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Estimated persistence of anti-HAV antibodies after single dose and booster hepatitis A vaccination (0-6 schedule)
Acta Tropica 69 (1998) 121 – 125
Estimated persistence of anti-HAV antibodies after single dose and booster hepatitis A vaccination (0-6 schedule) G. Wiedermann a,*, M. Kundi b, F. Ambrosch a a
Institute of Specific Prophylaxis and Tropical Medicine, Uni6ersity of Vienna, Kinderspitalgasse 15, A-1095 Vienna, Austria b Institute for En6ironmental Hygiene, Uni6ersity of Vienna, Kinderspitalgasse 15, A-1095 Vienna, Austria Received 8 July 1997; received in revised form 30 September 1997; accepted 2 October 1997
Abstract The persistence of antibodies after a single dose and booster vaccination against hepatitis A (Havrix® 1440) has not yet been assessed. By reanalysing previously published data of serum titres and application of a two-component model, we estimated the duration of protection. In 134 vaccinees, aged 20 – 39 years, the GMT 1 month after booster was 3629 mlU/ml, which would result in an estimated duration of protection of 34.5 years and in 66 vaccinees aged 40–62 years a GMT of 2320 mlU/ml was calculated, resulting in a duration of protection of 31.5 years. Even when taking the minimum observed titres in the older age group into account, the duration of protection will be more than 10 years. Considering at the same time, its good tolerability and compliance, the single dose hepatitis A vaccination appears highly recommendable in travel medicine. © 1998 Elsevier Science B.V. All rights reserved. Keywords: Single dose hepatitis A vaccine; Antibody persistence; Hepatitis A vaccination in travel medicine
* Corresponding author. Tel.: +43 1 40490350; fax: + 43 1 403834390. 0001-706X/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved. PII S 0 0 0 1 - 7 0 6 X ( 9 7 ) 0 0 1 2 0 - 4
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G. Wiedermann et al. / Acta Tropica 69 (1998) 121–125
The introduction of a single dose and booster vaccination schedule applying an inactivated hepatitis A vaccine with elevated antigen concentration (Havrix® 1440) proved to be advantageous in some respect, in comparison with the conventional two dose primary immunization schedule with a booster after 6–12 months (0-1-6/12 schedule). It resulted in quicker seroconversion and better compliance and could favourably be used in international travel. The persistence of antibodies after application of the 0-6 schedule was expected to induce a comparable long lasting protection after the booster by some authors (Van Damme et al., 1994a), as after application of the standard 0-1-6/12 schedule of Havrix® 720. Other authors stated that the persistence of antibodies after the 0-6 vaccination with Havrix® 1440 has still to be assessed (Laufs and Polywka, 1993). From earlier studies with short follow up periods of 18 months to 3 years (Ambrosch et al., 1991; Just and Berger, 1992), an annual antibody decline of 40–50% was estimated. These studies were the basis of a recently published communication (Stemberger, 1997), which stated, that considering the antibody titres of 600 vaccinees 2 years after vaccination with Havrix® 1440 applying the 0-6 schedule, a further protection period of only 1 year has to be expected in 15% (titres below 100 mlU/ml), a further 5 years in 70% (titres between 100 and 1000 mlU/ml) and of more than 10 years in 15% (titres above 1000 mlU/ml). Therefore, it was recommended to perform the single dose vaccination only in younger people. However, according to long term follow up studies (Van Damme et al., 1994b; Wiedermann et al., 1997) anti-HAV antibody decline does not follow simple first order kinetics. Rather, the decline of antibodies follows a two-component model. The fast component, with an annual disappearance rate of 80– 99%, will be practically eliminated within months or at most, 2 years. Afterwards, the slow component with an annual disappearance rate of 11–14% becomes predominant, resulting in a long lasting antibody persistence. By application of the two-component model, a very good agreement to the data of a 7 years follow up (the longest period ever covered) has been obtained (Wiedermann et al., 1997). However, it has to be considered, that although less underestimating the duration of protection as compared to simple first order kinetics models, the actual antibody decline might be even slower as predicted by our two-component model. To estimate the antibody persistence in different age groups after vaccination with Havrix®) 1440 applying the 0-6 schedule, we reanalyzed the data of Briem and Safary (1994): Geometric mean titres (GMT), the minimum and maximum observed titres of two age groups (134 vaccinees aged 20–30 years and 66 vaccinees 40– 62 years old) were computed considering the values 1 month after booster. Antibodies to HAV were measured by ELISA (SmithKline Beecham). The antibody titres were calculated in mlU/ml in comparison with an immunoglobulin preparation (WHO standard). Antibody decline was estimated using the two-component model (Wiedermann et al., 1997): Titret =TitreB{r · (1 −f )[t − 7]/12 + (1− r)(1− s)[t − 7]/12} This equation holds for t ]27 (=1 month after booster). TitreB = titre 1 month after booster. The constant r (0 B rB 1) reflects the relative contribution of the rapidly declining component at month seven, f its annual disappearance rate and s
Number of vaccinees 134 66
Age group (years) 20–30 40–62
3629 2320
GMT
34.5 31.5
Duration of protection (years) based on GMT
232 98
Minimum titre
Table 1 GMTs and lowest observed anti-HAV antibody titres and estimated duration of protection for two age groups
16.3 10.6
Duration of protection (years) based on min titre
G. Wiedermann et al. / Acta Tropica 69 (1998) 121–125 123
G. Wiedermann et al. / Acta Tropica 69 (1998) 121–125
124
Table 2 Estimated proportion of protected individuals (cut off = 10 mlU/ml) 10 – 30 years after booster for two age groups Age group (years)
20 – 30 40 – 62
Number of vaccinees
134 66
Estimated % protected individuals
10 years after booster vaccination
20 years after booster vaccination
30 years after booster vaccination
100 (97–100) 100 (95–100)
99 (97 – 100) 94 (89 – 98)
77 (72 – 83) 58 (50 – 68)
95% Confidence limits are given in brackets.
is the annual disappearance rate for the slow component. Based on Van Damme et al. (1994b) and Wiedermann et al. (1997), r was set to 0.5, f to 0.99 and s to 0.14. Following these principles, the duration of protection was estimated considering GMTs as well as the lowest observed litres. The cut off for the protective level was set to 10 mlU/ml following the evaluation of Ambrosch et al. (1991).(Table 1) Antibody titres were somewhat lower in the older age group, as expected (Wagstaff et al., 1996). The estimated duration of protection however, varied only negligibly between age groups and will last for more than 30 years when considering GMTs. It will be even more than 10 years when taking minimum titres of the older age group into account (Table 2). Considering the above mentioned communication on 600 vaccinees (Stemberger, 1997), an average duration of protection of more than 30 years is estimated, observing that the titres were obtained 2 years after vaccination, at a time when the antibody decline is only a function of the slow component. Thus, application of a single dose hepatitis A vaccine can be expected to result in long lasting protection similar to the one after a conventional schedule. Together with its good tolerability and easy application, it recommends itself for use in travel medicine.
References Ambrosch, F., Wiedermann, G., Andre´, F.E., D’Hondt, E., Delem, A., Safary, A., 1991. Comparison of HAV antibodies induced by vaccination, passive immunisation and natural infection. In: Holzinger, F.B., Lemon, S.M., Margolis, H.S. (Eds.), Viral Hepatitis and Liver Disease. Williams and Wilkins, Baltimore, pp. 98–100. Briem, M., Safary, A., 1994. Immunogenicity and safety in adults of hepatitis A virus vaccine administered as a single dose with a booster 6 months later. J. Med. Virol. 44, 443 – 445. Just, M., Berger, R., 1992. Reactogenicity and immunogenicity of inactivated hepatitis A vaccines. Vaccine 10 (Suppl. 1), 110–113. Laufs, R., Polywka, S., 1993. Hepatitis A. Aktive Impfung gewahrt schon nach 2 Wochen Vollschutz. Med. Tribune 17, 20. Stemberger, H., 1997. Impfschutz im Zweifelsfall u¨berpru¨fen. A8 rztewoche 4, 4.
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125
Van Damme, P., Mathei, C., Thoelen, S., Meheus, A., Safary, A., Andre´, F.E., 1994a. Single dose inactivated hepatitis A vaccine: Rationale and clinical assessment of the safety and immunogenicity. J. Med. Virol. 44, 435–441. Van Damme, P., Thoelen, S., Cramm, M., DeGroote, K., Safary, A., Maheus, A., 1994b. Inactivated hepatitis A vaccine: Reactogenicity, immunogenicity, and long-term persistence. J. Med. Virol. 44, 446–451. Wagstaff, A.J., Plosker, G.L., Balfour, J., 1996. Inactivated hepatitis A vaccine strain. A preliminary review of its immunogenicity, protective potential and tolerability in at-risk patients. Clin. Immunother. 1, 66–88. Wiedermann, G., Kundi, M., Ambrosch, F., Safary, A., D’Hondt, E., Delem, A., 1997. Inactivated hepatitis A vaccine: Long term antibody persistence. Vaccine 15, 612 – 615.
.
Estimated persistence of anti-HAV antibodies after single dose and booster hepatitis A vaccination (0-6 schedule) G. Wiedermann a,*, M. Kundi b, F. Ambrosch a a
Institute of Specific Prophylaxis and Tropical Medicine, Uni6ersity of Vienna, Kinderspitalgasse 15, A-1095 Vienna, Austria b Institute for En6ironmental Hygiene, Uni6ersity of Vienna, Kinderspitalgasse 15, A-1095 Vienna, Austria Received 8 July 1997; received in revised form 30 September 1997; accepted 2 October 1997
Abstract The persistence of antibodies after a single dose and booster vaccination against hepatitis A (Havrix® 1440) has not yet been assessed. By reanalysing previously published data of serum titres and application of a two-component model, we estimated the duration of protection. In 134 vaccinees, aged 20 – 39 years, the GMT 1 month after booster was 3629 mlU/ml, which would result in an estimated duration of protection of 34.5 years and in 66 vaccinees aged 40–62 years a GMT of 2320 mlU/ml was calculated, resulting in a duration of protection of 31.5 years. Even when taking the minimum observed titres in the older age group into account, the duration of protection will be more than 10 years. Considering at the same time, its good tolerability and compliance, the single dose hepatitis A vaccination appears highly recommendable in travel medicine. © 1998 Elsevier Science B.V. All rights reserved. Keywords: Single dose hepatitis A vaccine; Antibody persistence; Hepatitis A vaccination in travel medicine
* Corresponding author. Tel.: +43 1 40490350; fax: + 43 1 403834390. 0001-706X/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved. PII S 0 0 0 1 - 7 0 6 X ( 9 7 ) 0 0 1 2 0 - 4
122
G. Wiedermann et al. / Acta Tropica 69 (1998) 121–125
The introduction of a single dose and booster vaccination schedule applying an inactivated hepatitis A vaccine with elevated antigen concentration (Havrix® 1440) proved to be advantageous in some respect, in comparison with the conventional two dose primary immunization schedule with a booster after 6–12 months (0-1-6/12 schedule). It resulted in quicker seroconversion and better compliance and could favourably be used in international travel. The persistence of antibodies after application of the 0-6 schedule was expected to induce a comparable long lasting protection after the booster by some authors (Van Damme et al., 1994a), as after application of the standard 0-1-6/12 schedule of Havrix® 720. Other authors stated that the persistence of antibodies after the 0-6 vaccination with Havrix® 1440 has still to be assessed (Laufs and Polywka, 1993). From earlier studies with short follow up periods of 18 months to 3 years (Ambrosch et al., 1991; Just and Berger, 1992), an annual antibody decline of 40–50% was estimated. These studies were the basis of a recently published communication (Stemberger, 1997), which stated, that considering the antibody titres of 600 vaccinees 2 years after vaccination with Havrix® 1440 applying the 0-6 schedule, a further protection period of only 1 year has to be expected in 15% (titres below 100 mlU/ml), a further 5 years in 70% (titres between 100 and 1000 mlU/ml) and of more than 10 years in 15% (titres above 1000 mlU/ml). Therefore, it was recommended to perform the single dose vaccination only in younger people. However, according to long term follow up studies (Van Damme et al., 1994b; Wiedermann et al., 1997) anti-HAV antibody decline does not follow simple first order kinetics. Rather, the decline of antibodies follows a two-component model. The fast component, with an annual disappearance rate of 80– 99%, will be practically eliminated within months or at most, 2 years. Afterwards, the slow component with an annual disappearance rate of 11–14% becomes predominant, resulting in a long lasting antibody persistence. By application of the two-component model, a very good agreement to the data of a 7 years follow up (the longest period ever covered) has been obtained (Wiedermann et al., 1997). However, it has to be considered, that although less underestimating the duration of protection as compared to simple first order kinetics models, the actual antibody decline might be even slower as predicted by our two-component model. To estimate the antibody persistence in different age groups after vaccination with Havrix®) 1440 applying the 0-6 schedule, we reanalyzed the data of Briem and Safary (1994): Geometric mean titres (GMT), the minimum and maximum observed titres of two age groups (134 vaccinees aged 20–30 years and 66 vaccinees 40– 62 years old) were computed considering the values 1 month after booster. Antibodies to HAV were measured by ELISA (SmithKline Beecham). The antibody titres were calculated in mlU/ml in comparison with an immunoglobulin preparation (WHO standard). Antibody decline was estimated using the two-component model (Wiedermann et al., 1997): Titret =TitreB{r · (1 −f )[t − 7]/12 + (1− r)(1− s)[t − 7]/12} This equation holds for t ]27 (=1 month after booster). TitreB = titre 1 month after booster. The constant r (0 B rB 1) reflects the relative contribution of the rapidly declining component at month seven, f its annual disappearance rate and s
Number of vaccinees 134 66
Age group (years) 20–30 40–62
3629 2320
GMT
34.5 31.5
Duration of protection (years) based on GMT
232 98
Minimum titre
Table 1 GMTs and lowest observed anti-HAV antibody titres and estimated duration of protection for two age groups
16.3 10.6
Duration of protection (years) based on min titre
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124
Table 2 Estimated proportion of protected individuals (cut off = 10 mlU/ml) 10 – 30 years after booster for two age groups Age group (years)
20 – 30 40 – 62
Number of vaccinees
134 66
Estimated % protected individuals
10 years after booster vaccination
20 years after booster vaccination
30 years after booster vaccination
100 (97–100) 100 (95–100)
99 (97 – 100) 94 (89 – 98)
77 (72 – 83) 58 (50 – 68)
95% Confidence limits are given in brackets.
is the annual disappearance rate for the slow component. Based on Van Damme et al. (1994b) and Wiedermann et al. (1997), r was set to 0.5, f to 0.99 and s to 0.14. Following these principles, the duration of protection was estimated considering GMTs as well as the lowest observed litres. The cut off for the protective level was set to 10 mlU/ml following the evaluation of Ambrosch et al. (1991).(Table 1) Antibody titres were somewhat lower in the older age group, as expected (Wagstaff et al., 1996). The estimated duration of protection however, varied only negligibly between age groups and will last for more than 30 years when considering GMTs. It will be even more than 10 years when taking minimum titres of the older age group into account (Table 2). Considering the above mentioned communication on 600 vaccinees (Stemberger, 1997), an average duration of protection of more than 30 years is estimated, observing that the titres were obtained 2 years after vaccination, at a time when the antibody decline is only a function of the slow component. Thus, application of a single dose hepatitis A vaccine can be expected to result in long lasting protection similar to the one after a conventional schedule. Together with its good tolerability and easy application, it recommends itself for use in travel medicine.
References Ambrosch, F., Wiedermann, G., Andre´, F.E., D’Hondt, E., Delem, A., Safary, A., 1991. Comparison of HAV antibodies induced by vaccination, passive immunisation and natural infection. In: Holzinger, F.B., Lemon, S.M., Margolis, H.S. (Eds.), Viral Hepatitis and Liver Disease. Williams and Wilkins, Baltimore, pp. 98–100. Briem, M., Safary, A., 1994. Immunogenicity and safety in adults of hepatitis A virus vaccine administered as a single dose with a booster 6 months later. J. Med. Virol. 44, 443 – 445. Just, M., Berger, R., 1992. Reactogenicity and immunogenicity of inactivated hepatitis A vaccines. Vaccine 10 (Suppl. 1), 110–113. Laufs, R., Polywka, S., 1993. Hepatitis A. Aktive Impfung gewahrt schon nach 2 Wochen Vollschutz. Med. Tribune 17, 20. Stemberger, H., 1997. Impfschutz im Zweifelsfall u¨berpru¨fen. A8 rztewoche 4, 4.
G. Wiedermann et al. / Acta Tropica 69 (1998) 121–125
125
Van Damme, P., Mathei, C., Thoelen, S., Meheus, A., Safary, A., Andre´, F.E., 1994a. Single dose inactivated hepatitis A vaccine: Rationale and clinical assessment of the safety and immunogenicity. J. Med. Virol. 44, 435–441. Van Damme, P., Thoelen, S., Cramm, M., DeGroote, K., Safary, A., Maheus, A., 1994b. Inactivated hepatitis A vaccine: Reactogenicity, immunogenicity, and long-term persistence. J. Med. Virol. 44, 446–451. Wagstaff, A.J., Plosker, G.L., Balfour, J., 1996. Inactivated hepatitis A vaccine strain. A preliminary review of its immunogenicity, protective potential and tolerability in at-risk patients. Clin. Immunother. 1, 66–88. Wiedermann, G., Kundi, M., Ambrosch, F., Safary, A., D’Hondt, E., Delem, A., 1997. Inactivated hepatitis A vaccine: Long term antibody persistence. Vaccine 15, 612 – 615.
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