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Inactivated hepatitis A vaccine booster given ≥24 months after the primary dose
Vaccine 19 (2001) 399±402
www.elsevier.com/locate/vaccine
Short Communication
Inactivated hepatitis A vaccine booster given r24 months after the primary dose P. Landry*, S. Tremblay, R. Darioli, B. Genton Travel Clinic, University Medical Policlinic, Rue CeÂsar-Roux 19, 1005 Lausanne, Switzerland Received 29 June 1999; received in revised form 8 February 2000; accepted 15 May 2000
Abstract We investigated what happens with the immune response when people come back for their booster dose of inactivated hepatitis A vaccine later than the recommended time of 6±12 months after the primary dose. We recruited a group of 124 travellers who received either the primary doses of Havrix 7202 (two doses) or of Havrix 14402 (one dose) r24 months before study entry. They received a booster dose of Havrix 14402 and blood was drawn 1 month later. As a control group, we recruited a group of 125 travellers who followed a recommended schedule with a primary dose at month 0 and a booster dose at months 6±12. For both study groups, the GMTs increased dramatically and similarly upon the booster immunisation. Although signi®cantly more late travellers (32%) had lost detectable antibodies than controls (11%) before administration of the booster dose, all these subjects showed an anamnestic response to the booster dose. Delaying the booster dose up to 66 months after primary vaccination did not seem to in¯uence the immunogenicity of the booster dose. However, the recommended 6±12-month interval remains if detectable antibody titers are to be warranted constantly. 7 2000 Elsevier Science Ltd. All rights reserved. Keywords: Hepatitis A; Vaccine; Booster; Traveler
1. Introduction Around 40 million people are travelling every year between industrialised and developing countries [1]. Most of them will travel from areas with low endemicity for hepatitis A to regions where they might be exposed to infection with the hepatitis A virus. Such infections can be prevented by active immunisation with an inactivated hepatitis A vaccine. One such vaccine is Havrix 14402 (SmithKline Beecham Biologicals, Rixensart, Belgium) which has proven to be safe and ecient, and provides a long-lasting immunity [2,3]. This vaccine is a single primary dose vaccine with a booster dose required 6±12 months later to provide the long-lasting immunity. When ®rst licensed in early 1992, the primary dose consisted of two doses (at
months 0 and 1) with the booster dose given between month 6 and 12 (Havrix 7202). Many travellers receive their ®rst dose of vaccine prior to their departure but they do not come back to receive the booster dose 6 to 12 months later. Often these people come back at a much later date, often prior to a new travel, sometimes even years after receiving the ®rst dose of vaccine. One wonders if people in these circumstances only need a booster or if they need a complete new vaccination schedule. Therefore, we conducted a prospective study to investigate the immune response when the booster dose of Havrix 14402 is given r24 months after the primary dose of vaccine. This is the ®rst time that such a study has been conducted for hepatitis A vaccination. 2. Methods
* Corresponding author. Tel.: +41-21-345-22-22; fax: +41-21-34523-23.
The study population consisted of travellers who
0264-410X/00/$ - see front matter 7 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 2 6 4 - 4 1 0 X ( 0 0 ) 0 0 1 8 8 - 2
400
P. Landry et al. / Vaccine 19 (2001) 399±402
Table 1 Study of participants' characteristicsa Total
Delayed booster Control Total a
124 125 249
Sex Male
Female
60 58 118
64 67 131
Age (years)
BMI (kg/m2)
Interval [range] (months)
33.0 34.0 33.0
22.5 23.0 22.7
35.0 [24±66] 9.0 [6±14] 14.0
BMI = body mass index; Interval = time in months between ®rst dose and booster dose.
were r18 years of age and who received either a single dose of Havrix 14402 or two doses of Havrix 7202 more than 24 months before time of enrolment (group 1, delayed booster). As a control group, we recruited travellers Ð matched for age and gender Ð who received the primary dose of Havrix 14402 6±12 months before time of enrolment (group 2, controls). The study protocol did allow for concurrent or concomitant administration of other travel vaccines. The body mass index (BMI) was calculated as: weight in kilograms/height in meters2. All volunteers gave their informed consent, and at the time of enrolment, blood was drawn and antibodies against hepatitis A were measured with the Enzymmun anti-HAV assay (Boehringer). The cut-o was 33 mIU/ml. Subjects with titresr33 mIU/ml were considered as being seropositive. All vaccinees were invited to come back 30±40 days later for a second blood sample to test for anti-HAV antibodies. Statistical analysis was performed on an Epi-info 6 software using standard t test and Chi-square tests when appropriate. Spearman rank correlation and adjustment for age and BMI were done on Stata.
3. Results 3.1. Study of participants' characteristics Both study groups were comparable for their gender composition, age of subjects and BMI (Table 1). There were signi®cantly more other travel vaccines co-administered on the day of the booster dose in group 1 than in group 2 p < 0:0001).
3.3. In¯uence of gender, age and BMI on the immune response Table 3 details the in¯uence of dierent characteristics on the immune response in both study groups. There were statistically signi®cant dierences for the GMTs between men and women, except for the control group before the booster dose. The BMI was lower for females than males in both groups: 22.0 for women versus 23.1 for men p 0:03 in the delayed booster group; and 21.7 for women versus 24.0 for men p < 0:005 in the control group. However, there was no correlation between immune response and age or BMI. We could not detect an eect of concomitant vaccine administration on the immune response. After the booster dose, the GMT for the delayed booster group was 3427 mIU/ml n 52 for those who did receive other vaccines concomitantly and 4001 mIU/ml n 72 for those who did not p 0:9). In the control group, the GMTs were 3006 mIU/ml n 9 and 3234 mIU/ml n 16), respectively p 0:6). 3.4. No longer detectable antibodies In group 1, 32% had no longer detectable antibodies before administration of the booster dose, compared to 11% of the controls p < 0:001 RR 2.90; 95% CI = 1.67±5.06). Only 13% of the women had no detectable antibodies against 31% of the men p < 0:001 RR 0.41; 95% CI = 0.25±0.69). After the booster dose, all people with non-detectable antibody levels developed a good response.
Table 2 Comparative immune response of case and controlsa
3.2. Comparison of immune responses
GMT before booster
GMT after booster
The immune responses for both groups are summarised in Table 2. There were no statistically signi®cant dierences between the two study groups for their relative GMTs, neither before nor after the booster dose was given.
mIU/ml
95% CI
mIU/ml
95% CI
116 135
78±175 98±186
3342 3258
2618±4266 2565±4140
Delayed booster Control a
95% CI = 95% con®dence interval.
P. Landry et al. / Vaccine 19 (2001) 399±402
3.5. Single dose versus two doses In a subset of travellers, aged <35 years Ð comparable for age and BMI Ð we compared the GMTs before and after booster for subjects who received either Havrix2720 (24 subjects) or Havrix21440 (42 subjects). The GMT for the ®rst group was 139 (95% CI = 49.0±153.8) compared to 82.6 (95% CI = 89.1± 216.8) before booster p 0:03). However, there was no dierence in GMT level after the booster. 4. Discussion A lot of travellers are conscious of the risk of infection by hepatitis A if they plan to visit endemic countries and, therefore, seek protection through vaccination. Vaccines are available of which a single dose will provide rapid protection against infection [4]. The current vaccines against hepatitis A are single dose vaccines but current licensure foresees a booster dose 6 to 12 months later to ensure long-term protection. To date, follow-up data exist up to 5 years after the primary vaccination [5]. Several mathematical models have been developed which predict immunity up to 20 years [6] or even more than 30 years [2], depending on the model used. Our study investigates the immunogenicity pro®le when the administration of the booster dose is delayed. We detected no statistically signi®cant dierence between the pre-booster GMTs of the group of travellers with a delayed booster and the control group, who followed the recommended schedule. After the booster dose, both groups obtain nearly identical GMTs even though the group with delayed travellers had signi®cantly more people with
401
no longer detectable antibodies. This indicates that the immune memory has been primed and maintained for at least 5 years after the ®rst dose of vaccine administration in spite of waning humoral immunity. Evidence of T cell responses elicited by hepatitis A vaccination has been presented [7,8]. This also raises the possible question whether a single dose of hepatitis A vaccine would be enough to ensure a long-lasting protection. If cell mediated memory is present, a natural challenge by the hepatitis A virus might provoke a similar booster response as recently shown for hepatitis B [9]. However, since data are limited and the duration of cell mediated memory elicited by inactivated hepatitis A vaccine remains unknown, immunisation against hepatitis A should consist of a primary vaccination followed by a booster dose. A better immune response to hepatitis vaccination in women has been described before [10±12]. Our results show no in¯uence of concomitant administration of other vaccines on the GMTs elicited after a booster dose of hepatitis A vaccine. Similar results were shown before [13,14]. In summary, we illustrated that the time interval (maximum of 66 months) between the administration of the primary dose and booster doses of an inactivated hepatitis A vaccine does not seem to have an in¯uence on the immune response to that booster dose. Even when the antibody levels drop below detectable levels after the primary immunisation, all subjects we investigated did show an anamnestic response to the booster dose. This points to the eective development of cellular mediated immune memory. Still, until more data show that one single dose of vaccine is sucient for long-lasting protection, a booster dose more than 6 months after the priming dose is recommended.
Table 3 In¯uence of gender, age and BMI on immune responsea GMT before booster, mIU/ml [95% CI]
Gender Female Male p (logged data) Age BMI a b
GMT after booster, mIU/ml [95% CI]
Delayed booster
Controls
All
Delayed booster
Controls
All
179 [101±316]
174 [123± 246] 88 [60±127]
4764 [3491±6501]
74 [42±130]
169 [111± 256] 105 [64±281]
2291 [1592±3296]
0.03
0.14
0.0001
0.003
4581 [2265± 6238] 2193 [1549± 3105] 0.002
4667 [3673± 5794] 2239 [1746± 2871] < 0.0001
No correlation r ÿ0:0008)b No correlation r ÿ0:0993)b
95% CI = 95% con®dence interval. Spearman rank correlation between variable and log of titers.
No correlation r ÿ0:1829)b No correlation r ÿ0:2179)b
402
P. Landry et al. / Vaccine 19 (2001) 399±402
Acknowledgements We are very thankful to Dr A. Willer and the sta of Analysa SA, NeuchaÃtel, for their contribution in testing our samples. References [1] Iwarson S. What type of travelers would bene®t from combined vaccination against hepatitis A and B? J Travel Med 1998;5:80± 3. [2] Wiedermann G, Kundi M, Ambrosch F. Estimated persistence of anti-HAV antibodies after single and booster hepatitis A vaccination (0±6 schedule). Acta Tropica 1998;69:121±5. [3] Andre FE. Hepatitis A vaccine: current status and future use. In: Rizzetto M, Purcell RH, Gerin JL, Verme G, editors. Viral hepatitis and liver disease, 1997. p. 624±6. [4] Van Damme P, Mathei C, Thoelen S, Meheus A, Safary A, Andre FE. Single dose inactivated hepatitis A vaccine: rationale and clinical assessment of the safety and immunogenicity. J Med Virol 1994;44:435±41. [5] Van Heck K, van Damme P, Thoelen S. A high potency inactivated hepatitis A vaccine: long term follow-up. In: 6th Conference International Society of Travel Medicine. Montreal, June. 1999. [6] Van Damme P, Thoelen S, Cramm M, de Groote K, Safary A, Meheus A. Inactivated hepatitis A vaccine: reactogenicity, immunogenicity, and long-term antibody persistence. J Med Virol 1994;44:446±51.
[7] Cederna JB, Klinzman D, Stapleton JT. Inactivated hepatitis A vaccine ellicits HAV-speci®c T cell proliferation. In: IX Triennal International Symposium on Viral Hepatitis and Liver Disease, Rome April, 1996 [Abstract A78]. [8] Schmidtke P, Habermehl P, Knuf M, Meyer CU, Slaoui M, Safary A, Clemens R, Zepp F. Kinetics of hepatitis A virus (HAV) speci®c humoral and cell mediated immunity after vaccination. In: 35th ICAAC, 1997 [Abstract 586]. [9] WistroÈm J, Ahlm C, Lundberg S, Settergren B, TaÈrnvik A. Booster vaccination with recombinant hepatitis B vaccine four years after priming with one single dose. Vaccine 1999;17:2162± 5. [10] Goubau P, van Gerven, V, Safary A, et al. Eect of virus strain and antigen dose on immunogenicity and reactogenicity of an inactivated hepatitis A vaccine. Vaccine 1992;10:S114±118. [11] McMahon BJ, Williams J, Bulkow L, et al. Immunogenicity of an inactivated hepatitis A vaccine in Alaska native children and native and non-native adults. J Infect Dis 1995;171:676±9. [12] Sandman L, Davidson M, Krugman S. Inactivated hepatitis A vaccine: a safety and immunogenicity study in health professionals. J Infect Dis 1995;171:S50±52. [13] Bienzle U, Bock HL, Kruppenbacher JP, Hofmann F, Vogel GE, Clemens R. Immunogenicity of an inactivated hepatitis A vaccine administered according to two dierent schedules and the interference of other ``travellers'' vaccines with the immune response. Vaccine 1996;14:501±5. [14] Bovier PA, Althaus B, Glueck R, Chippaux A, Loutan L. Tolerance and immunogenicity of the simultaneous administration of virosome hepatitis A and yellow fever vaccines. J Travel Med 1999;6:228±33.
www.elsevier.com/locate/vaccine
Short Communication
Inactivated hepatitis A vaccine booster given r24 months after the primary dose P. Landry*, S. Tremblay, R. Darioli, B. Genton Travel Clinic, University Medical Policlinic, Rue CeÂsar-Roux 19, 1005 Lausanne, Switzerland Received 29 June 1999; received in revised form 8 February 2000; accepted 15 May 2000
Abstract We investigated what happens with the immune response when people come back for their booster dose of inactivated hepatitis A vaccine later than the recommended time of 6±12 months after the primary dose. We recruited a group of 124 travellers who received either the primary doses of Havrix 7202 (two doses) or of Havrix 14402 (one dose) r24 months before study entry. They received a booster dose of Havrix 14402 and blood was drawn 1 month later. As a control group, we recruited a group of 125 travellers who followed a recommended schedule with a primary dose at month 0 and a booster dose at months 6±12. For both study groups, the GMTs increased dramatically and similarly upon the booster immunisation. Although signi®cantly more late travellers (32%) had lost detectable antibodies than controls (11%) before administration of the booster dose, all these subjects showed an anamnestic response to the booster dose. Delaying the booster dose up to 66 months after primary vaccination did not seem to in¯uence the immunogenicity of the booster dose. However, the recommended 6±12-month interval remains if detectable antibody titers are to be warranted constantly. 7 2000 Elsevier Science Ltd. All rights reserved. Keywords: Hepatitis A; Vaccine; Booster; Traveler
1. Introduction Around 40 million people are travelling every year between industrialised and developing countries [1]. Most of them will travel from areas with low endemicity for hepatitis A to regions where they might be exposed to infection with the hepatitis A virus. Such infections can be prevented by active immunisation with an inactivated hepatitis A vaccine. One such vaccine is Havrix 14402 (SmithKline Beecham Biologicals, Rixensart, Belgium) which has proven to be safe and ecient, and provides a long-lasting immunity [2,3]. This vaccine is a single primary dose vaccine with a booster dose required 6±12 months later to provide the long-lasting immunity. When ®rst licensed in early 1992, the primary dose consisted of two doses (at
months 0 and 1) with the booster dose given between month 6 and 12 (Havrix 7202). Many travellers receive their ®rst dose of vaccine prior to their departure but they do not come back to receive the booster dose 6 to 12 months later. Often these people come back at a much later date, often prior to a new travel, sometimes even years after receiving the ®rst dose of vaccine. One wonders if people in these circumstances only need a booster or if they need a complete new vaccination schedule. Therefore, we conducted a prospective study to investigate the immune response when the booster dose of Havrix 14402 is given r24 months after the primary dose of vaccine. This is the ®rst time that such a study has been conducted for hepatitis A vaccination. 2. Methods
* Corresponding author. Tel.: +41-21-345-22-22; fax: +41-21-34523-23.
The study population consisted of travellers who
0264-410X/00/$ - see front matter 7 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 2 6 4 - 4 1 0 X ( 0 0 ) 0 0 1 8 8 - 2
400
P. Landry et al. / Vaccine 19 (2001) 399±402
Table 1 Study of participants' characteristicsa Total
Delayed booster Control Total a
124 125 249
Sex Male
Female
60 58 118
64 67 131
Age (years)
BMI (kg/m2)
Interval [range] (months)
33.0 34.0 33.0
22.5 23.0 22.7
35.0 [24±66] 9.0 [6±14] 14.0
BMI = body mass index; Interval = time in months between ®rst dose and booster dose.
were r18 years of age and who received either a single dose of Havrix 14402 or two doses of Havrix 7202 more than 24 months before time of enrolment (group 1, delayed booster). As a control group, we recruited travellers Ð matched for age and gender Ð who received the primary dose of Havrix 14402 6±12 months before time of enrolment (group 2, controls). The study protocol did allow for concurrent or concomitant administration of other travel vaccines. The body mass index (BMI) was calculated as: weight in kilograms/height in meters2. All volunteers gave their informed consent, and at the time of enrolment, blood was drawn and antibodies against hepatitis A were measured with the Enzymmun anti-HAV assay (Boehringer). The cut-o was 33 mIU/ml. Subjects with titresr33 mIU/ml were considered as being seropositive. All vaccinees were invited to come back 30±40 days later for a second blood sample to test for anti-HAV antibodies. Statistical analysis was performed on an Epi-info 6 software using standard t test and Chi-square tests when appropriate. Spearman rank correlation and adjustment for age and BMI were done on Stata.
3. Results 3.1. Study of participants' characteristics Both study groups were comparable for their gender composition, age of subjects and BMI (Table 1). There were signi®cantly more other travel vaccines co-administered on the day of the booster dose in group 1 than in group 2 p < 0:0001).
3.3. In¯uence of gender, age and BMI on the immune response Table 3 details the in¯uence of dierent characteristics on the immune response in both study groups. There were statistically signi®cant dierences for the GMTs between men and women, except for the control group before the booster dose. The BMI was lower for females than males in both groups: 22.0 for women versus 23.1 for men p 0:03 in the delayed booster group; and 21.7 for women versus 24.0 for men p < 0:005 in the control group. However, there was no correlation between immune response and age or BMI. We could not detect an eect of concomitant vaccine administration on the immune response. After the booster dose, the GMT for the delayed booster group was 3427 mIU/ml n 52 for those who did receive other vaccines concomitantly and 4001 mIU/ml n 72 for those who did not p 0:9). In the control group, the GMTs were 3006 mIU/ml n 9 and 3234 mIU/ml n 16), respectively p 0:6). 3.4. No longer detectable antibodies In group 1, 32% had no longer detectable antibodies before administration of the booster dose, compared to 11% of the controls p < 0:001 RR 2.90; 95% CI = 1.67±5.06). Only 13% of the women had no detectable antibodies against 31% of the men p < 0:001 RR 0.41; 95% CI = 0.25±0.69). After the booster dose, all people with non-detectable antibody levels developed a good response.
Table 2 Comparative immune response of case and controlsa
3.2. Comparison of immune responses
GMT before booster
GMT after booster
The immune responses for both groups are summarised in Table 2. There were no statistically signi®cant dierences between the two study groups for their relative GMTs, neither before nor after the booster dose was given.
mIU/ml
95% CI
mIU/ml
95% CI
116 135
78±175 98±186
3342 3258
2618±4266 2565±4140
Delayed booster Control a
95% CI = 95% con®dence interval.
P. Landry et al. / Vaccine 19 (2001) 399±402
3.5. Single dose versus two doses In a subset of travellers, aged <35 years Ð comparable for age and BMI Ð we compared the GMTs before and after booster for subjects who received either Havrix2720 (24 subjects) or Havrix21440 (42 subjects). The GMT for the ®rst group was 139 (95% CI = 49.0±153.8) compared to 82.6 (95% CI = 89.1± 216.8) before booster p 0:03). However, there was no dierence in GMT level after the booster. 4. Discussion A lot of travellers are conscious of the risk of infection by hepatitis A if they plan to visit endemic countries and, therefore, seek protection through vaccination. Vaccines are available of which a single dose will provide rapid protection against infection [4]. The current vaccines against hepatitis A are single dose vaccines but current licensure foresees a booster dose 6 to 12 months later to ensure long-term protection. To date, follow-up data exist up to 5 years after the primary vaccination [5]. Several mathematical models have been developed which predict immunity up to 20 years [6] or even more than 30 years [2], depending on the model used. Our study investigates the immunogenicity pro®le when the administration of the booster dose is delayed. We detected no statistically signi®cant dierence between the pre-booster GMTs of the group of travellers with a delayed booster and the control group, who followed the recommended schedule. After the booster dose, both groups obtain nearly identical GMTs even though the group with delayed travellers had signi®cantly more people with
401
no longer detectable antibodies. This indicates that the immune memory has been primed and maintained for at least 5 years after the ®rst dose of vaccine administration in spite of waning humoral immunity. Evidence of T cell responses elicited by hepatitis A vaccination has been presented [7,8]. This also raises the possible question whether a single dose of hepatitis A vaccine would be enough to ensure a long-lasting protection. If cell mediated memory is present, a natural challenge by the hepatitis A virus might provoke a similar booster response as recently shown for hepatitis B [9]. However, since data are limited and the duration of cell mediated memory elicited by inactivated hepatitis A vaccine remains unknown, immunisation against hepatitis A should consist of a primary vaccination followed by a booster dose. A better immune response to hepatitis vaccination in women has been described before [10±12]. Our results show no in¯uence of concomitant administration of other vaccines on the GMTs elicited after a booster dose of hepatitis A vaccine. Similar results were shown before [13,14]. In summary, we illustrated that the time interval (maximum of 66 months) between the administration of the primary dose and booster doses of an inactivated hepatitis A vaccine does not seem to have an in¯uence on the immune response to that booster dose. Even when the antibody levels drop below detectable levels after the primary immunisation, all subjects we investigated did show an anamnestic response to the booster dose. This points to the eective development of cellular mediated immune memory. Still, until more data show that one single dose of vaccine is sucient for long-lasting protection, a booster dose more than 6 months after the priming dose is recommended.
Table 3 In¯uence of gender, age and BMI on immune responsea GMT before booster, mIU/ml [95% CI]
Gender Female Male p (logged data) Age BMI a b
GMT after booster, mIU/ml [95% CI]
Delayed booster
Controls
All
Delayed booster
Controls
All
179 [101±316]
174 [123± 246] 88 [60±127]
4764 [3491±6501]
74 [42±130]
169 [111± 256] 105 [64±281]
2291 [1592±3296]
0.03
0.14
0.0001
0.003
4581 [2265± 6238] 2193 [1549± 3105] 0.002
4667 [3673± 5794] 2239 [1746± 2871] < 0.0001
No correlation r ÿ0:0008)b No correlation r ÿ0:0993)b
95% CI = 95% con®dence interval. Spearman rank correlation between variable and log of titers.
No correlation r ÿ0:1829)b No correlation r ÿ0:2179)b
402
P. Landry et al. / Vaccine 19 (2001) 399±402
Acknowledgements We are very thankful to Dr A. Willer and the sta of Analysa SA, NeuchaÃtel, for their contribution in testing our samples. References [1] Iwarson S. What type of travelers would bene®t from combined vaccination against hepatitis A and B? J Travel Med 1998;5:80± 3. [2] Wiedermann G, Kundi M, Ambrosch F. Estimated persistence of anti-HAV antibodies after single and booster hepatitis A vaccination (0±6 schedule). Acta Tropica 1998;69:121±5. [3] Andre FE. Hepatitis A vaccine: current status and future use. In: Rizzetto M, Purcell RH, Gerin JL, Verme G, editors. Viral hepatitis and liver disease, 1997. p. 624±6. [4] Van Damme P, Mathei C, Thoelen S, Meheus A, Safary A, Andre FE. Single dose inactivated hepatitis A vaccine: rationale and clinical assessment of the safety and immunogenicity. J Med Virol 1994;44:435±41. [5] Van Heck K, van Damme P, Thoelen S. A high potency inactivated hepatitis A vaccine: long term follow-up. In: 6th Conference International Society of Travel Medicine. Montreal, June. 1999. [6] Van Damme P, Thoelen S, Cramm M, de Groote K, Safary A, Meheus A. Inactivated hepatitis A vaccine: reactogenicity, immunogenicity, and long-term antibody persistence. J Med Virol 1994;44:446±51.
[7] Cederna JB, Klinzman D, Stapleton JT. Inactivated hepatitis A vaccine ellicits HAV-speci®c T cell proliferation. In: IX Triennal International Symposium on Viral Hepatitis and Liver Disease, Rome April, 1996 [Abstract A78]. [8] Schmidtke P, Habermehl P, Knuf M, Meyer CU, Slaoui M, Safary A, Clemens R, Zepp F. Kinetics of hepatitis A virus (HAV) speci®c humoral and cell mediated immunity after vaccination. In: 35th ICAAC, 1997 [Abstract 586]. [9] WistroÈm J, Ahlm C, Lundberg S, Settergren B, TaÈrnvik A. Booster vaccination with recombinant hepatitis B vaccine four years after priming with one single dose. Vaccine 1999;17:2162± 5. [10] Goubau P, van Gerven, V, Safary A, et al. Eect of virus strain and antigen dose on immunogenicity and reactogenicity of an inactivated hepatitis A vaccine. Vaccine 1992;10:S114±118. [11] McMahon BJ, Williams J, Bulkow L, et al. Immunogenicity of an inactivated hepatitis A vaccine in Alaska native children and native and non-native adults. J Infect Dis 1995;171:676±9. [12] Sandman L, Davidson M, Krugman S. Inactivated hepatitis A vaccine: a safety and immunogenicity study in health professionals. J Infect Dis 1995;171:S50±52. [13] Bienzle U, Bock HL, Kruppenbacher JP, Hofmann F, Vogel GE, Clemens R. Immunogenicity of an inactivated hepatitis A vaccine administered according to two dierent schedules and the interference of other ``travellers'' vaccines with the immune response. Vaccine 1996;14:501±5. [14] Bovier PA, Althaus B, Glueck R, Chippaux A, Loutan L. Tolerance and immunogenicity of the simultaneous administration of virosome hepatitis A and yellow fever vaccines. J Travel Med 1999;6:228±33.