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Intradermal and intramuscular route for vaccination against hepatitis B
Intradermal and intramuscular route for vaccination against hepatitis B M.L. Gonz~ilez *t, M. Usandizaga*, P. Alomar*, F. Saivh*, F. Martin*, M.J. Erroz* and R. Lardinois t A recombinant hepatitis B vaccine was administered to high-risk hospitalpersonnel by intramuscular (20 l~g) or intradermal (2 Itg) injections for the primary immunization (n=69) with three doses and booster immunization (n = 51) with one dose. Basic vaccination performed intramuscularly gave rise to significantly higher seroconversion levels (97.2% versus 78.1°/~) and geometric mean titres o f antibody (1649 versus 1261U1-1) as compared with the intradermal route. Intradermal administration did not boost antibody titres in patients previously vaccinated intradermally. Adverse reactions were not serious or severe. The intramuscular route is recommended as the procedure o f choice when vaccinating against hepatitis B. Keywords:Hepatitis B; recombinant vaccine; intramuscular; intradermal
Introduction In controlled studies carried out with three doses of hepatitis vaccine, no significant differences were established between the intramuscular (i.m.) and intradermal (i.d.) route in the incidence of local reactions, final seroconversion levels and anti-HBs titres I-4, although the latter were lower following i.d. administration. Since i.d. vaccination against hepatitis B may be performed with as low as one-tenth of the dose applied by the i.m. route, it should be possible to carry out large scale campaigns at low cost among high risk groups. The present study, performed with h!gh risk hospital personnel at Son Dureta Hospital, Palma de Mallorca, Spain, aimed at comparing, according to the route of administration, the immunogenicity and reactogenicity of a yeast recombinant hepatitis B vaccine, when performing primary and/or booster immunization.
Materials and methods This non-blind randomized controlled trial, carried out in parallel among high-risk susceptible hospital personnel s'6, started in March 1988 with the authorization of the Spanish Health Authorities. A group of 69 healthy personnel (36 women and 33 men) of 20 to 40 years of age with normal transaminase values and adequate weight for height (no more than 10% overweight) went through the primary vaccination, after consent was obtained before a witness. Pairs of men and women were constituted according to age (a difference of up to 1 year was allowed). Three doses of a recombinant hepatitis B vaccine from the same lot (Engerix-B, 130 A4, SK-RIT), were randomly administered to each vaccinee within a
pair at 0, 1 and 6 months, either i.m. (20 gg per dose) or i.d. (2/~g per dose). In December 1988, 51 staff members (22 women and 29 men) with antibody titres < 160 IU 1-1 were boosted with a fourth dose of the same batch of vaccine: 21 originated from the initial group of 69 participants, whereas 30 had been vaccinated, on a routine basis, one year before and exclusively by i.m. administration. Booster doses consisted of 2#g i.d., or 20#g i.m., and were randomly allocated within pairs of men or women, which were each homogeneous with respect to anti-HBs titres, age and weight. This procedure gave rise to four categories of subjects: those vaccinated and boosted by i.d. route (I) or by i.m. route (III), as well as those vaccinated by i.m. route and boosted by i.d. route (II) or vice versa (IV). Vaccinations in the left deltoid area were always performed by the same team of three nurses highly experienced in intramuscular and intradermal inoculations. Prior to vaccination as well as one month after the third and fourth dose, detection of HBsAg, anti-HBc and titration of anti-HBs were carried out by enzymoimmunoassay. Serum transaminase levels (normal values up to 50 IU 1-1) were determined by autoanalyser prior to and at the end of the trial. Mean values and percentages were statistically compared by means of the Student, Z2 and Fisher tests. Anti-HBs titres in each group were expressed in geometric means (GM) and were compared by the non-parametric Mann-Whitney test, attributing arbitrarily a value of 5 I U 1 - 1 to those sera in which antibody was not detectable.
Results *Hospital Son Dureta, Palma de Mallorca, Spain. tl.T.E.M.Pharma, Madrid, Spain. tCorrespondence should be addressed to: Maria Lourdes Gonz&lez Gonza.lez, Servicio de Obstetricia y Ginecologia, Hospital Son Dureta, C/ Andrea Doria, 55, 07014 Palma de Mallorca, Spain. (Received 25 September 1989; revised 22 February 1990; accepted 22 February 1990) 0264-410x/90/040402-04 © 1990 Butterworth-Heinemann Ltd
402 Vaccine, Vol. 8, August 1990
Following primary vaccination (Table I), i.m. administration (3 x 20 #g) induced significantly higher percentages of seroconversion ( > I O I U 1 - 1 ) as compared with i.d. regime (3 x 2 #g), both in the whole group of participants (97.2% versus 78.1%, p < 0.05) and in men (100% versus 64.3% , p<0.001).
Routes for vaccination against hepatitis B: M.L. Gonz~lez et al. Table
1
Seroconvemion levels and anti-HBs titres prior to and following primary and booster vaccination e i t h e r b y intramuscular or intradermal route Seroconversion No. of
Group
Prevaccination (%)
Vaccination route
volunteers
Primary vaccination i.m.
36
0
32 =
0
Anti-HBs
Postvaccination (%)
titres
Prevaccination
Postvaccination
-
1649
All volunteers
i.d.
Booster i.m. i.d.
24 27
66.7 59.2
_
97.2
p < 0.05
78.1
NS
-
100 92.6
NS
100
p<0.001
p < 0.001
126
-
22.1 21.2
NS
-
_
572.3
NS
158.2
Men Primary vaccination i.m.
18
0
i.d.
14
0
Booster i.m. i.d.
14 15
64.3 53.3
i.m. i.d.
18 18
0 0
Booster i.m. i.d.
10 12
70 66.7
_
64.3
NS
1667 37
-
100 86.7
NS
15.1 17.6
NS
94.4
NS
-
_
628.0 209.6
p<0.001
NS
Women Primary vaccination _
88.8
100 100
NS
37.6 30.7
NS
1638
p<0.0~,,
324 NS
502.6 166.2
NS
NS, not significant =One man vaccinated by i.d. route dropped out after the second dose (moved to another region)
Table
2
Anti-HBs titre following intramuscular or intradermal booster in the whole group and according to the primary vaccination route Titres (GM)
Group
Vaccination route
All' Women = Men' I II III IV
Primary Booster Primary Booster Primary Booster Primary Booster
vaccination vaccination vaccination
i.d. i.d. i.m. i.d. i.m. i.m.
vaccination
i.d. i.m.
No. in group
Prevaccination
Postvaccination
51 22 29
21.7 32.7 16.0
318.8 274.8 356.9
7
17.1
23.9
20
25.0
391.0
15
20.3
707.4
9
21.4
402.1
Statistical significance: women/men, not significant; group I/group II, p<0.01, group I/group III, p<0.001; group I/group iV, p<0.05 =The pre- and postvaccination anti-I-IBs titres are calculated irrespective of the vaccination route
Antibody titres were significantly higher following vaccination with 3x20/zg i.m.; the respective G M reached 1649 and 126IU1-1 in the whole group (p<0.001), 1667 and 37IU1-1 among men (p<0.001) and 1638 versus 324IU1-1 in women (p<0.05). At the end of the vaccination by i.d. or i.m. route, the only significant difference detected between men and women was observed in the i.d. regime, which induced higher titres (p<0.01) in women than in men (GM of 324 versus 37 IU 1-1, respectively). A booster dose given to poor (<160IU1 -I) and non-responders ( < 1 0 I U I -~) induced no statistical differences between i.d. and i.m. administration in seroconversion or anti-HBs levels, considering either the whole group (n=51), men (n=29) or women (n=22), and irrespective of the route selected for the primary vaccination. The four subgroups, constituted according to the regimen selected for the primary and for the booster
vaccination (Table 2), showed very similar pre-booster titres (17.1-25.0 IU 1= 1). No increase in antibody levels was obtained (23.9 IU1-1) in those who received i.d. administration of vaccine at both stages. In the other subgroups, the postbooster titres rose to 391.0IU1-1 (i.m. primary vaccination, i.d. booster), 402.1 IU 1-i (i.d. primary vaccination, i.r/a, booster) and 707.4 IU 1- ~ (i.m. primary vaccination, i.m. booster). No statistical difference in the postvaccination titres was observed between these three subgroups, which all showed significantly higher antibody titres than the first group (i.d. on both occasions). In relation to the primary vaccination, adverse reactions of a local nature were statistically more frequent (p<0.001) among i.d. vaccinees (84.4% versus 36.1%) and those of general nature among i.m. vaccinees (41.7% versus 6.1%). With the booster dose, either after i.d. or i.m. adminstration, no general reaction was recorded;
V a c c i n e , Vol. 8, A u g u s t 1990
403
Routes for vaccination against hepatitis B: M,L. Gonz~lez et al.
however, local adverse reactions were statistically more frequent (p<0.001) with the i.d. (96.3%) than with the i.m. regime (8.3%). The most frequent general adverse reactions observed consisted of headache and asthenia. Locally, at the injection site, pain was the most common feature associated with the i.m. regime, whereas i.d. injections were followed by frequent indurations, sometimes accompanied by swelling. With respect to the i.d. route, no antibody response was recorded in patients with no local adverse experience, whereas 92.5% of those with a local reaction responded to the vaccine (GM: 228 IUI-~). Seroconversion levels and anti-HBs titres (GM) were significantly higher among patients who presented a local reaction on two occasions (100% and 482IU1-1) rather than on one occasion (71.4% and 27IU1-1, respectively). Anti-HBs titres (GM) of 191 or 1442 IU1-1 (p < 0.05), respectively, were recorded in vaccinees, depending on whether the induration or swelling was lower or higher than 150 mm. Serum transaminase levels persisted within the normal range ( < 50 IU 1- 1) in each vaccinee throughout the trial, whereas HBsAg and anti-HBc markers remained negative.
Discussion The outputs of immunizations carried out with small amounts of antigen delivered by the intramuscular 7's or intradermal 1-4'9-14 route are still under study. Four controlled studies 1-4 with a three dose regime have been published, in which 2 #g, i.d., doses of vaccine have been compared with 20/~g, i.m., doses. All these studies have been performed on a small number of subjects (9 to 25 in each set) by experienced personnel and in ideal conditions (young healthy adults with no antecedents of serious disease and normal serum transaminase levels). One month after the third dose, the seroconversion levels were similar between i.d. and i.m. vaccinees, whereas anti-HBs titres were lower after i.d. administration, although no statistical difference was established between the routes selected. Following revaccination, the data recorded by Horowitz 15 show almost identical levels of seroconversion and antibody titres after i.m. and i.d. administration. On the other hand, the persistence of anti-HBs protective levels, which is associated with the length of the antibody response recorded at the end of the primary vaccination 1°'16'17 was quite similar in the studies of Jilg 16 and Irving ~1 comparing i.m. and i.d. administration. This study performed on carefully matched groups shows that primary vaccination with 3 x 2 # g , i.d., induced seroconversion in a significantly lower percentage of recipients and that the titres recorded in responders are also statistically lower (sixfold), as compared with the i.m. regime (3 x 20#g,, i.m.). It was for this reason that we attempted to reinforce the immunity of the poor and non-responders using a fourth dose (booster) administered in a controlled and randomized manner by i.m. or i.d. route. Our data on the i.d. performance indicates that to continue boosting by i.d. administration did not increment anti-HBs titres, whereas the switch to the i.m. route increased the antibody levels by approximately 20-fold. It should be stressed that the switch to i.d. administration, after a poor response to a primary vaccination performed by the i.m. route, similarly gave rise to a 15-fold increase in the anti-HBs titres. However,
404
Vaccine, Vol. 8, A u g u s t 1990
the best response (35-fold increment) was obtained with the standard regime in which i.m. route is used for both the primary immunization and revaccination. The local and general adverse reactions were neither serious nor severe and resolved spontaneously without any special therapy. Several features indicate that the intervention of an immunological mechanism in the production of local adverse reactions following vaccination by the i.d. route: local induration, which was not seen following the first contact with HBsAg, persisted for progressively increasing periods following the second, third and booster dose. In addition, a significant relationship was demonstrated between the occurrence, size and recurrence of reactions at the injection site and the immune response (seroconversion levels and antiHBs titres), as previously pointed out by Zoulek 2 and Horowitz15. Although the size of the population included in the distinct subgroups of this trial is small, the data permit the conclusion that in spite of the economic advantages which would derive from the use of small vaccine doses, the intradermal route is not recommendable in healthy adults for the primary immunization against hepatitis B. According to our data, the only practical interest to be expected from i.d. administration would be an appreciable rise in anti-HBs titres when boosting the subjects who do not respond satisfactorily to the primary vaccination by i.m. route. The intramuscular route remains, therefore, the regimen of choice, for both the primary immunization and revaccination against hepatitis B.
Acknowledgement The authors are grateful for the technical assistance of A. Garau, P. Ferrer and C. Serra.
References 1
Redfield, R.R., Innis, B.L., Scott, R. et al. Clinical evaluation of low-dose intradermally adminstered hepatitis B virus vaccine. A cost reduction strategy. J. Am. Med. Assoc. 1985, 2.54, 3203 2 Zoulek, G., Lorbeer, B., Jilg, W. et al. Evaluation of a reduced dose of hepatitis B vaccine administered intradermally. J. Med. Virol. 1984, 14, 27 3 Halsey, N.A., Reppert, E.J., Margolis, H.S. eta/. Intradermal hepatitis B vaccination in an abbreviated schedule. Vaccine 1986, 4, 228 4 Wahl, M. and Hermodsson, S. Intradermal, subcutaneous or intramuscular administration of hepatitis B vaccine: side effects and antibody response. Scand. J. Infect. Dis. 1987, 19, 617 5 Gonz~lez, M.L., Roses, A., Ferret, P. et al. Prevalencia de la infeccibn por VHB entre las parturientas y el personal de un Centro Materno-lnfantil en Palma de Mallorca. C/in. Invest. Gin. Obst. 1988, 15,32 6 Gonz&lez, M.L., Roses, A., Alomar, P. eta/. The Maternal-lnfantil Center in the control of hepatitis B. Acta Obstet. Gynecol. Scand. 1988, 67, 421 7 Shou-Dong, L., Kwang-Juei, L., Yang-Te, T. e t a / . Hepatitis B vaccination in healthy Chinese adults with low dose regimens. Vaccine 1987, 5, 195 8 Moyes, C.D., Milne, A., Dimitrakakis, M. et al. Very low dose hepatitis B vaccine in newborn infants: an economic option for control in endemic areas. Lancet 1987, i, 29 9 Miller, K.D., Gibbs, R.D., Mulligan, M.M. et al. Intradermal hepatitis B vaccine. Immunogenicity and side-effects in adults. Lancet 1983, Ii, 1454 10 Irving, W.L, Alder, M., Kurtz, J.B. e t a / . Intradermal vaccination against hepatitis B. Lancet 1986, ii, 1340 11 Irving, W.L, Parsons, A.J., Kurtz, J.B. et al. Intradermal hepatitis B vaccine. Lancet 1987, il, 561
Routes for v a c c i n a t i o n a g a i n s t hepatitis B: M.L. Gonz&lez et al. 12
Dienstag, J.L. Low-dose intradermal hepatitis B vaccine. J. Am. Med. Assoc. 1986, 256, 351 13 Centers for Disease Control. Intradermat route for hepatitis B vaccination. Hepatitis Surveillance Report No. 51, Department of Health and Human Services, Washington, 1987, pp. 1-4 14 Zuckerman, A.J. Appraisal of intradermal immunization against hepatitis B. Lancet 1987, I, 435
15 Horowitz, M.M., Ershler, W.B., McKinney, W. et al. Duration of immunity after hepatitis B. Vaccination, efficacy of low-dose booster vaccine. Ann. Intern. Ivied..1988, 108, 185 16 Jilg, W., Schmidt, M., Zoulek, G. et al. Clinical evaluation of a recombinant hepatitis B vaccine. Lancet 1984, II, 1174 17 Krugman, S. and Davidson, M. Hepatitis B vaccine: Prospects for duration of immunity. Yale J. Biol. Med. 1987, 60, 333
Vaccine, Vol. 8, A u g u s t 1990
405
Introduction In controlled studies carried out with three doses of hepatitis vaccine, no significant differences were established between the intramuscular (i.m.) and intradermal (i.d.) route in the incidence of local reactions, final seroconversion levels and anti-HBs titres I-4, although the latter were lower following i.d. administration. Since i.d. vaccination against hepatitis B may be performed with as low as one-tenth of the dose applied by the i.m. route, it should be possible to carry out large scale campaigns at low cost among high risk groups. The present study, performed with h!gh risk hospital personnel at Son Dureta Hospital, Palma de Mallorca, Spain, aimed at comparing, according to the route of administration, the immunogenicity and reactogenicity of a yeast recombinant hepatitis B vaccine, when performing primary and/or booster immunization.
Materials and methods This non-blind randomized controlled trial, carried out in parallel among high-risk susceptible hospital personnel s'6, started in March 1988 with the authorization of the Spanish Health Authorities. A group of 69 healthy personnel (36 women and 33 men) of 20 to 40 years of age with normal transaminase values and adequate weight for height (no more than 10% overweight) went through the primary vaccination, after consent was obtained before a witness. Pairs of men and women were constituted according to age (a difference of up to 1 year was allowed). Three doses of a recombinant hepatitis B vaccine from the same lot (Engerix-B, 130 A4, SK-RIT), were randomly administered to each vaccinee within a
pair at 0, 1 and 6 months, either i.m. (20 gg per dose) or i.d. (2/~g per dose). In December 1988, 51 staff members (22 women and 29 men) with antibody titres < 160 IU 1-1 were boosted with a fourth dose of the same batch of vaccine: 21 originated from the initial group of 69 participants, whereas 30 had been vaccinated, on a routine basis, one year before and exclusively by i.m. administration. Booster doses consisted of 2#g i.d., or 20#g i.m., and were randomly allocated within pairs of men or women, which were each homogeneous with respect to anti-HBs titres, age and weight. This procedure gave rise to four categories of subjects: those vaccinated and boosted by i.d. route (I) or by i.m. route (III), as well as those vaccinated by i.m. route and boosted by i.d. route (II) or vice versa (IV). Vaccinations in the left deltoid area were always performed by the same team of three nurses highly experienced in intramuscular and intradermal inoculations. Prior to vaccination as well as one month after the third and fourth dose, detection of HBsAg, anti-HBc and titration of anti-HBs were carried out by enzymoimmunoassay. Serum transaminase levels (normal values up to 50 IU 1-1) were determined by autoanalyser prior to and at the end of the trial. Mean values and percentages were statistically compared by means of the Student, Z2 and Fisher tests. Anti-HBs titres in each group were expressed in geometric means (GM) and were compared by the non-parametric Mann-Whitney test, attributing arbitrarily a value of 5 I U 1 - 1 to those sera in which antibody was not detectable.
Results *Hospital Son Dureta, Palma de Mallorca, Spain. tl.T.E.M.Pharma, Madrid, Spain. tCorrespondence should be addressed to: Maria Lourdes Gonz&lez Gonza.lez, Servicio de Obstetricia y Ginecologia, Hospital Son Dureta, C/ Andrea Doria, 55, 07014 Palma de Mallorca, Spain. (Received 25 September 1989; revised 22 February 1990; accepted 22 February 1990) 0264-410x/90/040402-04 © 1990 Butterworth-Heinemann Ltd
402 Vaccine, Vol. 8, August 1990
Following primary vaccination (Table I), i.m. administration (3 x 20 #g) induced significantly higher percentages of seroconversion ( > I O I U 1 - 1 ) as compared with i.d. regime (3 x 2 #g), both in the whole group of participants (97.2% versus 78.1%, p < 0.05) and in men (100% versus 64.3% , p<0.001).
Routes for vaccination against hepatitis B: M.L. Gonz~lez et al. Table
1
Seroconvemion levels and anti-HBs titres prior to and following primary and booster vaccination e i t h e r b y intramuscular or intradermal route Seroconversion No. of
Group
Prevaccination (%)
Vaccination route
volunteers
Primary vaccination i.m.
36
0
32 =
0
Anti-HBs
Postvaccination (%)
titres
Prevaccination
Postvaccination
-
1649
All volunteers
i.d.
Booster i.m. i.d.
24 27
66.7 59.2
_
97.2
p < 0.05
78.1
NS
-
100 92.6
NS
100
p<0.001
p < 0.001
126
-
22.1 21.2
NS
-
_
572.3
NS
158.2
Men Primary vaccination i.m.
18
0
i.d.
14
0
Booster i.m. i.d.
14 15
64.3 53.3
i.m. i.d.
18 18
0 0
Booster i.m. i.d.
10 12
70 66.7
_
64.3
NS
1667 37
-
100 86.7
NS
15.1 17.6
NS
94.4
NS
-
_
628.0 209.6
p<0.001
NS
Women Primary vaccination _
88.8
100 100
NS
37.6 30.7
NS
1638
p<0.0~,,
324 NS
502.6 166.2
NS
NS, not significant =One man vaccinated by i.d. route dropped out after the second dose (moved to another region)
Table
2
Anti-HBs titre following intramuscular or intradermal booster in the whole group and according to the primary vaccination route Titres (GM)
Group
Vaccination route
All' Women = Men' I II III IV
Primary Booster Primary Booster Primary Booster Primary Booster
vaccination vaccination vaccination
i.d. i.d. i.m. i.d. i.m. i.m.
vaccination
i.d. i.m.
No. in group
Prevaccination
Postvaccination
51 22 29
21.7 32.7 16.0
318.8 274.8 356.9
7
17.1
23.9
20
25.0
391.0
15
20.3
707.4
9
21.4
402.1
Statistical significance: women/men, not significant; group I/group II, p<0.01, group I/group III, p<0.001; group I/group iV, p<0.05 =The pre- and postvaccination anti-I-IBs titres are calculated irrespective of the vaccination route
Antibody titres were significantly higher following vaccination with 3x20/zg i.m.; the respective G M reached 1649 and 126IU1-1 in the whole group (p<0.001), 1667 and 37IU1-1 among men (p<0.001) and 1638 versus 324IU1-1 in women (p<0.05). At the end of the vaccination by i.d. or i.m. route, the only significant difference detected between men and women was observed in the i.d. regime, which induced higher titres (p<0.01) in women than in men (GM of 324 versus 37 IU 1-1, respectively). A booster dose given to poor (<160IU1 -I) and non-responders ( < 1 0 I U I -~) induced no statistical differences between i.d. and i.m. administration in seroconversion or anti-HBs levels, considering either the whole group (n=51), men (n=29) or women (n=22), and irrespective of the route selected for the primary vaccination. The four subgroups, constituted according to the regimen selected for the primary and for the booster
vaccination (Table 2), showed very similar pre-booster titres (17.1-25.0 IU 1= 1). No increase in antibody levels was obtained (23.9 IU1-1) in those who received i.d. administration of vaccine at both stages. In the other subgroups, the postbooster titres rose to 391.0IU1-1 (i.m. primary vaccination, i.d. booster), 402.1 IU 1-i (i.d. primary vaccination, i.r/a, booster) and 707.4 IU 1- ~ (i.m. primary vaccination, i.m. booster). No statistical difference in the postvaccination titres was observed between these three subgroups, which all showed significantly higher antibody titres than the first group (i.d. on both occasions). In relation to the primary vaccination, adverse reactions of a local nature were statistically more frequent (p<0.001) among i.d. vaccinees (84.4% versus 36.1%) and those of general nature among i.m. vaccinees (41.7% versus 6.1%). With the booster dose, either after i.d. or i.m. adminstration, no general reaction was recorded;
V a c c i n e , Vol. 8, A u g u s t 1990
403
Routes for vaccination against hepatitis B: M,L. Gonz~lez et al.
however, local adverse reactions were statistically more frequent (p<0.001) with the i.d. (96.3%) than with the i.m. regime (8.3%). The most frequent general adverse reactions observed consisted of headache and asthenia. Locally, at the injection site, pain was the most common feature associated with the i.m. regime, whereas i.d. injections were followed by frequent indurations, sometimes accompanied by swelling. With respect to the i.d. route, no antibody response was recorded in patients with no local adverse experience, whereas 92.5% of those with a local reaction responded to the vaccine (GM: 228 IUI-~). Seroconversion levels and anti-HBs titres (GM) were significantly higher among patients who presented a local reaction on two occasions (100% and 482IU1-1) rather than on one occasion (71.4% and 27IU1-1, respectively). Anti-HBs titres (GM) of 191 or 1442 IU1-1 (p < 0.05), respectively, were recorded in vaccinees, depending on whether the induration or swelling was lower or higher than 150 mm. Serum transaminase levels persisted within the normal range ( < 50 IU 1- 1) in each vaccinee throughout the trial, whereas HBsAg and anti-HBc markers remained negative.
Discussion The outputs of immunizations carried out with small amounts of antigen delivered by the intramuscular 7's or intradermal 1-4'9-14 route are still under study. Four controlled studies 1-4 with a three dose regime have been published, in which 2 #g, i.d., doses of vaccine have been compared with 20/~g, i.m., doses. All these studies have been performed on a small number of subjects (9 to 25 in each set) by experienced personnel and in ideal conditions (young healthy adults with no antecedents of serious disease and normal serum transaminase levels). One month after the third dose, the seroconversion levels were similar between i.d. and i.m. vaccinees, whereas anti-HBs titres were lower after i.d. administration, although no statistical difference was established between the routes selected. Following revaccination, the data recorded by Horowitz 15 show almost identical levels of seroconversion and antibody titres after i.m. and i.d. administration. On the other hand, the persistence of anti-HBs protective levels, which is associated with the length of the antibody response recorded at the end of the primary vaccination 1°'16'17 was quite similar in the studies of Jilg 16 and Irving ~1 comparing i.m. and i.d. administration. This study performed on carefully matched groups shows that primary vaccination with 3 x 2 # g , i.d., induced seroconversion in a significantly lower percentage of recipients and that the titres recorded in responders are also statistically lower (sixfold), as compared with the i.m. regime (3 x 20#g,, i.m.). It was for this reason that we attempted to reinforce the immunity of the poor and non-responders using a fourth dose (booster) administered in a controlled and randomized manner by i.m. or i.d. route. Our data on the i.d. performance indicates that to continue boosting by i.d. administration did not increment anti-HBs titres, whereas the switch to the i.m. route increased the antibody levels by approximately 20-fold. It should be stressed that the switch to i.d. administration, after a poor response to a primary vaccination performed by the i.m. route, similarly gave rise to a 15-fold increase in the anti-HBs titres. However,
404
Vaccine, Vol. 8, A u g u s t 1990
the best response (35-fold increment) was obtained with the standard regime in which i.m. route is used for both the primary immunization and revaccination. The local and general adverse reactions were neither serious nor severe and resolved spontaneously without any special therapy. Several features indicate that the intervention of an immunological mechanism in the production of local adverse reactions following vaccination by the i.d. route: local induration, which was not seen following the first contact with HBsAg, persisted for progressively increasing periods following the second, third and booster dose. In addition, a significant relationship was demonstrated between the occurrence, size and recurrence of reactions at the injection site and the immune response (seroconversion levels and antiHBs titres), as previously pointed out by Zoulek 2 and Horowitz15. Although the size of the population included in the distinct subgroups of this trial is small, the data permit the conclusion that in spite of the economic advantages which would derive from the use of small vaccine doses, the intradermal route is not recommendable in healthy adults for the primary immunization against hepatitis B. According to our data, the only practical interest to be expected from i.d. administration would be an appreciable rise in anti-HBs titres when boosting the subjects who do not respond satisfactorily to the primary vaccination by i.m. route. The intramuscular route remains, therefore, the regimen of choice, for both the primary immunization and revaccination against hepatitis B.
Acknowledgement The authors are grateful for the technical assistance of A. Garau, P. Ferrer and C. Serra.
References 1
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