Persistence of antibody to hepatitis B surface antigen after low-dose, intradermal hepatitis B immunization and response to a booster dose J o e P. B r y a n *t, M a r i a H. S j o g r e n t, P h i l i p M a c a r t h y t, E l i z a b e t h C o x * , L l e w e l l y n J. L e g t e r s * a n d P e t e r L. P e r i n e *
To determine the duration of antibody after low-dose, intradermal (i.d.), plasma-derived hepatitis B vaccination and the response to a booster dose, we studied two classes of medical students who were immunized with 2 I~g doses i.d. In one class, 73/88 (85%) who had been immunized by skilled personnel at O, i and 6 months, had protective concentrations (>~ 10 m l U m1-1 ) of anti-HBs at 20 months after the first dose. Twelve (92%) out of 13 students who received only two doses at 0 and 1 months also had protective concentrations at month 20, At month 27, 11/16 (69%) with antibody 10 m l U ml-1 and 48% had concentrations /> 100 m l U m1-1 (Table 1). Of the 13 students with concentrations < 10 m l U m l - 1, anti-HBs concentrations were < 1.0 m l U m l - 1 in five and 1.0-9.9 m l U m1-1 in eight. Nine students (10%) had concentrations > 1000 m l U m l - 1. The geometric mean concentration of antibody was 74 m l U m l - 1. Thirteen students received only two doses of vaccine (administered by trained nurses). Twelve of the 13 had concentrations /> 10 m l U m l - 1 20 months after dose 1 (Table I ). In contrast, among the nine students who administered the first two vaccine doses to each other, with a third dose administered by a skilled nurse, only three (33%) had anti-HBs concentrations /> 10 m l U m l - 1 at 20 months. The response to an i.d. booster dose of 2 #g was studied in 16 students who, after three doses of vaccine, had low anti-HBs antibody concentrations ( < 10 m l U m l - 1) at month 27 after dose 1. Eleven out of 16 (69%) developed protective concentrations of antibody including seven of the 11 immunized by skilled workers and four out of five students initially immunized by other students (Figure I ). The geometric mean concentration of anti-HBs after the booster dose was 33 (95% confidence intervals 1 0 . 6 - 1 0 6 m l U m l - 1 ) . All five whose response to the booster dose was < 10 mlU ml- 1 had concentrations of antibody ~ 10 m l U ml- 1 had concentrations ~>0.2 m l U m l - 1 before the booster dose. Class of 1988 The anti-HBs response in students who received three doses of vaccine is shown in Figure 2 and Table 2. At month 14 (8 months after receiving the third dose of vaccine), 90 out of 93 (97%) of the students had anti-HBs concentrations >/10 mlU ml- 1, with a geometric mean concentration of 193 m l U ml- 1. At month 25 ( 19 months after the third dose), 71/80 (89%) still had protective concentrations of antibody, with a geometric mean of 78 m l U ml- 1. Concentrations /> 100 m l U ml- 1 were present in 62% at 14 months and in 40% at 25 months. After the booster dose, 57/60 (95%) had protective Table 1 Anti-HBs levels 20 months after dose 1 in class of 1989 students who had received either two or three doses of 2/~g i.d. 'Student administered' indicates first two doses were administered by other students
Statistical methods Geometric mean and 95% confidence intervals of concentrations of anti-HBs were computed by transforming the values to log (x + 1 ), thereby allowing the inclusion of values less than 1 in the computation. Values < 0.1 m l U m l - 1 were assigned the value 0. The value 1.0 was then subtracted from the anti-log of the mean and 95% confidence intervals. Mean values of anti-HBs were compared by unpaired t test of log-transformed values.
Three doses Two doses
Nurse administered No. %
Student administered No. %
0 8 77 0 15 0 0
5 8 18 15 28 5 9
6 9 20 17 32 6 10
2 4 1 0 1 1 0
22 45 11 0 11 11 0
100
88
100
9
100
Anti-HBs (mlU m1-1)
No.
1000
0 1 10 0 2 0 0
RESULTS
Total
13
Class of 1989
Geometric mean 20 (8; 48) (95% confidence intervals) anti-HBs (mlU ml -~)
At 20 months after initial hepatitis B vaccine administration, 75 (85%) out of 88 students who were immunized
34
Vaccine, Vol. 10, Issue 1, 1992
%
74 (48; 116)
8 (1.2; 52.7)
Anti-HBs after intradermal HBV immunization: J.P. Bryan et al.
antibody concentrations, with a geometric mean concentration of 1198 mlU ml-1. Six of the nine students with pre-booster concentrations 10 mlU ml- t. The three students who did not respond with concentrations >/10 mlU ml- 1 all had pre-booster concentrations ~100 mIU ml- ~. We did not measure peak concentrations of antibody after immunization as we have in other studies 3. However, since it is clear that anti-HBs concentrations fall by ~ 9 0 % in the first year ~5, we expect that peak concentrations of anti-HBs antibody in these groups were similar to others we have measured. Our data indicate that anti-HBs antibody remains well above presumed protective concentrations for at least 2 years after immunization. Another study reported follow-up of medical students immunized with three 2 #g doses of plasma-derived vaccine i.d. 30 months after the first dose. Concentrations of anti-HBs remained > 10 mIU m l - t in 27/34 (79%)16. 10000 -
1000
n=60
1oo 1000
n=16
T
3" "E
n=93 u....,...
10
-
I00
p=0.0001
/
p = 0. 002~f/ n =31 10
0.1
_
i
I
Month 27
I
,
,
,
10
,
I
,
15
Month 30
,
,
~
I
t
,
n=,16 I ,
20
,
,
,
25
,
I
30
Months
Time Figure 1 Response to a fourth 2/~g intradermal dose at month 27 after the initial dose in 16 subjects in the class of 1989 with anti-HBs concentrations ~~ 10 m l U m1-1, similar to a group that had received three doses of 20/~g intramuscularly (i.m.) 17. Our experience is consistent with these findings. The duration of anti-HBs antibody after i.m. immunization with three doses of 20/~g of plasma-derived vaccine at 0, 1, and 6 months has been reported in different populations 1s-2°. At 30 months after initiation of vaccination, 69% of a cohort of homosexual men who had seroconverted had concentrations /> 10 m l U m l - 1 of antibody is. However, some of these men were (or became) infected with HIV-1 during the study, an infection known to impair response to hepatitis B vaccine and accelerate loss of existing antibody 21. A study in health care workers found 62% had concentrations of anti-HBs /> 1 0 m l U ml-1 36 months after immunization 19. A study in Eskimo Indians found that concentrations ~>10 m l U ml-1 were maintained at 5 years in 8 4 o of those 0 - 1 9 years of age, 73% of those 20-49 years of age and 63% in those/> 50 years of age 2°. Overall, the duration of antibody in patients immunized i.d. with low doses appears similar to those who receive full-dose intramuscular vaccination. This study demonstrates the need for good i.d. injection technique. Only one-third of the subjects who received their first two injections by untrained students developed protective levels. Others have demonstrated the poor result of subcutaneous injection of vaccine 22. However, skill in the intradermal injection technique, such as is used to apply a Mantoux test for tuberculosis, is easily acquired. Low-dose i.d. hepatitis B vaccination may be useful in producing an antibody response in those in whom concentrations of anti-HBs have fallen below 10 m l U m1-1. In our study, 19 (76%) of 25 students with concentrations ~ 10 m l U ml- 1, including all subjects with concentrations of antibody >/0.2 m l U ml-1 before booster immunization. Similar results were reported in another study of hospital workers previously immunized with three 20/~g doses of plasma-derived vaccine whose concentrations of anti-HBs were below
36
V a c c i n e , Vol. 10, I s s u e 1, 1992
No.
%
18 (8.1; 40)
No.
%
1054 (334; 3162)
10 m l U ml-1. After subjects were given a booster dose of plasma-derived vaccine of either 2 #g i.d. or 20/~g i.m., the proportions of subjects who responded with concentrations /> 10 mlU m l - 1 were similar in each group; 76 versus 78%o, respectively 19. However, 2 years after the booster, the proportion of those who had levels /> 10 m l U ml-1 was lower in the group which received the 2/~g i.d. booster dose compared with subjects given the 20/~g dose i.m. (64 versus 89°,/0 ; p = 0.055, respectively) 23. Another study reported the results o f a 5/~g i.d. booster dose in children with thalassaemia and health care workers after three i.m. doses of 20 #g of plasmaderived vaccine. All children and health care workers with pre-booster concentrations of 1 - 1 0 m l U m 1 - 1 responded to a single i.d. dose, while multiple doses were required to produce protective concentrations in those with undetectable anti-HBs before booster 24. Production of anti-HBs has been obtained in vaccine non-responders using 5/~g i.d. doses of a plasma-derived vaccine produced in Japan 25'26. The present study also demonstrates that a booster dose of only 2 pg i.d. given to young healthy adults results in a sharp increase in antibody to HBsAg; 67% responded with concentrations of anti-HBs i> 1000 m l U ml-1, and the geometric mean concentration increased from < 100 to > 1100 m l U ml- 1. Children who were immunized as neonates have also responded well to a booster dose of 5 #g i.d. at 2-3 years of age 27. Therefore, an i.d. booster dose at approximately 24 months after initial immunization results in protective concentrations of antibody in most subjects with low but detectable concentrations of anti-HBs and sharply increases concentrations in those with anti-HBs above 10 m l U ml- 1 Even though the plasma-derived vaccine used in this trial is no longer generally available in the United States, at least 12 plasma-derived vaccines are being manufactured around the world, including vaccines produced by the Green Cross in Korea, as well as in Thailand, Japan and China 2s. The results of low-dose, i.d. hepatitis B vaccine trials with some of these vaccines indicate that they perform in a fashion similar to the MSD plasmaderived
vaccine 29-31 .
The role of recombinant vaccines in low-dose, i.d. hepatitis B immunization remains to be determined. Initial studies of low-dose, i.d. immunization with
Anti-HBs after intradermal HBV immunization: J.P. Bryan et al.
recombinant vaccines produced by Merck Sharp and Dohme 3'32'33 and SmithKline Biologicals 1° are less encouraging than with plasma-derived vaccines. However, recombinant vaccines may be useful as a low-dose booster. Ten out of 14 children with schistosomiasis responded to a 2 #g i.d. dose of recombinant vaccine ( M S D ) 4 - 5 years after initial immunization with full-dose, plasma-derived vaccine 34. CONCLUSIONS Vaccination with low-dose i.d., plasma-derived hepatitis B vaccine results in protective concentrations of anti-HBs which are maintained for at least 2 years in the majority of young adults immunized with three doses. A fourth dose results in an anamnestic response which should afford protection for these health care workers for many years. Response to hepatitis B vaccination is diminished in those >/40 years old, those who smoke, are obese or have immunodeficiencies 5,19.35,36 ; such individuals may not be good candidates for low-dose i.d. immunization. Neonates 37 and children 15 respond well to low-dose i.d. plasma-derived vaccine. The role of i.d. administration of recombinant hepatitis B vaccines remains to be determined. It is likely that recombinant vaccines with the Pre-S determinants will be more immunogenic than present recombinant vaccines 38. ACKNOWLEDGEMENTS This study was supported in part by a grant from the Uniformed Services University of the Health Sciences, Number RO-87-BJ. The opinions or assertions contained herein are the private ones of the authors and are not to be construed as official or necessarily reflecting the views of the Department of Defense or the Uniformed Services University of the Health Sciences. © 1992 US Government REFERENCES 1
2
3
4
5
6
7
8
9
Centers for Disease Control. Protection against viral hepatitis: Recommendations of the Immunization Practices Advisory Committee (ACIP). Morbid. Mortal Week. Rep. 1990, 39(RR-2), 8 Centers for Disease Control. Guidelines for prevention of transmission of human immunodeficiency virus and hepatitis B virus to health-care and public-safety workers. Morbid. Mortal. Week. Rep. 1989, 38(S-6), 5 Bryan, J., Sjogren, M., Iqbal, M., Khattak, A., Nabi, S., Ahmed, A. et al. Comparative trial of low-dose, intradermal, recombinantand plasma-derived hepatitis B vaccination. J. Infect. Dis. 1990, 162, 789-793 Clarke, J., Hollinger, F., Lewis, E., Russell, L., Miller, C., Huntley, A. and Flynn, N. Intradermal inoculation with Heptavax-B: Immune response and histologic evaluation of injection sites. J. Am. Med. Assoc. 1989, 262, 2567 2571 Coleman, P., Re, S., Hadler, S., Margois, H. and Serovich, J. Intradermal hepatitis B vaccination in a large hospital employee population. Vaccine 1991 9, 723-727 Frazer, I., Bronwyn, J., Dimitrakikis, M. and Mackay, I. Intramuscular versus low-dose intradermal hepatitis B surface antigen. Med. J. Aust. 1987, 146, 242-245 Heijtink, R., Breukers, A., den Hartigh, G., Schepman, R., Schmitz, P., Schalm, S. and Masurel, N. Low dose intradermal vaccination against hepatitis B in mentally retarded patients. Vaccine 1988, 6, 59-61 Heijtink, R., Knol, R. and Schalm, S. Comparable immunogenicity for intramuscular and intradermal routes. J. Med. Virol. 1989, 27, 151-154 Irving, W., Alder, M., Kurtz, J. and JueI-Jensen, B. Intradermal vaccination against hepatitis B. Lancet 1986, i, 1340
10 Kurtz, J., Alder, M., Mayon-White, R., JueI-Jensen, B., Rodgers, T. and Babic, G. Plasma-derived versus recombinant hepatitis B vaccines. Lancet 1989, I, 451 11 Redfield, R., Innis, B., Scott, R., Cannon, H. and Bancroft, W. Clinical evaluation of low-dose intradermally administered hepatitis B virus vaccine: A cost-reduction strategy. J. Am. Med. Assoc. 1985, 254, 3203-3206 12 Wilkins, T. and Cossart, Y. Low-dose intradermal vaccination of medical and dental students. Med. J. Aust. 1990, 152, 140-143 13 Herbert, M., Butler, A., Roome, A. and Caul, E. Comparison of intradermal and intramuscular hepatitis B vaccination in university students. Vaccine 1989, 7, 395-396 14 Hollinger, F. and Dienstag, J. Hepatitis viruses. In: Manual of C/inical Microbiology (Eds Lennette, E., Balows, A., Hausler, W. and Shadomy, H.) American Society for Microbiology, Washington, DC, 1985, pp. 813-835 15 Whittle, H., Inskip, H., Hall, A,, Mendy, M., Dowries, R. and Hoare, S. Vaccination against hepatitis B and protection against chronic viral carriage in The Gambia. Lancet 1991, 337, 747-750 16 Irving, W., Parsons, A., Kurtz, J. and JueI-Jensen, B. Intradermal hepatitis B vaccine. Lancet 1987, ii, 561 17 King, J., Taylor, E., Crow, S., White, M., Todd, J., Poe, M. et al. Comparison of the immunogenicity of hepatitis B vaccine administered intradermally and intramuscularly Rev. Infect. Dis. 1990, 12, 1035-1043 18 Hadler, H., Francis, D., Maynard, J., Thompson, S., Judson, F., Echenberg, D. et al. Long-term immunogenicity and efficacy of hepatitis B vaccine in homosexual men. N. Eng/. J. Mad. 1986, 315, 209-214 19 Horowitz, M., Ershler, W., McKinney, W. and Battiola, R. Duration of immunity after hepatitis B vaccination: Efficacy of low-dose booster vaccine. Ann. Intern. Med. 1988, 108, 185-189 20 Wainwright, R., McMahon, B., Bulkow, L., Hall, D., Fitzgerald, M., Harpster, A. et al. Duration of immunogenicity and efficacy of hepatitis B vaccine in a Yupik Eskimo population. J. Am. Med. Assoc. 1989, 261, 2362-2366 21 Hadler, S., Judson, F., O'Malley, P., Altrnan, N., Penley, K., Buchbinder, S. et al. Outcome of hepatitis B virus infection in homosexual men and its relation to prior human immunodeficiency virus infection. J. Infect. Dis. 1991, 163, 454-459 22 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, 617-621 23 McKinney, W., Russler, S., Horowitz, M., Battiola, R. and Lee, M. Duration of response to intramuscular versus low dose intradermal hepatitis B booster immunization. Infect. Control Hosp. Epidemiol. 1991, 12, 226-230 24 Leonardi, S., Leggio, T., Sciacca, A. Di Gregorio, F. and Musumeci, S. Intradermal hepatitis B vaccination in thalassemia. Arch. Dis. Childhood 1990, 65, 527-529 25 Nagafuchi, S. and Kashiwagi, S. Reversal by intradermal hepatitis B vaccination of unresponsiveness to HBsAg. Lancet 1987, ii, 1522- 1523 26 Nagafuchi, S., Seizaburo, K., Okada, K., Anzai, K., Nakamura, M., Nishimura, Y. et al. Reversal of nonresponders and postexposure prophylaxis by intradermal hepatitis B vaccination in Japanese medical personnel. J. Am. Med. Assoc. 1991, 265, 2679-2683 27 Leonardi, S., Leggio, T., Fischer, A., Sciacca, A. and Musumeci, S. Intradermal hepatitis B vaccination: Efficacy and timing in infants at risk. Pediatr. Infect. Dis. J. 1989, 8, 337 28 Maynard, J. Hepatitis B: global importance and need for control. Vaccine 1990, 8 (suppl.), $18-20 29 Chung, L. Observation of immunogenic effects of intradermal inoculation of small doses of hepatitis B vaccine. Chung Hun Liu Hsing Ping Hsueh Tsa Chih 1989, 10, 109-112 30 Fadda, G., Maida, A., Masia, C., Obino, G., Romano, G. and Spano, E. Efficacy of hepatitis B immunization with reduced intradermal doses. Eur. J. Epidemio/. 1987, 3, 176-180 31 Hayashi, J., Kashiwagi, S., Noguchi, A., Nakashima, K., Ikematsu, H. and Kajiyama, W. Intradermal hepatitis B vaccination for mentally retarded patients. J. Infect. 1989, 19, 119-125 32 Lancaster, D., Elam, S. and Kaiser, A. Immunogenicity of the intradermal route of hepatitis B vaccination with the use of recombinant hepatitis B vaccine. Am. J. Infect. Control 1989, 17, 126-128 33 Wistrom, J., Settergren, B., Gustafsson, A., Juto, P. and Norby, R. Intradermal vs intramuscular hepatitis B vaccinations. J. Am. Med. Assoc. 1990, 264, 181-182 34 Bassily, S., Hyams, K., EI-Ghorab, N. and EI-Masry, N. Hepatitis B vaccination in patients infected with Schistosoma mansoni: duration
Vaccine, Vol. 10, Issue 1, 1992
37
Anti-HBs after i n t r a d e r m a l H B V i m m u n i z a t i o n : J.P. B r y a n et al.
of immunity and immunogenicity of a low dose intradermal booster. Trans. R. Soc. Trop. Med. Hyg. 1990, 84, 401-402 35 Hadler, S. Hepatitis B prevention and Human Immunodeficiency Virus (HIV) infection. Ann. Int. Med. 1988, 109, 92-94 36 Weber, D., Rutala, W., Samsa, G., SanUmaw, J. and'SM, L. Obesity as a predictor of poor antibody response to hepatitis B plasma vaccine. J. Am. Med. Assoc. 1985, 254, 3187-3189 37 Coberly, J., Halsey, N., Townsend, T., Repke, J., Fields, H., Margolis,
38
Vaccine, Vol. 10, Issue 1, 1992
H. and Maskell, G. Low-cost, low.dose hepatitis B vaccination. 29th Interscience Conference on Antimicrobial Agents and Chemotherapy, Houston, TX, American Society for Microbiology, 1989, abstract no. 192,American Society for Microbiology, Washington, DC 38 Milch, D., Thornton, G., Neurath, A. et al. Enhanced immunogenicity of the pre-S region of the hepatitis B surface antigen. Science 1985, 228, 1195-1199
To determine the duration of antibody after low-dose, intradermal (i.d.), plasma-derived hepatitis B vaccination and the response to a booster dose, we studied two classes of medical students who were immunized with 2 I~g doses i.d. In one class, 73/88 (85%) who had been immunized by skilled personnel at O, i and 6 months, had protective concentrations (>~ 10 m l U m1-1 ) of anti-HBs at 20 months after the first dose. Twelve (92%) out of 13 students who received only two doses at 0 and 1 months also had protective concentrations at month 20, At month 27, 11/16 (69%) with antibody 10 m l U ml-1 and 48% had concentrations /> 100 m l U m1-1 (Table 1). Of the 13 students with concentrations < 10 m l U m l - 1, anti-HBs concentrations were < 1.0 m l U m l - 1 in five and 1.0-9.9 m l U m1-1 in eight. Nine students (10%) had concentrations > 1000 m l U m l - 1. The geometric mean concentration of antibody was 74 m l U m l - 1. Thirteen students received only two doses of vaccine (administered by trained nurses). Twelve of the 13 had concentrations /> 10 m l U m l - 1 20 months after dose 1 (Table I ). In contrast, among the nine students who administered the first two vaccine doses to each other, with a third dose administered by a skilled nurse, only three (33%) had anti-HBs concentrations /> 10 m l U m l - 1 at 20 months. The response to an i.d. booster dose of 2 #g was studied in 16 students who, after three doses of vaccine, had low anti-HBs antibody concentrations ( < 10 m l U m l - 1) at month 27 after dose 1. Eleven out of 16 (69%) developed protective concentrations of antibody including seven of the 11 immunized by skilled workers and four out of five students initially immunized by other students (Figure I ). The geometric mean concentration of anti-HBs after the booster dose was 33 (95% confidence intervals 1 0 . 6 - 1 0 6 m l U m l - 1 ) . All five whose response to the booster dose was < 10 mlU ml- 1 had concentrations of antibody ~ 10 m l U ml- 1 had concentrations ~>0.2 m l U m l - 1 before the booster dose. Class of 1988 The anti-HBs response in students who received three doses of vaccine is shown in Figure 2 and Table 2. At month 14 (8 months after receiving the third dose of vaccine), 90 out of 93 (97%) of the students had anti-HBs concentrations >/10 mlU ml- 1, with a geometric mean concentration of 193 m l U ml- 1. At month 25 ( 19 months after the third dose), 71/80 (89%) still had protective concentrations of antibody, with a geometric mean of 78 m l U ml- 1. Concentrations /> 100 m l U ml- 1 were present in 62% at 14 months and in 40% at 25 months. After the booster dose, 57/60 (95%) had protective Table 1 Anti-HBs levels 20 months after dose 1 in class of 1989 students who had received either two or three doses of 2/~g i.d. 'Student administered' indicates first two doses were administered by other students
Statistical methods Geometric mean and 95% confidence intervals of concentrations of anti-HBs were computed by transforming the values to log (x + 1 ), thereby allowing the inclusion of values less than 1 in the computation. Values < 0.1 m l U m l - 1 were assigned the value 0. The value 1.0 was then subtracted from the anti-log of the mean and 95% confidence intervals. Mean values of anti-HBs were compared by unpaired t test of log-transformed values.
Three doses Two doses
Nurse administered No. %
Student administered No. %
0 8 77 0 15 0 0
5 8 18 15 28 5 9
6 9 20 17 32 6 10
2 4 1 0 1 1 0
22 45 11 0 11 11 0
100
88
100
9
100
Anti-HBs (mlU m1-1)
No.
1000
0 1 10 0 2 0 0
RESULTS
Total
13
Class of 1989
Geometric mean 20 (8; 48) (95% confidence intervals) anti-HBs (mlU ml -~)
At 20 months after initial hepatitis B vaccine administration, 75 (85%) out of 88 students who were immunized
34
Vaccine, Vol. 10, Issue 1, 1992
%
74 (48; 116)
8 (1.2; 52.7)
Anti-HBs after intradermal HBV immunization: J.P. Bryan et al.
antibody concentrations, with a geometric mean concentration of 1198 mlU ml-1. Six of the nine students with pre-booster concentrations 10 mlU ml- t. The three students who did not respond with concentrations >/10 mlU ml- 1 all had pre-booster concentrations ~100 mIU ml- ~. We did not measure peak concentrations of antibody after immunization as we have in other studies 3. However, since it is clear that anti-HBs concentrations fall by ~ 9 0 % in the first year ~5, we expect that peak concentrations of anti-HBs antibody in these groups were similar to others we have measured. Our data indicate that anti-HBs antibody remains well above presumed protective concentrations for at least 2 years after immunization. Another study reported follow-up of medical students immunized with three 2 #g doses of plasma-derived vaccine i.d. 30 months after the first dose. Concentrations of anti-HBs remained > 10 mIU m l - t in 27/34 (79%)16. 10000 -
1000
n=60
1oo 1000
n=16
T
3" "E
n=93 u....,...
10
-
I00
p=0.0001
/
p = 0. 002~f/ n =31 10
0.1
_
i
I
Month 27
I
,
,
,
10
,
I
,
15
Month 30
,
,
~
I
t
,
n=,16 I ,
20
,
,
,
25
,
I
30
Months
Time Figure 1 Response to a fourth 2/~g intradermal dose at month 27 after the initial dose in 16 subjects in the class of 1989 with anti-HBs concentrations ~~ 10 m l U m1-1, similar to a group that had received three doses of 20/~g intramuscularly (i.m.) 17. Our experience is consistent with these findings. The duration of anti-HBs antibody after i.m. immunization with three doses of 20/~g of plasma-derived vaccine at 0, 1, and 6 months has been reported in different populations 1s-2°. At 30 months after initiation of vaccination, 69% of a cohort of homosexual men who had seroconverted had concentrations /> 10 m l U m l - 1 of antibody is. However, some of these men were (or became) infected with HIV-1 during the study, an infection known to impair response to hepatitis B vaccine and accelerate loss of existing antibody 21. A study in health care workers found 62% had concentrations of anti-HBs /> 1 0 m l U ml-1 36 months after immunization 19. A study in Eskimo Indians found that concentrations ~>10 m l U ml-1 were maintained at 5 years in 8 4 o of those 0 - 1 9 years of age, 73% of those 20-49 years of age and 63% in those/> 50 years of age 2°. Overall, the duration of antibody in patients immunized i.d. with low doses appears similar to those who receive full-dose intramuscular vaccination. This study demonstrates the need for good i.d. injection technique. Only one-third of the subjects who received their first two injections by untrained students developed protective levels. Others have demonstrated the poor result of subcutaneous injection of vaccine 22. However, skill in the intradermal injection technique, such as is used to apply a Mantoux test for tuberculosis, is easily acquired. Low-dose i.d. hepatitis B vaccination may be useful in producing an antibody response in those in whom concentrations of anti-HBs have fallen below 10 m l U m1-1. In our study, 19 (76%) of 25 students with concentrations ~ 10 m l U ml- 1, including all subjects with concentrations of antibody >/0.2 m l U ml-1 before booster immunization. Similar results were reported in another study of hospital workers previously immunized with three 20/~g doses of plasma-derived vaccine whose concentrations of anti-HBs were below
36
V a c c i n e , Vol. 10, I s s u e 1, 1992
No.
%
18 (8.1; 40)
No.
%
1054 (334; 3162)
10 m l U ml-1. After subjects were given a booster dose of plasma-derived vaccine of either 2 #g i.d. or 20/~g i.m., the proportions of subjects who responded with concentrations /> 10 mlU m l - 1 were similar in each group; 76 versus 78%o, respectively 19. However, 2 years after the booster, the proportion of those who had levels /> 10 m l U ml-1 was lower in the group which received the 2/~g i.d. booster dose compared with subjects given the 20/~g dose i.m. (64 versus 89°,/0 ; p = 0.055, respectively) 23. Another study reported the results o f a 5/~g i.d. booster dose in children with thalassaemia and health care workers after three i.m. doses of 20 #g of plasmaderived vaccine. All children and health care workers with pre-booster concentrations of 1 - 1 0 m l U m 1 - 1 responded to a single i.d. dose, while multiple doses were required to produce protective concentrations in those with undetectable anti-HBs before booster 24. Production of anti-HBs has been obtained in vaccine non-responders using 5/~g i.d. doses of a plasma-derived vaccine produced in Japan 25'26. The present study also demonstrates that a booster dose of only 2 pg i.d. given to young healthy adults results in a sharp increase in antibody to HBsAg; 67% responded with concentrations of anti-HBs i> 1000 m l U ml-1, and the geometric mean concentration increased from < 100 to > 1100 m l U ml- 1. Children who were immunized as neonates have also responded well to a booster dose of 5 #g i.d. at 2-3 years of age 27. Therefore, an i.d. booster dose at approximately 24 months after initial immunization results in protective concentrations of antibody in most subjects with low but detectable concentrations of anti-HBs and sharply increases concentrations in those with anti-HBs above 10 m l U ml- 1 Even though the plasma-derived vaccine used in this trial is no longer generally available in the United States, at least 12 plasma-derived vaccines are being manufactured around the world, including vaccines produced by the Green Cross in Korea, as well as in Thailand, Japan and China 2s. The results of low-dose, i.d. hepatitis B vaccine trials with some of these vaccines indicate that they perform in a fashion similar to the MSD plasmaderived
vaccine 29-31 .
The role of recombinant vaccines in low-dose, i.d. hepatitis B immunization remains to be determined. Initial studies of low-dose, i.d. immunization with
Anti-HBs after intradermal HBV immunization: J.P. Bryan et al.
recombinant vaccines produced by Merck Sharp and Dohme 3'32'33 and SmithKline Biologicals 1° are less encouraging than with plasma-derived vaccines. However, recombinant vaccines may be useful as a low-dose booster. Ten out of 14 children with schistosomiasis responded to a 2 #g i.d. dose of recombinant vaccine ( M S D ) 4 - 5 years after initial immunization with full-dose, plasma-derived vaccine 34. CONCLUSIONS Vaccination with low-dose i.d., plasma-derived hepatitis B vaccine results in protective concentrations of anti-HBs which are maintained for at least 2 years in the majority of young adults immunized with three doses. A fourth dose results in an anamnestic response which should afford protection for these health care workers for many years. Response to hepatitis B vaccination is diminished in those >/40 years old, those who smoke, are obese or have immunodeficiencies 5,19.35,36 ; such individuals may not be good candidates for low-dose i.d. immunization. Neonates 37 and children 15 respond well to low-dose i.d. plasma-derived vaccine. The role of i.d. administration of recombinant hepatitis B vaccines remains to be determined. It is likely that recombinant vaccines with the Pre-S determinants will be more immunogenic than present recombinant vaccines 38. ACKNOWLEDGEMENTS This study was supported in part by a grant from the Uniformed Services University of the Health Sciences, Number RO-87-BJ. The opinions or assertions contained herein are the private ones of the authors and are not to be construed as official or necessarily reflecting the views of the Department of Defense or the Uniformed Services University of the Health Sciences. © 1992 US Government REFERENCES 1
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