This study demonstrates that a booster dose of the virosome-formulated, aluminum-free hepatitis A vaccine Epaxal (Berna Biotech) is highly immunogenic in subjects who received a single primary dose of this vaccine 18-54 months earlier. There were no significant differences in geometric mean antibody titers (GMTs) among subjects who received the booster dose 18-29 months (GMT, 2330 mIU/mL), 30-41 months (GMT, 2395 mIU/mL), or 42-54 months (GMT, 2432 mIU/mL) after primary vaccination, indicating that delays in the administration of booster vaccination do not lead to a loss of immunogenicit

Beck, Bernhard R.

Brönnimann, Rainer

Hatz, Christoph

Herzog, Christian

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e126 • CID 2003:37 (1 November) • BRIEF REPORTB R I E F R E P O R TSuccessful Booster AntibodyResponse up to 54 Months after SinglePrimary Vaccination with Virosome-Formulated, Aluminum-FreeHepatitis A VaccineBernhard R. Beck,1 Christoph Hatz,1 Rainer Bro¨nnimann,2and Christian Herzog21Swiss Tropical Institute, Basel, and 2Berna Biotech, Berne, SwitzerlandThis study demonstrates that a booster dose of the virosome-formulated, aluminum-free hepatitis A vaccine Epaxal (BernaBiotech) is highly immunogenic in subjects who received asingle primary dose of this vaccine 18–54 months earlier.There were no significant differences in geometric mean an-tibody titers (GMTs) among subjects who received thebooster dose 18–29 months (GMT, 2330 mIU/mL), 30–41months (GMT, 2395 mIU/mL), or 42–54 months (GMT, 2432mIU/mL) after primary vaccination, indicating that delaysin the administration of booster vaccination do not lead toa loss of immunogenicity.Hepatitis A is an acute, usually self-limiting infection causedby hepatitis A virus (HAV). In areas of high endemicity, suchas Africa and parts of Asia and Latin America, infection withHAV primarily occurs during childhood, which provides life-long immunity against the disease. However, adult travelersfrom countries of low HAV endemicity who visit regions ofhigh endemicity are at risk of acquiring clinically symptomaticinfection, and it is therefore recommended that they receivevaccination against HAV infection [1–3]. To obtain long-lastingprotection against HAV, 2 doses of vaccine, administered 6–18months apart, are recommended [3]. In practice, however,many travelers do not return within 18 months for boostervaccination. Therefore, it is important to know how longReceived 3 December 2002; accepted 1 July 2003; electronically published 30 September2003.Financial support: Berna Biotech, Berne, Switzerland.Reprints or correspondence: Dr. Bernhard R. Beck, Swiss Tropical Institute, Socinstrasse57, CH-4002 Basel, Switzerland (bernhard.beck@unibas.ch).Clinical Infectious Diseases 2003; 37:e126–8 2003 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2003/3709-00E1$15.00the booster vaccination can be delayed without loss ofseroprotection.Epaxal (Berna Biotech), the only aluminum-free anti-HAVvaccine available, is based on formalin-inactivated HAV, whichis attached to the surface of special liposomes (virosomes).These virosomes replace aluminum hydroxide as the adjuvantprinciple. The virosomes contain the hemagglutinin antigenfrom the influenza A virus, which physiologically enhances theimmune response to inactivated HAV [4, 5]. A single injectionof Epaxal has been shown to be safe, well tolerated, and highlyimmunogenic [5–7]. The aim of this study was to investigatethe immunogenicity of Epaxal given as a booster dose 118months after primary vaccination with the same vaccine inhealthy adult travelers.Patients, materials, and methods. This open-label, non-comparative, single-center study assessed the immunogenicityand tolerability of a single booster dose of Epaxal in 115 healthymen and women (age,18 years) who had undergone primaryvaccination with a single dose of Epaxal 18 months earlier.Subjects who had previously undergone both primary andbooster vaccination against HAV infection; who had an acutefebrile illness, known immunodeficiency, or history of allergyor atopy; who had participated in another study; or who werepregnant or lactating were excluded from the study. Concom-itant treatment with any immunosuppressive drug was alsoprohibited, as was receipt of a blood transfusion, immuno-globulins, or any investigational drug during the 3 monthsbefore the study. The study was approved by the Ethics Com-mittee of Basel (Basel, Switzerland) and was conducted in ac-cordance with the Declaration of Helsinki. All subjects providedwritten informed consent before entry into the study.Eligible subjects were vaccinated with a single dose of Epaxal,which was injected intramuscularly into the deltoid muscle ofthe left or right upper arm. The vaccine was supplied in ready-to-use syringes containing 0.5 mL of vaccine, which included500 RIA units of HAV antigen, 10 mg of influenza A (H1N1)hemagglutinin, and 350 mg of phospholipid. The inactivated,whole HAV contained in Epaxal is derived from the HAV strainRG-SB, purified from MRC-5 human diploid cell cultures, andinactivated in formalin [4, 5].Blood samples were obtained at baseline (before injection[day 1]) and ∼1 month later (days 26–46) for measurement ofserum HAV antibody titers by EIA (Enzymun; BoehringerMannheim) at the University Children’s Hospital (Basel). Titerswere expressed as HAV antibody concentrations in mIU/mL.BRIEF REPORT • CID 2003:37 (1 November) • e127Figure 1. Scatterplot of log-transformed hepatitis A virus (HAV) an-tibody titers after booster vaccination, as a function of the time betweenprimary and booster vaccination. aData for a 31-year-old man who re-sponded to the booster dose with a titer of 31 mIU/mL only (see Results).bData for a subject who participated in an earlier trial of primary vac-cination 81 months before booster vaccination.Solicited data on adverse events and spontaneously reportedadverse events were documented and assessed by the investi-gator at each clinic visit (i.e., before vaccination [baseline] and∼1 month later). Subjects completed a checklist for specificlocal and systemic reactions, including pain/tenderness, hard-ness, swelling/tumefaction, redness (diameter, 15 mm), head-ache, fatigue, arthralgia, loss of appetite, and nausea, and re-corded their axillary temperature over a 4-day period afterinjection. The intensity of each adverse event was assessed usinga 4-point rating scale, as follows: 0 for “none,” 1 for “mild”(i.e., event did not interfere with daily activities), 2 for “mod-erate” (i.e., event interfered with daily activities), and 3 for“severe” (i.e., event prohibited normal daily activities).Subjects were evaluated if they had no evidence of prior HAVinfection (i.e., an anti-HAV titer of !7000 mIU/mL) beforereceiving the booster dose of Epaxal, and subjects had HAVantibody titers measured before and after receipt of this boosterdose. Seroprotection was defined as an HAV antibody titer of20 mIU/mL. In exploratory analyses, an HAV antibody titerof 10 mIU/mL was also considered seroprotective, which isconsistent with studies of another inactivated HAV vaccine,Vaqta (Merck) [8]. Geometric mean titers (GMTs) and sero-protection rates were summarized according to time intervalafter primary vaccination. The effect of the time interval sinceprimary vaccination on the HAV antibody response was ana-lyzed using logistic regression analysis. All subjects who receivedthe study vaccine and completed the follow-up were evaluatedfor safety.Results. One hundred seventeen subjects were enrolled, ofwhom 115 (53 men and 62 women) completed the study andwere evaluable for safety. The mean age was 44.8 years (range,20–70 years). One subject was withdrawn from the study be-cause of a screening error, and 1 subject failed to attend afollow-up assessment.Ninety-seven subjects were evaluated for immunogenicity.Eighteen subjects were excluded from efficacy evaluation: 16subjects had evidence of prior HAV infection (anti-HAV titeron day 1, 11,559–70,000 mIU/mL), the serum sample obtainedon day 1 was missing for 1 subject, and the date of primaryvaccination could not be confirmed for 1 subject.Before booster vaccination, 89% and 67% of 36 subjects whoreceived the booster dose at 18–29 months had HAV antibodytiters of 10 or 20 mIU/mL, respectively. These HAV anti-body titers were found in 91% and 77% of 34 subjects, re-spectively, who received the booster dose at 30–41 months andin 85% and 70% of 27 subjects, respectively, who received thebooster dose at 42–54 months. One month after booster vac-cination, the GMT was 2385 mIU/mL for the whole group,and seroprotection was achieved in 100% of subjects. Logisticregression analysis showed that there were no statistically sig-nificant differences in GMT between subjects who received thebooster dose 18–29 months (GMT, 2330 mIU/mL; 95% CI,1538–3529 mIU/mL), 30–41 months (GMT, 2395 mIU/mL;95% CI, 1563–3672 mIU/mL), or 42–54 months (GMT, 2432mIU/mL; 95% CI, 1506–3928 mIU/mL) after the first dose—that is, the immune response was independent of the time sinceprimary vaccination (figure 1).The antibody titers of 1 vaccinee (see footnote a in figure1) require comment. A 31-year-old man responded to thebooster dose with a titer of 31 mIU/mL only. Before receivingthe booster dose (36 months after the primary vaccination),the antibody titer had decreased to 8 mIU/mL. A thoroughclinical and laboratory evaluation did not reveal any abnor-malities. A third dose was given 17 months after the booster,and, 6 weeks after the third dose, the titer was 261 mIU/mL.At the same time, an anti–hepatitis B antibody titer of 11500mIU/mL was recorded after receipt of a third dose of hepatitisB vaccine. No factor (e.g., age or whether the subject smokedor was overweight) that could explain this low response to anti-HAV antigen was found in this apparently healthy subject.Booster vaccination was well tolerated by all subjects. Noserious systemic or local adverse events were reported. The vastmajority of local adverse events were of mild intensity andresolved later the same day. Local adverse events were reportedby 31% of subjects. The most common local events were painor tenderness (23% of subjects) and induration (17% of sub-jects). Systemic adverse events were reported by 46% of sub-jects. However, a considerable proportion (24%) of these sub-jects reported the same adverse symptoms before boostervaccination upon solicited questioning. Only 1 subject had anincreased axillary temperature (37.5C). The most frequentlye128 • CID 2003:37 (1 November) • BRIEF REPORTreported systemic symptoms at baseline and after vaccinationwere fatigue, headache, and arthralgia.Discussion. The results of this study demonstrate that adelay of up to 54 months between primary vaccination andreceipt of a booster dose does not influence the immune re-sponse to Epaxal. Seroprotection rates after primary vaccinationwere similar in subjects who received the booster dose after18–29, 30–41, or 42–54 months, suggesting that the rate ofdecline in antibody response after priming did not increaseover time. A single booster dose of Epaxal induced a strongantibody response in all groups, including subjects with HAVantibody titers of !10 mIU/mL at enrollment, which suggeststhat an anamnestic immunological response was effectively de-veloped [9]. The booster vaccination with Epaxal was well tol-erated in all groups. The observation that the interval betweenadministration of primary and booster vaccinations did nothave any influence on the immune response to the booster doseare consistent with results from similar studies using an alu-minum-adsorbed vaccine [10, 11].The results of this study are of practical relevance for cli-nicians in travel medicine, because they demonstrate that delaysin the administration of booster vaccination do not lead to lossof immunogenicity. Many travelers return for booster vacci-nation much later than the recommended 12 months, oftenbefore new travel. The antibody response found in the presentstudy indicates that booster doses are highly immunogenic forup to 4–5 years after primary vaccination.AcknowledgmentWe thank Jacqueline Glaus for performing the serological tests.References1. Koff RS. Hepatitis A. Lancet 1998; 351:1643–9.2. Cuthbert JA. Hepatitis A: old and new. Clin Microbiol Rev 2001; 14:38–58.3. World Health Organization. Hepatitis A vaccines: WHO position paper.Wkly Epidemiol Rec 2000; 75:38–44.4. Just M, Berger R, Drechsler H, Brantschen S, Glu¨ck R. A single vac-cination with an inactivated hepatitis A liposome vaccine induces pro-tective antibodies after only two weeks. Vaccine 1992; 10:737–9.5. Loutan L, Bovier P, Althaus B, Glu¨ck R. Inactivated virosome hepatitisA vaccine. Lancet 1994; 343:322–4.6. Ambrosch F, Wiedermann G, Jonas S, et al. Immunogenicity and pro-tectivity of a new liposomal hepatitis A vaccine. Vaccine 1997; 15:1209–13.7. Bovier PA, Althaus B, Glueck R, Chippaux A, Loutan L. Tolerance andimmunogenicity of the simultaneous administration of virosome hep-atitis A and yellow fever vaccines. J Travel Med 1999; 6:228–33.8. Wiens BL, Bohidar NR, Pigeon JG, et al. Duration of protection fromclinical hepatitis A: disease after vaccination with Vaqta. J Med Virol1996; 49:235–41.9. Holzer BR, Hatz C, Schmidt-Sissolak D, Glu¨ck R, Althaus B, Egger M.Immunogenicity and adverse effects of inactivated virosome versusalum-absorbed hepatitis A vaccine: a randomized controlled trial. Vac-cine 1996; 14:982–6.10. Landry P, Tremblay S, Darioli R, Genton B. Inactivated hepatitis Avaccine booster given 24 months after the primary dose. Vaccine2000; 19:399–402.11. Iwarson S, Lindh M, Widerstrom ML. Excellent booster response 4–6y after a single primary dose of an inactivated hepatitis A vaccine.Scand J Infect Dis 2002; 34:110–1.

Successful Booster Antibody Response up to 54 Months after Single Primary Vaccination with Virosome-Formulated, Aluminum-Free Hepatitis A Vaccine

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