Immunogenicity of a recombinant DNA hepatitis B vaccine in institutionalized patients with Down's syndrome P. Van Damrne *:, R. Vranckx t and A. Meheus § Residents of institutions for the mentally handicapped, especially Down's syndrome ( DS) patients, are at increased risk for exposure to hepatitis B virus ( HB V). Indeed, during a serological survey o f 770 mentally retarded residents in institutions in Antwerp in 1985, 32.6% of the 92 DS patients screened were HBsAg positive, compared with 7.2% of the 678 other mentally retarded (OMR) patients ( p < 0.001). Seronegative mentally handicapped individuals (275 in number including 18 DS patients) from three institutions were vaccinated with 20 Itg of a recombinant yeast-derived hepatitis B vaccine (YDV) according to a O, 1, 6 month schedule. Serum samples were tested at months 1, 2, 7, 12 and 24 for HBV markers by radioimmunoassay. One month after the third vaccine dose, 81.3 and 97.7% of DS and OMR patients had seroconverted, respectively, with GMTs of 516.3 and 1078.7 mlUml -z. Two years after the start of the vaccination course, 66.7 and 96°/~ of subjects in the two groups still had protective antibody levels ( >I10 mlU nd- l ) , although GMTs had decreased to 40.1 and 166.3 m l U m i - t in the two groups, respectively. Only o n e of the 18 DS patients had transient asymptomatic anti-HBc infection at month 2, no subject followed up being infected after the full vaccination course. Thus, the institutionally mentally handicapped, including DS patients are capable of responding adequately to YD V.
Keywords:HepatitisB; Down's syndrome;immunogenicity;mentally handicapped Introduction Hepatitis B virus (HBV) infection poses a significant health risk for mentally handicapped individuals living in residential institutions. Numerous surveys T M have documented the relatively higher risk of HBV transmission in this population which may be attributable to such factors as frequent close interpersonal contact, poor hygiene, special behavioural and medical characteristics 5, the higher prevalence of hepatitis B e antigen (HBeAg), and the greater number of chronic HBV carriers, especially among those with Down's syndrome (DS) 6. Between 3 and 53% of institutionalized mentally retarded persons are positive for hepatitis B surface antigen (HBsAg) and the number of individuals found positive for the antibody to HBsAg (anti-HBs) ranges from 26 to 77% 7'8. In 1985-1986, we carried out a serological survey of HBV markers in 770 residents at four long-stay mental handicap institutions in the Antwerp area (mean age 19.5 years). The overall frequency for HBsAg was 10.3%, for anti-HBs 39.6%, and for antibodies to hepatitis B core antigen (anti-HBc) 47.8% 9. It was noteworthy that DS patients (n = 92) had a significantly higher frequency of HBsAg compared with OMR patients (32.6 versus 7.2%, p 10 mlU ml-1. The booster data are not included in the analysis at month 24. Two years after the beginning of the vaccination course, GMTs in DS and OMR patients who did not receive a booster dose were 40.1 and 166.3 mlU ml-1, respectively. Two thirds of the DS patients still had protective antibody titres at this time. Of the eight patients who became positive for HBV markers during seven months after the first injection and who were not included in the final analysis 12, one was a Down's syndrome patient who was transiently anti-HBc positive at month 2. During the period from months 8 to 24, no further DS patients followed up developed HBsAg or anti-HBc. Of documented injections (symptom sheets returned) > 70% were symptom-free. No adverse reaction attributable to vaccination was observed in any subject t2.
Discussion While in-patients of residential institutions for the mentally handicapped are at high risk for exposure to HBV t-+, the extent of this risk may vary considerably. The prevalence of potential HBV infectivity may depend on institutionally related factors such as the number of DS patients, the population under 5 years of age at admission, overcrowding, patient behavioural characteristics and mobility, urban versus rural setting, as well as the extent of HBV endemicity and chronic carriage in the surrounding region. Institutionalized patients with DS are especially
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Results at month
Vaccine, Vol. 8, S u p p l e m e n t 1990
1
2
7
12
24a
All patients n Seroconversion (%) Seroprotection (%) GMT (mlUml -1)
231 39.0 10.8 6.4
193 82.4 51.8 234
233 96.6 92.3 1033.7
214 95.8 88.3 268.8
163 98.8 93.9 149.6
Down's syndrome n Seroconversion (%) Seroprotection (%) GMT (mlU m1-1)
14 28.6 21.4 14.7
12 75.0 50.0 19.6
16 81.3 75.0 516.3
12 75.0 75.0 255.5
12 100 66.7 40.1
Other mentally retarded n 217 Seroconversion (%) 39.6 Seroprotection (%) 10.1 GMT (mlU m1-1) 6.1
181 82.9 51.9 23.6
217 97.7 93.5 1078.7
202 97.0 89.1 269.5
151 98.7 96.0 166.3
Seroconversion is defined as anti-HBs titres > ~ l m l U m l l ; seroprotection ~>10mlUml-l+ Geometric mean titres are calculated on seropositive subjects a Does not include the data of those who received a booster
predisposed to develop chronic HBV infection as these long-stay patients are continuously exposed to multiple infections which compromize an already defective immune system 17. As such, they act as a reservoir of infectivity in these institutions. Indeed, one possible reason for the low prevalence of hepatitis B markers recently reported in a hospital for the mentally handicapped in northeast England 9 may have been the rather limited number of DS patients. In the four hospitals we surveyed in the Antwerp area, patients with DS showed a significantly higher frequency of HBsAg and HBeAg compared with OMR patients. The immunogenic response of a small group of DS patients to the YDV used in this study was similar to that reported in previous trials with either plasma- or yeast-derived vaccines 4"1~-2o. Furthermore, in our study., although the GMTs, attained in DS residents were somewhat lower than those attained in OMR patients, either of the twelve DS patients followed up and who had not received a booster still had protective anti-HBs levels (~>10mIUm1-1) two years after the start of vaccination. Only one DS pauent had transient HBV infection at month 2 (anti-HBc positive), no new cases being reported during the postvaccination period (months 8 to 24). Vaccination with 20/~g YDV has therefore also been shown to be safe and immunogenic in a relatively small subgroup of institutionalized DS patients. By vaccinating such individuals as early as possible - either after birth or at least prior to admission into specialized institutions - both their fellow patients and hospital staff members can be protected against HBV infection and its long-term sequelae.
References 1 Chaudhary, R.K., Perry, E. and Cleary, T.E. Prevalence of hepatitis B infection among residents of an institution for the mentally retarded. Am. J. EpidemioL 1977, 105, 123 2 McMillan, B.C., Hanson, R.P., Golubjatnikov, R. et al. Hepatitis B surface antigen and antibody: prevalence and persistence in
Hepatitis B vaccine in Down's s y n d r o m e patients: P. Van D a m m e et al.
3 4
5 6
7 8 9 10 11
12
institutionalized and non-institutionalized persons. Public Health Rep. 1979, 94, 262 Szmuness, W. and Prince, A.M. The epidemiology of serum hepatitis (SH) infections: a controlled study in two closed institutions. Am. J. Epidemiol. 1971, 94, 585 Perillo, R.P., Storch, G.A., Bodicky, C.J., Campbell, C.R. and Sanders, G.E. Survey of hepatitis B viral markers at a public school and a residential institution sharing mentally handicapped students. J. Infect. Dis. 1984, 148, 796 Cancio-Bello, T.P., De Medina, M., Shorey, J., Valleda, M.D. and Schiff, E.R. An institutional outbreak of hepatitis B related to a human biting carrier. J. Infect. Dis. 1982, 148, 652 Hawkes, R.A., Boughton, C.R., Schroeter, D.R., Decker, R.H. and Overby, L.R. Hepatitis B infection in institutionalized Down's syndrome inmates: a longitudinal study with five hepatitis B virus markers. Clin. Exp. Immunol. 1980, 40, 478 Reniers, J. and Meheus, A. Hepatitis B in instellingen voor mentaal gehandicapten. Tijdschr. Soc. Gezondheidszorg. 1985, 63, 748 Coutinho, R.A. Virale hepatitis. Tijdschr. Soc. Gezondheidszorg. 1984, 62, 228 Van Damme, P. and Meheus, A. Hepatitis B in mental handicap hospitals (Letter). Lancet 1989, I, 840 De Wilde, M., Cabezon, T., Harford, N., Rutgers, T., Simoen, E. and Van Wijnendaele, F. Production in yeast of hepatitis B surface antigen by R-DNA technology. Dev. Biol. Stand. 1985, 59, 99 Van Damme, P., Vranckx, R., Salary, A., Andr6, F. and Meheus, A. Immunogenicity and efficacy of recombinant DNA hepatitis B vaccine in institutionalized mentally retarded patients: preliminary results. In: Viral Hepatitis and Liver Disease (Ed. Zuckerman, A.J.) Alan R. Liss, Inc., New York, 1988, pp. 1065-1067 Van Damme, P., Vranckx, R., Salary, A., Andr6, F. and Meheus, A.
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17
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Protective efficacy of a recombinant DNA hepatitis B vaccine in institutionalized mentally handicapped clients. Am. J. Meal. 1989, 87 (3A), 265 Dudley, F.J., Fox, R.A. and Sherlock, S. Cellular immunity and hepatitis-associated, Australian antigen liver disease. Lancet 1972, I, 723 Riges, D.A., Elsasser, P. and Hecht, F. Impaired in vitro response of circulating lymphocytes to phytohemegglutinin in Down's syndrome: dose- and time-response curves and relation to cellular immunity. Intern. Arch. Allergy 1970, 39, 587 Siegel, M. Susceptibility of mongoloids to infection. Incidence of pneumonia, influenza A, and Shigella dysenteriae (Sonne). Am. J. Hyg. 1948, 48, 53 Hollinger, F.B., Adam, E., Heiberg, F. and Melnick, J.L. Response to hepatitis B vaccine in a young adult population. In: Viral Hepatitis (Eds Szmuness, W., Alter, H.J., Maynard, J.E.) The Franklin Institute Press, Philadelphia, 1982, pp.'451~166 Troisi, C.L., Heiberg, D.A. and Hollinger, F.B. Normal immune response to hepatitis B vaccine in patients with Down's syndrome: a basis for immunization guidelines. J. Am. Med. Assoc. 1985, 254, 3196 Hollinger, F.B., Goyal, R.K., Hersh, T., Powell, H.C., Schulman, R.J. and Melnick, J.L. Immune response to hepatitis virus type B in Down's syndrome and other mentally retarded patients. Am. J. Epidemiol. 1972, 95, 356 Wahl, M., Hermodsson, S. and Iwarson, S. Immune responses to hepatitis B vaccine in the mentally retarded. J. Infect. 1983, 7, (suppl. 1), 47 Heijtink, R.A., De Jong, P., Schalm, S.W. and Masurel, N. Hepatitis B vaccination in Dewn's syndrome and other mentally retarded patients. Hepatology 1984, 4, 611
Vaccine, Vol. 8, S u p p l e m e n t 1990
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Keywords:HepatitisB; Down's syndrome;immunogenicity;mentally handicapped Introduction Hepatitis B virus (HBV) infection poses a significant health risk for mentally handicapped individuals living in residential institutions. Numerous surveys T M have documented the relatively higher risk of HBV transmission in this population which may be attributable to such factors as frequent close interpersonal contact, poor hygiene, special behavioural and medical characteristics 5, the higher prevalence of hepatitis B e antigen (HBeAg), and the greater number of chronic HBV carriers, especially among those with Down's syndrome (DS) 6. Between 3 and 53% of institutionalized mentally retarded persons are positive for hepatitis B surface antigen (HBsAg) and the number of individuals found positive for the antibody to HBsAg (anti-HBs) ranges from 26 to 77% 7'8. In 1985-1986, we carried out a serological survey of HBV markers in 770 residents at four long-stay mental handicap institutions in the Antwerp area (mean age 19.5 years). The overall frequency for HBsAg was 10.3%, for anti-HBs 39.6%, and for antibodies to hepatitis B core antigen (anti-HBc) 47.8% 9. It was noteworthy that DS patients (n = 92) had a significantly higher frequency of HBsAg compared with OMR patients (32.6 versus 7.2%, p 10 mlU ml-1. The booster data are not included in the analysis at month 24. Two years after the beginning of the vaccination course, GMTs in DS and OMR patients who did not receive a booster dose were 40.1 and 166.3 mlU ml-1, respectively. Two thirds of the DS patients still had protective antibody titres at this time. Of the eight patients who became positive for HBV markers during seven months after the first injection and who were not included in the final analysis 12, one was a Down's syndrome patient who was transiently anti-HBc positive at month 2. During the period from months 8 to 24, no further DS patients followed up developed HBsAg or anti-HBc. Of documented injections (symptom sheets returned) > 70% were symptom-free. No adverse reaction attributable to vaccination was observed in any subject t2.
Discussion While in-patients of residential institutions for the mentally handicapped are at high risk for exposure to HBV t-+, the extent of this risk may vary considerably. The prevalence of potential HBV infectivity may depend on institutionally related factors such as the number of DS patients, the population under 5 years of age at admission, overcrowding, patient behavioural characteristics and mobility, urban versus rural setting, as well as the extent of HBV endemicity and chronic carriage in the surrounding region. Institutionalized patients with DS are especially
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Results at month
Vaccine, Vol. 8, S u p p l e m e n t 1990
1
2
7
12
24a
All patients n Seroconversion (%) Seroprotection (%) GMT (mlUml -1)
231 39.0 10.8 6.4
193 82.4 51.8 234
233 96.6 92.3 1033.7
214 95.8 88.3 268.8
163 98.8 93.9 149.6
Down's syndrome n Seroconversion (%) Seroprotection (%) GMT (mlU m1-1)
14 28.6 21.4 14.7
12 75.0 50.0 19.6
16 81.3 75.0 516.3
12 75.0 75.0 255.5
12 100 66.7 40.1
Other mentally retarded n 217 Seroconversion (%) 39.6 Seroprotection (%) 10.1 GMT (mlU m1-1) 6.1
181 82.9 51.9 23.6
217 97.7 93.5 1078.7
202 97.0 89.1 269.5
151 98.7 96.0 166.3
Seroconversion is defined as anti-HBs titres > ~ l m l U m l l ; seroprotection ~>10mlUml-l+ Geometric mean titres are calculated on seropositive subjects a Does not include the data of those who received a booster
predisposed to develop chronic HBV infection as these long-stay patients are continuously exposed to multiple infections which compromize an already defective immune system 17. As such, they act as a reservoir of infectivity in these institutions. Indeed, one possible reason for the low prevalence of hepatitis B markers recently reported in a hospital for the mentally handicapped in northeast England 9 may have been the rather limited number of DS patients. In the four hospitals we surveyed in the Antwerp area, patients with DS showed a significantly higher frequency of HBsAg and HBeAg compared with OMR patients. The immunogenic response of a small group of DS patients to the YDV used in this study was similar to that reported in previous trials with either plasma- or yeast-derived vaccines 4"1~-2o. Furthermore, in our study., although the GMTs, attained in DS residents were somewhat lower than those attained in OMR patients, either of the twelve DS patients followed up and who had not received a booster still had protective anti-HBs levels (~>10mIUm1-1) two years after the start of vaccination. Only one DS pauent had transient HBV infection at month 2 (anti-HBc positive), no new cases being reported during the postvaccination period (months 8 to 24). Vaccination with 20/~g YDV has therefore also been shown to be safe and immunogenic in a relatively small subgroup of institutionalized DS patients. By vaccinating such individuals as early as possible - either after birth or at least prior to admission into specialized institutions - both their fellow patients and hospital staff members can be protected against HBV infection and its long-term sequelae.
References 1 Chaudhary, R.K., Perry, E. and Cleary, T.E. Prevalence of hepatitis B infection among residents of an institution for the mentally retarded. Am. J. EpidemioL 1977, 105, 123 2 McMillan, B.C., Hanson, R.P., Golubjatnikov, R. et al. Hepatitis B surface antigen and antibody: prevalence and persistence in
Hepatitis B vaccine in Down's s y n d r o m e patients: P. Van D a m m e et al.
3 4
5 6
7 8 9 10 11
12
institutionalized and non-institutionalized persons. Public Health Rep. 1979, 94, 262 Szmuness, W. and Prince, A.M. The epidemiology of serum hepatitis (SH) infections: a controlled study in two closed institutions. Am. J. Epidemiol. 1971, 94, 585 Perillo, R.P., Storch, G.A., Bodicky, C.J., Campbell, C.R. and Sanders, G.E. Survey of hepatitis B viral markers at a public school and a residential institution sharing mentally handicapped students. J. Infect. Dis. 1984, 148, 796 Cancio-Bello, T.P., De Medina, M., Shorey, J., Valleda, M.D. and Schiff, E.R. An institutional outbreak of hepatitis B related to a human biting carrier. J. Infect. Dis. 1982, 148, 652 Hawkes, R.A., Boughton, C.R., Schroeter, D.R., Decker, R.H. and Overby, L.R. Hepatitis B infection in institutionalized Down's syndrome inmates: a longitudinal study with five hepatitis B virus markers. Clin. Exp. Immunol. 1980, 40, 478 Reniers, J. and Meheus, A. Hepatitis B in instellingen voor mentaal gehandicapten. Tijdschr. Soc. Gezondheidszorg. 1985, 63, 748 Coutinho, R.A. Virale hepatitis. Tijdschr. Soc. Gezondheidszorg. 1984, 62, 228 Van Damme, P. and Meheus, A. Hepatitis B in mental handicap hospitals (Letter). Lancet 1989, I, 840 De Wilde, M., Cabezon, T., Harford, N., Rutgers, T., Simoen, E. and Van Wijnendaele, F. Production in yeast of hepatitis B surface antigen by R-DNA technology. Dev. Biol. Stand. 1985, 59, 99 Van Damme, P., Vranckx, R., Salary, A., Andr6, F. and Meheus, A. Immunogenicity and efficacy of recombinant DNA hepatitis B vaccine in institutionalized mentally retarded patients: preliminary results. In: Viral Hepatitis and Liver Disease (Ed. Zuckerman, A.J.) Alan R. Liss, Inc., New York, 1988, pp. 1065-1067 Van Damme, P., Vranckx, R., Salary, A., Andr6, F. and Meheus, A.
13 14
15
16
17
18
19 20
Protective efficacy of a recombinant DNA hepatitis B vaccine in institutionalized mentally handicapped clients. Am. J. Meal. 1989, 87 (3A), 265 Dudley, F.J., Fox, R.A. and Sherlock, S. Cellular immunity and hepatitis-associated, Australian antigen liver disease. Lancet 1972, I, 723 Riges, D.A., Elsasser, P. and Hecht, F. Impaired in vitro response of circulating lymphocytes to phytohemegglutinin in Down's syndrome: dose- and time-response curves and relation to cellular immunity. Intern. Arch. Allergy 1970, 39, 587 Siegel, M. Susceptibility of mongoloids to infection. Incidence of pneumonia, influenza A, and Shigella dysenteriae (Sonne). Am. J. Hyg. 1948, 48, 53 Hollinger, F.B., Adam, E., Heiberg, F. and Melnick, J.L. Response to hepatitis B vaccine in a young adult population. In: Viral Hepatitis (Eds Szmuness, W., Alter, H.J., Maynard, J.E.) The Franklin Institute Press, Philadelphia, 1982, pp.'451~166 Troisi, C.L., Heiberg, D.A. and Hollinger, F.B. Normal immune response to hepatitis B vaccine in patients with Down's syndrome: a basis for immunization guidelines. J. Am. Med. Assoc. 1985, 254, 3196 Hollinger, F.B., Goyal, R.K., Hersh, T., Powell, H.C., Schulman, R.J. and Melnick, J.L. Immune response to hepatitis virus type B in Down's syndrome and other mentally retarded patients. Am. J. Epidemiol. 1972, 95, 356 Wahl, M., Hermodsson, S. and Iwarson, S. Immune responses to hepatitis B vaccine in the mentally retarded. J. Infect. 1983, 7, (suppl. 1), 47 Heijtink, R.A., De Jong, P., Schalm, S.W. and Masurel, N. Hepatitis B vaccination in Dewn's syndrome and other mentally retarded patients. Hepatology 1984, 4, 611
Vaccine, Vol. 8, S u p p l e m e n t 1990
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