build up a solid basis for future TBE booster recommendations.
References Anonymous, 2004. Impfplan 2004 O¨sterreich. Empfehlungen des Obersten Sanita¨tsrates (Impfausschuss) vom 4. November 2003. www.bmgf.gv.at. Anonymous, 2005. Fachinformation (Zusammenfassung der Produkteigenschaften/SPC), FSME-IMMUN Erwachsene, Baxter Deutschland GmbH, Heidelberg, February 2005. Barret, P.N., Dorner, F., Ehrlich, H., Plotkin, S.A., 2004. Tick-borne encephalitis vaccine. In: Plotkin, S.A., Orenstein, W.A. (Eds.), Vaccines. W.B. Saunders Company, London, pp. 1039–1055. Beran, J., Douda, P., Gniel, D., Zent, O., 2004. Long-term immunity after vaccination against tick-borne encephalitis with Encepur using the rapid vaccination schedule. Int. J. Med. Microbiol. Suppl. 37, 130–133. Harabacz, I., Bock, H., Ju¨ngst, Ch., Klockmann, U., Praus, M., Weber, R., 1992. A randomized phase II study of new tick-borne encephalitis vaccine using three different doses and two immunization regimen. Vaccine 10, 145–150. Holzmann, H., Kundi, M., Stiasny, K., Clement, J., McKenna, P., Kunz, C., Heinz, F.X., 1996. Correlation between ELISA, hemagglutination inhibition, and neutralization test after vaccination against tick-borne encephalitis. J. Med. Virol. 48, 102–107. Kaiser, R., 1999. Impfung gegen FSME – fraglicher Nutzen der Antiko¨rperbestimmung zur U¨berpru¨fung der Immunita¨tslage. Dt. Med. Wschr. 124, 542. Kaiser, R., Neumann-Haefelin, D., Hartmann, J., Stunder, W.A., 1999. Impfung gegen FSME: Wie lange ha¨lt der Impfschutz und was bringt die Antiko¨rperbestimmung zur U¨berpru¨fung der Immunita¨tslage? Z. Allg. Med. 75, 373–374. Kind, A., 2004. Wie viele Auffrischimpfungen sind notwendig gegen die Zeckenencephalitis FSME (Fru¨hsommermeningoencephalitis)? Schweiz. A¨rztezeitung 85, 844–848. Kunz, C., 1989. Erfahrungen mit einem modernen Impfstoff am Beispiel der FSME-Impfung in O¨sterrreich. In: Stickl,
ARTICLE IN PRESS P. Rendi-Wagner et al. / International Journal of Medical Microbiology 296 (2006) S1, 202–207
H.A., Kunz, C. (Eds.), Moderne Impfungen. Springer, Berlin, pp. 15–25. Kunz, C., 1996. Epidemiology of tick-borne encephalitis and the impact of vaccination on the incidence of disease. In: Eible, M.M., Huber, C., Peter, H.H., Wahn, V. (Eds.), Proceedings of the Fifth Symposium on Immunology. Springer, Berlin, pp. 143–149. Pazdiora, P., Janusˇ ka, J., 2004. Dynamics of antibody formation after vaccination against tick-borne encephalitis. Epidemiol. Mikrobiol. Imunol. 1, 17–21 (in Czech). Rendi-Wagner, P., Kundi, M., Zent, O., Dvorak, G., Jaehnig, P., Holzmann, H., Mikolasek, A., Kollaritsch, H., 2004a. Protective immunity following vaccination against tickborne encephalitis: antibody persistence longer than expected? Vaccine 22, 2743–2749. Rendi-Wagner, P., Kundi, M., Zent, O., Banzhoff, A., Jaehnig, P., Stemberger, R., Dvorak, G., Grumbeck, E.,
207
Laaber, B., Kollaritsch, H., 2004b. Immunogenicity and safety of a booster vaccination against tick-borne encephalitis more than 3 years following the last immunization. Vaccine 23, 427–434. Zent, O., Banzhoff, A., Hilbert, A.K., Meriste, S., Sluzewski, W., Wittermann, Ch., 2003. Safety, immunogenicity and tolerability of a new pediatric tick-borne encephalitis (TBE) vaccine, free of protein-derived stabilizer. Vaccine 21, 3584–3592. Zent, O., Plentz, A., Schwarz, T.F., Fru¨hwein, N., Kuhr, H.B., Broeker, M., Banzhoff, A., Jilg, W., 2004. TBE immunization according to the rapid immunization schedule: are 3-year booster intervals really necessary? Vaccine 23, 312–315. Zent, O., Hennig, R., Banzhoff, A., Broeker, M., 2005. Protection against tick-borne encephalitis (TBE) with a new vaccine formulation – free of protein-derived stabilizers. J. Travel. Med. 12, 85–93.