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Hepatitis A vaccination: Schedule for accelerated immunization
Hepatitis A vaccination: schedule for accelerated immunization R. M f i i l e r * * , H. C h r i s k e t, F. D e i n h a r d t } , J. Jilg ++, L. T h e i l m a n n ~ , G . H e s s ' , F. H o f m a n n e , U. H o p f '~, H. Stickl +, H. M a i w a l d +, U. Bienzle °, C. S c h 6 f e l d °, H. Z i m m e r m a n n =~, M . Dietrich/~ B. M a y v, H . L . B o c k * , R. C l e m e n s * a n d H. B o g a e r t s *
Hepatitis A vaccine, strain HM175, was investigatedJor Onmunogenici O, and tolerabili O, in a prospective multicentre trial. The Jbllowing vaccination scheduh, s and antigen contents were evaluated. days 0 and 14 with 720 E L I S A units (El. U) (?/antigen, days 0 and 28 with 720 El. U and days 0 and 28 with 360 El. U. In all stud), groups, the seroconversion rates /bllowhlg two vaccinations were between 95 and 100%o. Higher geometric mean eoncenlrations of antibody to hepatitis A virus (anti-HA V) were reached by the vaccine containing 720 El. U o f HA V antigen. The vaccine was equal@ well toh, rated in all groups, hi addition, an abbreviated schedule, in which 720 El.U oJ'HA V antigen was given on days 0 and 14, resulted in 100% seroconversion by day 28 and a level q f anti-HA V that was substantially higher than that observed after passive immunization. This implies that such a vaccine could replace #nmune globulin administration if tone permits. Keywords: Hepatitis A: travellers: short-term schedule
INTRODUCTION
MATERIAL AND METHODS
Active immunization for travellers to endemic areas is needed due to both a decrease of natural immunity against hepatitis A in most of the European countries t.-' and an increase of tourism to countries with a high incidence of hepatitis A infections3. Recent studies have shown that hepatitis A vaccine strain HM175 (Havrix, SmithKline Beecham Biologicals, Rixensart, Belgium) is well tolerated, highly immunogenic and induces antibody levels which are significantly higher than those achieved following passive immunization 4. The hepatitis A vaccine, HM175, was used in an open, prospective, multicentre, randomized trial investigating three different short-term vaccination schedules. The objective of the study was to induce active immunity against hepatitis A virus (HAV) in travellers who, for protection, consult their doctor relatively late, usually just prior to their departure.
In this study, 133 healthy male and female adults, 20 to 65 years of age (mean 28 years), were randomized into three groups to receive 1 ml doses of hepatitis A vaccine intramuscularly in the deltoid region. The vaccination schedules and the doses employed were 720 ELISA units (El.U) at days 0 and 14 (group 1), 720 E1.U at days 0 and 28 (group 2) and 360 (El.U) at days 0 and 28 (group 3). Exclusion criteria included liver disease, recent immunoglobulin administration, pregnancy, permanent drug medication (especially immunosuppressive therapy) and chronic alcohol abuse. Blood sampling for anti-HAV screening and quantitative anti-HAV analysis was performed at days 0, 14 and 28 and at months 2 and 6 after vaccination. A highly sensitive anti-HAV ELISA was used for anti-HAV testing s. Titres < 20 mIU/ml were considered negative. Sera of all candidates were non-reactive for anti-HAV prior to inclusion in the study. In addition, liver enzyme activities (alanine aminotransferase, ALT, and asparate aminotransferase, AST) were measured in every blood sample. Local and general signs and symptoms were evaluated at days 0 to 3 following vaccination. For statistical analysis the Mann-Whitney, X-' and Fisher exact tests were applied.
*Medizinische Hochschule Hannover, Germany. tArbeitsmed. Dienst, KNn, Germany. *Max-von-Pettenkofer Institut M0nchen, Germany. §Universit&tsklinik Heidelberg, Germany. ~Universit&tsklinik Mainz, Germany. °Universit~.tsklinik Freiburg, Germany. "Klinikum Charlottenburg, Berlin, Germany. +lnstitut for Toxologie und Umwelthygiene, M0nchen, Germany. °Landesinstitut for Tropenmedizin, Berlin, Germany. -Klinikum Lahnberge, Marburg, Germany. - Bernhard Nocht Institut, Hamburg, Germany. Krankenanstalten Bergmannsheil, Bochum, Germany. *SmithKline Beecham, M0nchen, Germany. *SmithKline Beecham Biologicals, Rixensart, Belgium. ~To whom correspondence should be addressed
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Vaccine, Vol. 10, Suppl. 1, 1992
RESULTS All three study groups were comparable with respect to age and gender. Seroconversion rates for the different times of blood sampling are depicted in Tabh, 1. In all 0264-410X/92/100S124-02 ~© 1992Butterworth-HeinemannLtd
Short-term HA V vaccination: R. M u l l e r et al. Table 1
Seroconversion rates of anti-HAV in three groups of vaccinees at different times after vaccination Seroconversion at
Group
Day 14
1 2 3
Day 28
Month 2
Month 6
No. positive/total
%
No. positive/total
%
No positive/total
%
No. positive/total
%
18/41 18/39 17/36
43.9 46.2 47.2
41/41 33/42 27136
100 78.6 75.0
39/39 37/39 36136
100 94.9 100
41141 58/40 36136
100 95.0 100
Group 1 received 720 EI.U on days 0 and 14; group 2 received 720 EI.U on days 0 and 28; group 3 received 360 EI.U on days 0 and 28 700
100
a
600
b
8o 500 o~O
400
> < -t-
60 -
u
300
I
200
<
-~
100 0 Day' 0
I D a y 14
I D a y 28
I Month 2
Month 6
Time
Figure 1 Geometric mean anti-HAV concentration after short-term vaccination with hepatitis A vaccine, HM175, in three groups of adults vaccinated with different doses and schedules. Vaccination: C], days 0 and 14 with 720 EU; +, days 0 and 28 with 720 EU; * , days 0 and 28 with 360 EU a
~oo
80
b
-
o 60 u
40 Q) "O u3
20 0
V//,//~
1/////~
Figure 2 Local side effects in the three groups of vaccinees for the first two injections, a, First injection; b, second injection. I~1, Reddening; rS, swelling; [], induration
groups, seroconversion rates in months 2 and 4 were between 95 and 100%. In addition, in group 1 a seroconversion rate of 100% was found at day 28. For group 3 (360 El.U), lower antibody levels were found in samples at months 1, 2 and 4 (Figure 1). Local and general side effects were mild and transient and were infrequently observed (Figures 2 and 3). No differences were found between the three groups (p = 0.807; range of 20-26% with side effects). No pathological increase in the transaminase levels was found. In general, the second vaccination was better tolerated than the first one. The relative number of subjects with side effects after vaccination was independent of the amount of antigen administered.
DISCUSSION Seroconversion to anti-HAV was observed in all 48 subjects of study group 1 within 4 weeks, indicating that
20 o
f////1[
[',.~"~
Figure 3 Systemic side effects in the three groups of vaccinees for the first two injections, a, First injection; b, Second injection. I~1, Fever; CJ, headache; [], malaise
anti-HAV levels > 20 m l U / m l can be induced by two injections of the vaccine given at a two-week interval. Data from the literature has shown that only 50% of subjects given routine immune globulin injections were found to have anti-HAV titres of 20 m I U / m l or more with a geometric mean anti-HAV concentration of 34.7 mIU/mP. In contrast, the subjects in our study group achieved a geometric mean of almost 600 mIU/ml. Protection following passive immunization is transient, and standard immune globulin must be given in 45 month intervals for lasting protection. As the duration of immunity appears to be at least partially dependent on the antibody level, it can be deduced that the development of antibody levels following active immunization that are up to 190-fold higher than those observed after passive immunization should provide protection that will last for several years. Because high seroconversion rates and anti-HAV levels are induced early by the inactivated hepatitis A vaccine when used in an abbreviated schedule of 0 and 14 days, the vaccine may be appropriate for accelerated immunization of travellers to endemic countries.
REFERENCES 1 Fr6sner, G.G., Roggendorf, M., Fr6sner, H.R., Gerth, H.S., Borst, U.E., Blochinger, G. and Schmid, W. Epidemiology of hepatitis A and B infection in Western European countries and in Germans travelling abroad. In: Viral Hepatitis (Eds Szmuness, W., Alter, H.J., Maynard, J.E.) The Franklin Institute Press, Philadelphia, 1982, pp. 157-167. 2 Stroffolini, T., De Crescenzo, L., Giammanco, A., Intonazzo, V., La Rosa, G., CasciopA., Sarazana, A., Chiarini, A. and Dardanoni, L. Changing patterns of hepatitis A virus infection in children in Palermo, Italy. Eur. J. EpidemioL 1990, 6, 84-87 3 Yearbook of Tourism Statistics. World Tourism Organization, 1989 4 Wiedermann, G., Ambrosch, F., Kollaritsch, H., Hoffmann, H., Kunz, C.H., D'Hondt, E., Delem, A., Andr6, F.E., Safary, A. and Stephene, J. Safety and immunogenicity of an inactivated hepatitis A candidate vaccine in healthy adult volunteers, Vaccine 1990 8, 581-584 5 Andre, F.E., Hepurn, A. and D'Hondt, E. Inactivated candidate vaccines for hepatitis A. Prog. Med. ViroL 1990, 37, 72-95
Vaccine, Vol. 10, Suppl. 1, 1992
$125
Hepatitis A vaccine, strain HM175, was investigatedJor Onmunogenici O, and tolerabili O, in a prospective multicentre trial. The Jbllowing vaccination scheduh, s and antigen contents were evaluated. days 0 and 14 with 720 E L I S A units (El. U) (?/antigen, days 0 and 28 with 720 El. U and days 0 and 28 with 360 El. U. In all stud), groups, the seroconversion rates /bllowhlg two vaccinations were between 95 and 100%o. Higher geometric mean eoncenlrations of antibody to hepatitis A virus (anti-HA V) were reached by the vaccine containing 720 El. U o f HA V antigen. The vaccine was equal@ well toh, rated in all groups, hi addition, an abbreviated schedule, in which 720 El.U oJ'HA V antigen was given on days 0 and 14, resulted in 100% seroconversion by day 28 and a level q f anti-HA V that was substantially higher than that observed after passive immunization. This implies that such a vaccine could replace #nmune globulin administration if tone permits. Keywords: Hepatitis A: travellers: short-term schedule
INTRODUCTION
MATERIAL AND METHODS
Active immunization for travellers to endemic areas is needed due to both a decrease of natural immunity against hepatitis A in most of the European countries t.-' and an increase of tourism to countries with a high incidence of hepatitis A infections3. Recent studies have shown that hepatitis A vaccine strain HM175 (Havrix, SmithKline Beecham Biologicals, Rixensart, Belgium) is well tolerated, highly immunogenic and induces antibody levels which are significantly higher than those achieved following passive immunization 4. The hepatitis A vaccine, HM175, was used in an open, prospective, multicentre, randomized trial investigating three different short-term vaccination schedules. The objective of the study was to induce active immunity against hepatitis A virus (HAV) in travellers who, for protection, consult their doctor relatively late, usually just prior to their departure.
In this study, 133 healthy male and female adults, 20 to 65 years of age (mean 28 years), were randomized into three groups to receive 1 ml doses of hepatitis A vaccine intramuscularly in the deltoid region. The vaccination schedules and the doses employed were 720 ELISA units (El.U) at days 0 and 14 (group 1), 720 E1.U at days 0 and 28 (group 2) and 360 (El.U) at days 0 and 28 (group 3). Exclusion criteria included liver disease, recent immunoglobulin administration, pregnancy, permanent drug medication (especially immunosuppressive therapy) and chronic alcohol abuse. Blood sampling for anti-HAV screening and quantitative anti-HAV analysis was performed at days 0, 14 and 28 and at months 2 and 6 after vaccination. A highly sensitive anti-HAV ELISA was used for anti-HAV testing s. Titres < 20 mIU/ml were considered negative. Sera of all candidates were non-reactive for anti-HAV prior to inclusion in the study. In addition, liver enzyme activities (alanine aminotransferase, ALT, and asparate aminotransferase, AST) were measured in every blood sample. Local and general signs and symptoms were evaluated at days 0 to 3 following vaccination. For statistical analysis the Mann-Whitney, X-' and Fisher exact tests were applied.
*Medizinische Hochschule Hannover, Germany. tArbeitsmed. Dienst, KNn, Germany. *Max-von-Pettenkofer Institut M0nchen, Germany. §Universit&tsklinik Heidelberg, Germany. ~Universit&tsklinik Mainz, Germany. °Universit~.tsklinik Freiburg, Germany. "Klinikum Charlottenburg, Berlin, Germany. +lnstitut for Toxologie und Umwelthygiene, M0nchen, Germany. °Landesinstitut for Tropenmedizin, Berlin, Germany. -Klinikum Lahnberge, Marburg, Germany. - Bernhard Nocht Institut, Hamburg, Germany. Krankenanstalten Bergmannsheil, Bochum, Germany. *SmithKline Beecham, M0nchen, Germany. *SmithKline Beecham Biologicals, Rixensart, Belgium. ~To whom correspondence should be addressed
$124
Vaccine, Vol. 10, Suppl. 1, 1992
RESULTS All three study groups were comparable with respect to age and gender. Seroconversion rates for the different times of blood sampling are depicted in Tabh, 1. In all 0264-410X/92/100S124-02 ~© 1992Butterworth-HeinemannLtd
Short-term HA V vaccination: R. M u l l e r et al. Table 1
Seroconversion rates of anti-HAV in three groups of vaccinees at different times after vaccination Seroconversion at
Group
Day 14
1 2 3
Day 28
Month 2
Month 6
No. positive/total
%
No. positive/total
%
No positive/total
%
No. positive/total
%
18/41 18/39 17/36
43.9 46.2 47.2
41/41 33/42 27136
100 78.6 75.0
39/39 37/39 36136
100 94.9 100
41141 58/40 36136
100 95.0 100
Group 1 received 720 EI.U on days 0 and 14; group 2 received 720 EI.U on days 0 and 28; group 3 received 360 EI.U on days 0 and 28 700
100
a
600
b
8o 500 o~O
400
> < -t-
60 -
u
300
I
200
<
-~
100 0 Day' 0
I D a y 14
I D a y 28
I Month 2
Month 6
Time
Figure 1 Geometric mean anti-HAV concentration after short-term vaccination with hepatitis A vaccine, HM175, in three groups of adults vaccinated with different doses and schedules. Vaccination: C], days 0 and 14 with 720 EU; +, days 0 and 28 with 720 EU; * , days 0 and 28 with 360 EU a
~oo
80
b
-
o 60 u
40 Q) "O u3
20 0
V//,//~
1/////~
Figure 2 Local side effects in the three groups of vaccinees for the first two injections, a, First injection; b, second injection. I~1, Reddening; rS, swelling; [], induration
groups, seroconversion rates in months 2 and 4 were between 95 and 100%. In addition, in group 1 a seroconversion rate of 100% was found at day 28. For group 3 (360 El.U), lower antibody levels were found in samples at months 1, 2 and 4 (Figure 1). Local and general side effects were mild and transient and were infrequently observed (Figures 2 and 3). No differences were found between the three groups (p = 0.807; range of 20-26% with side effects). No pathological increase in the transaminase levels was found. In general, the second vaccination was better tolerated than the first one. The relative number of subjects with side effects after vaccination was independent of the amount of antigen administered.
DISCUSSION Seroconversion to anti-HAV was observed in all 48 subjects of study group 1 within 4 weeks, indicating that
20 o
f////1[
[',.~"~
Figure 3 Systemic side effects in the three groups of vaccinees for the first two injections, a, First injection; b, Second injection. I~1, Fever; CJ, headache; [], malaise
anti-HAV levels > 20 m l U / m l can be induced by two injections of the vaccine given at a two-week interval. Data from the literature has shown that only 50% of subjects given routine immune globulin injections were found to have anti-HAV titres of 20 m I U / m l or more with a geometric mean anti-HAV concentration of 34.7 mIU/mP. In contrast, the subjects in our study group achieved a geometric mean of almost 600 mIU/ml. Protection following passive immunization is transient, and standard immune globulin must be given in 45 month intervals for lasting protection. As the duration of immunity appears to be at least partially dependent on the antibody level, it can be deduced that the development of antibody levels following active immunization that are up to 190-fold higher than those observed after passive immunization should provide protection that will last for several years. Because high seroconversion rates and anti-HAV levels are induced early by the inactivated hepatitis A vaccine when used in an abbreviated schedule of 0 and 14 days, the vaccine may be appropriate for accelerated immunization of travellers to endemic countries.
REFERENCES 1 Fr6sner, G.G., Roggendorf, M., Fr6sner, H.R., Gerth, H.S., Borst, U.E., Blochinger, G. and Schmid, W. Epidemiology of hepatitis A and B infection in Western European countries and in Germans travelling abroad. In: Viral Hepatitis (Eds Szmuness, W., Alter, H.J., Maynard, J.E.) The Franklin Institute Press, Philadelphia, 1982, pp. 157-167. 2 Stroffolini, T., De Crescenzo, L., Giammanco, A., Intonazzo, V., La Rosa, G., CasciopA., Sarazana, A., Chiarini, A. and Dardanoni, L. Changing patterns of hepatitis A virus infection in children in Palermo, Italy. Eur. J. EpidemioL 1990, 6, 84-87 3 Yearbook of Tourism Statistics. World Tourism Organization, 1989 4 Wiedermann, G., Ambrosch, F., Kollaritsch, H., Hoffmann, H., Kunz, C.H., D'Hondt, E., Delem, A., Andr6, F.E., Safary, A. and Stephene, J. Safety and immunogenicity of an inactivated hepatitis A candidate vaccine in healthy adult volunteers, Vaccine 1990 8, 581-584 5 Andre, F.E., Hepurn, A. and D'Hondt, E. Inactivated candidate vaccines for hepatitis A. Prog. Med. ViroL 1990, 37, 72-95
Vaccine, Vol. 10, Suppl. 1, 1992
$125