- Email: [email protected]
Immunogenicity and safety of a virosomal hepatitis A vaccine in HIV-positive patients
Vaccine 25 (2007) 6310–6312
Short communication
Immunogenicity and safety of a virosomal hepatitis A vaccine in HIV-positive patients L. Loutan a , P. Bovier b , C. Herzog c,∗ a
Travel and Migration Medicine Unit, Geneva University Hospitals, rue Micheli-du-Crest 24, 1211 Geneva 14, Switzerland b Department of Community Medicine, Geneva University Hospitals, 1211 Geneva 14, Switzerland c Berna Biotech, a Crucell Company, Rehhagstrasse 79, 3018 Berne, Switzerland Received 4 May 2007; received in revised form 11 June 2007; accepted 11 June 2007 Available online 29 June 2007
Abstract This short report presents results of an open uncontrolled single centre study which evaluated immunogenicity and safety of a virosomeformulated hepatitis A vaccine (Epaxal® ) in 14 HIV-positive adult patients and 64 healthy adults receiving a primary immunisation and a booster dose 12 months later. Seroconversion rates (≥20 mIU/mL), geometric mean concentration (GMC) of anti-HAV antibodies, local and systemic adverse events (AEs) were assessed at baseline and at Months 1, 6, 12, and 13. The seroconversion rate was 63.6% at Month 1 and 91.7% at Month 13 in HIV-positive patients versus 93.8 and 100% in healthy adults. The booster dose increased GMCs from 25.5 to 659.2 mIU/mL in HIV-positive patients versus 104 and 2986 mIU/mL in healthy adults. Epaxal® was well tolerated by the HIV-positive patients and was at least as immunogenic as reported for aluminium-adsorbed vaccines. In conclusion, Epaxal® can be considered an immunogenic and safe hepatitis A vaccine in HIV-positive patients. © 2007 Elsevier Ltd. All rights reserved. Keywords: Hepatitis A vaccine; HIV; Immunogenicity; Safety
1. Introduction In their meta-analysis of eight independent trials, Shire et al. determined the immunogenicity of inactivated hepatitis A virus (HAV) vaccines in HIV-positive adult patients [1]. They reported an overall seroconversion rate of 64% (95% CI 52–75%) after two to three doses, and suggested that this relatively low rate of response to hepatitis A vaccines may not confer adequate protection for a significant proportion of HIV-positive patients. Heterogeneity between studies regarding population size (range: n = 14–123), mean CD4 count (372–495 cells/mm3 ), patient characteristics and hepatitis A vaccination schedule was, however, significant [1]. In addition to Shire et al.’s meta-analysis, data from two paediatric studies have recently been published, reporting seroconversion rates of 100% in 32 HIV-positive children ∗
Corresponding author. E-mail address: [email protected] (C. Herzog).
0264-410X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2007.06.013
aged 2–9 years (mean CD4 count: 1483 cells/mm3 ) [2] and of 97% in 151 HIV-positive children and adolescents aged 2–20 years (mean CD4 count: 830 cells/mm3 ) [3]. The HAV vaccines used in the trials analysed by Shire et al. and in the two paediatric studies were all aluminiumadsorbed. In this context, we would like to report the effect of a virosome-formulated HAV vaccine [4] in HIV-positive patients. This inactivated HAV vaccine (Epaxal® ) is the first commercially available, aluminium-free HAV vaccine and has proven to be highly immunogenic and safe in children, adults, and elderly people [4–8].
2. Methods In an open, uncontrolled single centre study we investigated the immunogenicity and safety of a single i.m. dose of the virosome-formulated HAV vaccine Epaxal® (Berna
L. Loutan et al. / Vaccine 25 (2007) 6310–6312
Biotech Ltd., Berne, Switzerland), containing 24 IU (formerly 500 RIA units) of hepatitis A antigen per 0.5 mL, coupled to virosomes. The vaccine was given to 14 HIVpositive, HAV naive adult patients (mean CD4 count of 547 [range: 145–1537] cells/mm3 ; mean age 34.6 [22–43] years) on Day 1 (primary immunisation) and at Month 12 (booster dose), and to 64 young healthy HAV naive adult subjects (mean age 24.1 [18–43] years) treated by the same regimen. All three of the HIV-positive patients who did not seroconvert by Day 29 received a 2nd primary dose 2–3 months after the 1st dose. One female patient (age 32 years, CD4 count: 415 cells/mm3 ) dropped out prior to Day 29 and only safety data of the primary vaccine dose became available. Immunogenicity of Epaxal® was assessed by measuring hepatitis A serum antibodies at baseline (Day 1), Day 29, and at Months 6, 12 and 13 in both study groups. The primary endpoint of the study was seroconversion based on a protective antibody concentration of ≥20 mIU/mL. Antibody levels were determined by a standard ELISA (Enzymun® AntiHAV, Boehringer Mannheim). Secondary endpoints of the study were rates and duration of solicited local (pain, redness, swelling) and solicited systemic (fatigue, headache, arthralgia, anorexia, nausea, raised body temperature) adverse events (AEs).
3. Results The characteristics and the individual results of the 13 patients evaluable for immunogenicity are listed in Table 1. The denominators for the antibody results vary between
6311
time points as several subjects missed visits or dropped out. The seroconversion rate in HIV-positive patients on Day 29 (n = 11) was 63.6%, increasing to 91.7% 1 month after the booster dose at Month 13 (n = 12), while the geometric mean concentration (GMC) of anti-HAV antibodies increased 26fold from 25.5 mIU/mL on Day 29 (n = 11) to 659.2 mIU/mL at Month 13 (n = 12), i.e., an antibody booster response documenting a good priming. Patient 13 with a low CD4 cell count of 145 cells/mm3 was the only subject not responding to the booster dose (Table 1). When excluding the three patients who received two primary doses, the seroconversion rate at Month 13 was 88.9% (n = 9), and the GMC was 670.9 mIU/mL (n = 9). Hence, exclusion of the three subjects with two primary vaccine doses did not change the results substantially. The 64 healthy subjects in the control group, all vaccinated according to the standard 0/12 months schedule, seroconverted after the priming dose by Day 29 to 93.8% and 1 month after the booster to 100%, with GMC’s of 104 and 2986 mIU/mL, respectively. The virosome-formulated HAV vaccine was well tolerated among HIV-positive and healthy subjects. The most commonly reported local adverse event (AE) was pain or tenderness at the site of injection, reported in 14.3 and 11.1% by the HIV-positive and in 37.1 and 50.0% by the healthy subjects, following primary and booster dose, respectively. Any solicited systemic reactions were reported by 35.7 and 44.4% of the HIV-positive and by 70.0 and 45.2% of the healthy subjects, following primary and booster dose, respectively. No cases of fever ≥38.5 ◦ C were reported among the HIV-positive subjects and only in one case in the control group.
Table 1 Demographic characteristics, CD4 cell count, dosing schedule and anti-HAV antibody response in 13 HIV-positive patients Subject ID
1 (FF) 2 (EL) 3 (DL) 4 (OM) 5 (YR)b 6 (TF)b 7 (JPH) 9 (RZ) 10 (PF) 11 (JM)b 12 (PW) 13 (YS) 14 (CP) Mean
a b c
Sex
Male Male Male Male Male Male Male Male Male Male Male Male Male
CD4 count (cells/mm3 )
Dosing schedule
43 39 22 32 32 40 36 43 31 40 29 32 33
517 504 718 207 272 390 533 408 659 659 1537 145 ND
34.8
557
Age (years)
Dropout after Month 6. 2nd priming dose at Month 2–3. Subjects receiving only 1 priming dose.
Anti-HAV antibody concentration (mIU/mL) Day 29
Month 6
Month 12
Month 13
0/12 months 0/12 months 0/12 months 0/12 months 0/3/12 months 0/3/12 months 0/12 months 0/12 months 0/12 months 0/2/12 months 0/12 months 0/12 months 0/12 months
51 58 27 30 15 13 44 <10 ND <10 72 ND 32
19 15 14 <10.0 25 43 79 <10 ND <10 42 ND ND
17 20 ND –a 19 20 59 54 96 116 13 47 19
1704 1333 609 –a 550 734 3825 562 1096 606 2755 13 236
Seroconversion ≥10 mIU/mL Seroconversion ≥20 mIU/mL GMC (mIU/mL)
81.8% 63.6% 23.5
70% (71%)c 40% (28.6%)c 16.8 (16.5)c
100% (100%)c 63.6% (62.5%)c 33.2 (32.4)c
100% (100%)c 91.7% (88.9%)c 659.2 (670.9)c
6312
L. Loutan et al. / Vaccine 25 (2007) 6310–6312
4. Discussion
References
The seroconversion rates seen with Epaxal® were higher when compared to the results presented in the meta-analysis of Shire et al., but still lower when compared to healthy young adults. Immunodeficient (e.g. HIV-positive patients) and elderly subjects have a delayed immune response compared to healthy young adults [8–11]. HIV-positive patients may, in some cases, benefit from a 2nd primary dose, to ensure conversion against HAV infection, as shown in three of the initially non-responding patients. However, a 2nd primary dose did not seem to change seroconversion rates and GMC’s significantly. In general, the virosome-formulated vaccine induces seroconversion rates similar to aluminium-adsorbed vaccines, but induces less local reactions [12,13]. An explanation for the excellent local tolerability profile of the virosomal vaccine (0.5 mL) is that the virosomal formulation does not contain aluminium salts and therefore hardly induces any inflammatory reactions at the injection site. The better local tolerability of Epaxal® in HIV-positive patients compared to healthy subjects needs, however, confirmation, as the low number of HIV-positive patients prevents drawing definite conclusions. In conclusion, Epaxal® can be considered a safe hepatitis A vaccine for HIV-positive patients, eliciting an immune response at least as good as reported so far for aluminiumadsorbed hepatitis A vaccines. However, further research is needed to confirm these results in a larger group of patients stratified according to their immune status (CD4 count) and to determine if the initial and the post-booster seroconversion in HIV-positive patients can be increased substantially by giving an early 2nd primary dose at Months 1–3.
[1] Shire NJ, Welge JA, Sherman KE. Efficacy of inactivated hepatitis A vaccine in HIV-infected patients: a hierarchical bayesian meta-analysis. Vaccine 2006;24(3):272–9. [2] Gouvea AF, De Moraes-Pinto MI, Ono E, Dinelli MIS, Machado DM, Weckx LY, et al. Immunogenicity and tolerability of hepatitis A vaccine in HIV-infected children. Clin Infect Dis 2005;41(4): 544–8. [3] Weinberg A, Gona P, Nachman SA, Defechereux P, Yogev R, Hughes W, et al. Antibody responses to hepatitis A virus vaccine in HIVinfected children with evidence of immunologic reconstitution while receiving highly active antiretroviral therapy. J Infect Dis 2006;193(2): 302–11. [4] Moser C, Metcalfe IC, Viret J-F. Virosomal adjuvanted antigen delivery system. Expert Rev Vac 2003;2(2):189–96. [5] Loutan L, Bovier P, Althaus B, Gl¨uck R. Inactivated virosome hepatitis A vaccine. Lancet 1994;343(8893):322–4. [6] Ambrosch F, Wiedermann G, Jonas S, Althaus B, Finkel B, Gl¨uck R, et al. Immunogenicity and protectivity of a new liposomal hepatitis A vaccine. Vaccine 1997;15(11):1209–13. [7] Usonis V, Bakasenas V, Valentelis R, Katiliene G, Vidzeniene D, Herzog C. Antibody titres after primary and booster vaccination of infants and young children with a virosomal hepatitis A vaccine (Epaxal® ). Vaccine 2003;21(31):4588–92. [8] D’Acremont V, Herzog C, Genton B. Immunogenicity and safety of a virosomal hepatitis A vaccine (Epaxal® ) in the elderly. J Travel Med 2006;13(2):78–83. [9] Leder K, Weller PF, Wilson ME. Travel vaccines and elderly persons: review of vaccines available in the United States. Clin Infect Dis 2001;33(9):1553–66. [10] Kemper CA, Haubrich R, Frank I, Dubin G, Buscarino C, McCutchan JA, et al. Safety and immunogenicity of hepatitis A vaccine in human immunodeficiency virus-infected patients: a double-blind, randomized, placebo-controlled trial. J Infect Dis 2003;187(8):1327–31. [11] Genton B, D’Acremont V, Furrer HJ, Hatz C, Loutan L. Hepatitis A vaccines and the elderly. Travel Med Infect Dis 2006;4(6): 303–12. [12] Clarke PD, Adams P, Ib´an˜ ez R, Herzog C. Rate, intensity, and duration of local reactions to a virosome-adjuvanted versus an aluminiumadsorbed hepatitis A vaccine in UK travellers. Travel Med Infect Dis 2006;4(6):313–8. [13] Bovier PA, Farinelli T, Loutan L. Interchangeability and tolerability of a virosomal and an aluminum-adsorbed hepatitis A vaccine. Vaccine 2005;23(19):2424–9.
Acknowledgement Our thanks go to Jacqueline Glaus, University Children’s Hospital in Basel, for the anti-HAV testing.
Short communication
Immunogenicity and safety of a virosomal hepatitis A vaccine in HIV-positive patients L. Loutan a , P. Bovier b , C. Herzog c,∗ a
Travel and Migration Medicine Unit, Geneva University Hospitals, rue Micheli-du-Crest 24, 1211 Geneva 14, Switzerland b Department of Community Medicine, Geneva University Hospitals, 1211 Geneva 14, Switzerland c Berna Biotech, a Crucell Company, Rehhagstrasse 79, 3018 Berne, Switzerland Received 4 May 2007; received in revised form 11 June 2007; accepted 11 June 2007 Available online 29 June 2007
Abstract This short report presents results of an open uncontrolled single centre study which evaluated immunogenicity and safety of a virosomeformulated hepatitis A vaccine (Epaxal® ) in 14 HIV-positive adult patients and 64 healthy adults receiving a primary immunisation and a booster dose 12 months later. Seroconversion rates (≥20 mIU/mL), geometric mean concentration (GMC) of anti-HAV antibodies, local and systemic adverse events (AEs) were assessed at baseline and at Months 1, 6, 12, and 13. The seroconversion rate was 63.6% at Month 1 and 91.7% at Month 13 in HIV-positive patients versus 93.8 and 100% in healthy adults. The booster dose increased GMCs from 25.5 to 659.2 mIU/mL in HIV-positive patients versus 104 and 2986 mIU/mL in healthy adults. Epaxal® was well tolerated by the HIV-positive patients and was at least as immunogenic as reported for aluminium-adsorbed vaccines. In conclusion, Epaxal® can be considered an immunogenic and safe hepatitis A vaccine in HIV-positive patients. © 2007 Elsevier Ltd. All rights reserved. Keywords: Hepatitis A vaccine; HIV; Immunogenicity; Safety
1. Introduction In their meta-analysis of eight independent trials, Shire et al. determined the immunogenicity of inactivated hepatitis A virus (HAV) vaccines in HIV-positive adult patients [1]. They reported an overall seroconversion rate of 64% (95% CI 52–75%) after two to three doses, and suggested that this relatively low rate of response to hepatitis A vaccines may not confer adequate protection for a significant proportion of HIV-positive patients. Heterogeneity between studies regarding population size (range: n = 14–123), mean CD4 count (372–495 cells/mm3 ), patient characteristics and hepatitis A vaccination schedule was, however, significant [1]. In addition to Shire et al.’s meta-analysis, data from two paediatric studies have recently been published, reporting seroconversion rates of 100% in 32 HIV-positive children ∗
Corresponding author. E-mail address: [email protected] (C. Herzog).
0264-410X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2007.06.013
aged 2–9 years (mean CD4 count: 1483 cells/mm3 ) [2] and of 97% in 151 HIV-positive children and adolescents aged 2–20 years (mean CD4 count: 830 cells/mm3 ) [3]. The HAV vaccines used in the trials analysed by Shire et al. and in the two paediatric studies were all aluminiumadsorbed. In this context, we would like to report the effect of a virosome-formulated HAV vaccine [4] in HIV-positive patients. This inactivated HAV vaccine (Epaxal® ) is the first commercially available, aluminium-free HAV vaccine and has proven to be highly immunogenic and safe in children, adults, and elderly people [4–8].
2. Methods In an open, uncontrolled single centre study we investigated the immunogenicity and safety of a single i.m. dose of the virosome-formulated HAV vaccine Epaxal® (Berna
L. Loutan et al. / Vaccine 25 (2007) 6310–6312
Biotech Ltd., Berne, Switzerland), containing 24 IU (formerly 500 RIA units) of hepatitis A antigen per 0.5 mL, coupled to virosomes. The vaccine was given to 14 HIVpositive, HAV naive adult patients (mean CD4 count of 547 [range: 145–1537] cells/mm3 ; mean age 34.6 [22–43] years) on Day 1 (primary immunisation) and at Month 12 (booster dose), and to 64 young healthy HAV naive adult subjects (mean age 24.1 [18–43] years) treated by the same regimen. All three of the HIV-positive patients who did not seroconvert by Day 29 received a 2nd primary dose 2–3 months after the 1st dose. One female patient (age 32 years, CD4 count: 415 cells/mm3 ) dropped out prior to Day 29 and only safety data of the primary vaccine dose became available. Immunogenicity of Epaxal® was assessed by measuring hepatitis A serum antibodies at baseline (Day 1), Day 29, and at Months 6, 12 and 13 in both study groups. The primary endpoint of the study was seroconversion based on a protective antibody concentration of ≥20 mIU/mL. Antibody levels were determined by a standard ELISA (Enzymun® AntiHAV, Boehringer Mannheim). Secondary endpoints of the study were rates and duration of solicited local (pain, redness, swelling) and solicited systemic (fatigue, headache, arthralgia, anorexia, nausea, raised body temperature) adverse events (AEs).
3. Results The characteristics and the individual results of the 13 patients evaluable for immunogenicity are listed in Table 1. The denominators for the antibody results vary between
6311
time points as several subjects missed visits or dropped out. The seroconversion rate in HIV-positive patients on Day 29 (n = 11) was 63.6%, increasing to 91.7% 1 month after the booster dose at Month 13 (n = 12), while the geometric mean concentration (GMC) of anti-HAV antibodies increased 26fold from 25.5 mIU/mL on Day 29 (n = 11) to 659.2 mIU/mL at Month 13 (n = 12), i.e., an antibody booster response documenting a good priming. Patient 13 with a low CD4 cell count of 145 cells/mm3 was the only subject not responding to the booster dose (Table 1). When excluding the three patients who received two primary doses, the seroconversion rate at Month 13 was 88.9% (n = 9), and the GMC was 670.9 mIU/mL (n = 9). Hence, exclusion of the three subjects with two primary vaccine doses did not change the results substantially. The 64 healthy subjects in the control group, all vaccinated according to the standard 0/12 months schedule, seroconverted after the priming dose by Day 29 to 93.8% and 1 month after the booster to 100%, with GMC’s of 104 and 2986 mIU/mL, respectively. The virosome-formulated HAV vaccine was well tolerated among HIV-positive and healthy subjects. The most commonly reported local adverse event (AE) was pain or tenderness at the site of injection, reported in 14.3 and 11.1% by the HIV-positive and in 37.1 and 50.0% by the healthy subjects, following primary and booster dose, respectively. Any solicited systemic reactions were reported by 35.7 and 44.4% of the HIV-positive and by 70.0 and 45.2% of the healthy subjects, following primary and booster dose, respectively. No cases of fever ≥38.5 ◦ C were reported among the HIV-positive subjects and only in one case in the control group.
Table 1 Demographic characteristics, CD4 cell count, dosing schedule and anti-HAV antibody response in 13 HIV-positive patients Subject ID
1 (FF) 2 (EL) 3 (DL) 4 (OM) 5 (YR)b 6 (TF)b 7 (JPH) 9 (RZ) 10 (PF) 11 (JM)b 12 (PW) 13 (YS) 14 (CP) Mean
a b c
Sex
Male Male Male Male Male Male Male Male Male Male Male Male Male
CD4 count (cells/mm3 )
Dosing schedule
43 39 22 32 32 40 36 43 31 40 29 32 33
517 504 718 207 272 390 533 408 659 659 1537 145 ND
34.8
557
Age (years)
Dropout after Month 6. 2nd priming dose at Month 2–3. Subjects receiving only 1 priming dose.
Anti-HAV antibody concentration (mIU/mL) Day 29
Month 6
Month 12
Month 13
0/12 months 0/12 months 0/12 months 0/12 months 0/3/12 months 0/3/12 months 0/12 months 0/12 months 0/12 months 0/2/12 months 0/12 months 0/12 months 0/12 months
51 58 27 30 15 13 44 <10 ND <10 72 ND 32
19 15 14 <10.0 25 43 79 <10 ND <10 42 ND ND
17 20 ND –a 19 20 59 54 96 116 13 47 19
1704 1333 609 –a 550 734 3825 562 1096 606 2755 13 236
Seroconversion ≥10 mIU/mL Seroconversion ≥20 mIU/mL GMC (mIU/mL)
81.8% 63.6% 23.5
70% (71%)c 40% (28.6%)c 16.8 (16.5)c
100% (100%)c 63.6% (62.5%)c 33.2 (32.4)c
100% (100%)c 91.7% (88.9%)c 659.2 (670.9)c
6312
L. Loutan et al. / Vaccine 25 (2007) 6310–6312
4. Discussion
References
The seroconversion rates seen with Epaxal® were higher when compared to the results presented in the meta-analysis of Shire et al., but still lower when compared to healthy young adults. Immunodeficient (e.g. HIV-positive patients) and elderly subjects have a delayed immune response compared to healthy young adults [8–11]. HIV-positive patients may, in some cases, benefit from a 2nd primary dose, to ensure conversion against HAV infection, as shown in three of the initially non-responding patients. However, a 2nd primary dose did not seem to change seroconversion rates and GMC’s significantly. In general, the virosome-formulated vaccine induces seroconversion rates similar to aluminium-adsorbed vaccines, but induces less local reactions [12,13]. An explanation for the excellent local tolerability profile of the virosomal vaccine (0.5 mL) is that the virosomal formulation does not contain aluminium salts and therefore hardly induces any inflammatory reactions at the injection site. The better local tolerability of Epaxal® in HIV-positive patients compared to healthy subjects needs, however, confirmation, as the low number of HIV-positive patients prevents drawing definite conclusions. In conclusion, Epaxal® can be considered a safe hepatitis A vaccine for HIV-positive patients, eliciting an immune response at least as good as reported so far for aluminiumadsorbed hepatitis A vaccines. However, further research is needed to confirm these results in a larger group of patients stratified according to their immune status (CD4 count) and to determine if the initial and the post-booster seroconversion in HIV-positive patients can be increased substantially by giving an early 2nd primary dose at Months 1–3.
[1] Shire NJ, Welge JA, Sherman KE. Efficacy of inactivated hepatitis A vaccine in HIV-infected patients: a hierarchical bayesian meta-analysis. Vaccine 2006;24(3):272–9. [2] Gouvea AF, De Moraes-Pinto MI, Ono E, Dinelli MIS, Machado DM, Weckx LY, et al. Immunogenicity and tolerability of hepatitis A vaccine in HIV-infected children. Clin Infect Dis 2005;41(4): 544–8. [3] Weinberg A, Gona P, Nachman SA, Defechereux P, Yogev R, Hughes W, et al. Antibody responses to hepatitis A virus vaccine in HIVinfected children with evidence of immunologic reconstitution while receiving highly active antiretroviral therapy. J Infect Dis 2006;193(2): 302–11. [4] Moser C, Metcalfe IC, Viret J-F. Virosomal adjuvanted antigen delivery system. Expert Rev Vac 2003;2(2):189–96. [5] Loutan L, Bovier P, Althaus B, Gl¨uck R. Inactivated virosome hepatitis A vaccine. Lancet 1994;343(8893):322–4. [6] Ambrosch F, Wiedermann G, Jonas S, Althaus B, Finkel B, Gl¨uck R, et al. Immunogenicity and protectivity of a new liposomal hepatitis A vaccine. Vaccine 1997;15(11):1209–13. [7] Usonis V, Bakasenas V, Valentelis R, Katiliene G, Vidzeniene D, Herzog C. Antibody titres after primary and booster vaccination of infants and young children with a virosomal hepatitis A vaccine (Epaxal® ). Vaccine 2003;21(31):4588–92. [8] D’Acremont V, Herzog C, Genton B. Immunogenicity and safety of a virosomal hepatitis A vaccine (Epaxal® ) in the elderly. J Travel Med 2006;13(2):78–83. [9] Leder K, Weller PF, Wilson ME. Travel vaccines and elderly persons: review of vaccines available in the United States. Clin Infect Dis 2001;33(9):1553–66. [10] Kemper CA, Haubrich R, Frank I, Dubin G, Buscarino C, McCutchan JA, et al. Safety and immunogenicity of hepatitis A vaccine in human immunodeficiency virus-infected patients: a double-blind, randomized, placebo-controlled trial. J Infect Dis 2003;187(8):1327–31. [11] Genton B, D’Acremont V, Furrer HJ, Hatz C, Loutan L. Hepatitis A vaccines and the elderly. Travel Med Infect Dis 2006;4(6): 303–12. [12] Clarke PD, Adams P, Ib´an˜ ez R, Herzog C. Rate, intensity, and duration of local reactions to a virosome-adjuvanted versus an aluminiumadsorbed hepatitis A vaccine in UK travellers. Travel Med Infect Dis 2006;4(6):313–8. [13] Bovier PA, Farinelli T, Loutan L. Interchangeability and tolerability of a virosomal and an aluminum-adsorbed hepatitis A vaccine. Vaccine 2005;23(19):2424–9.
Acknowledgement Our thanks go to Jacqueline Glaus, University Children’s Hospital in Basel, for the anti-HAV testing.