Intradermal hepatitis B vaccination for mentally retarded patients

Journal of Infection (x989) xg, II9-I25

I n t r a d e r m a l hepatitis B v a c c i n a t i o n for m e n t a l l y r e t a r d e d patients Jun Hayashi, Seizaburo Kashiwagi, Akinori Noguchi, Kouya Nakashima, Hideyuki Ikematsu and Wataru Kajiyama The Department of General Medicine, Kyushu University Hospital Higashi-ku Fukuoka 8 I2, Japan Accepted for publication 8 February I989 Summary We investigated immune responses in 63 mentally retarded patients each given a lowdose (4 #g) intradermaUy of plasma-derived hepatitis B vaccine made in Japan and which was repeated after I and 6 months. Two doses of the vaccine induced antibodies in 85"5 % these patients. A further dose 6 months later induced antibodies in 93"5 % of the recipients and markedly increased the proportion of recipients with acceptable or high concentrations of antibody. The numbers of acceptable and high responders decreased slightly during a period of I2 months. The rate of acquiring antibody was significantly higher in the males. No significant differences in antibody response with regard to age and type of disease were observed. One patient with Down's syndrome, who acquired a low concentration of antibody after vaccination, was infected with hepatitis B virus. Supplementary vaccination may be necessary for poor responders in order to obtain protection. Side-effects resulting from the vaccination were not severe in any patients. These results suggest that low-dose, intradermal hepatitis B vaccination is safe and effective.

Introduction Hepatitis B presents particular p r o b l e m s in institutions for the mentally retarded due to the aberrant social behaviour of the patients, unique medical p r o b l e m s such as bleeding gums and drooling as well as c r o w d e d living conditions. I-3 Patients in such institutions seem to respond unconventionally to infection with hepatitis B virus (HBV). F u r t h e r m o r e , patients with D o w n ' s s y n d r o m e usually have an impaired i m m u n e response. 4, 5 Hence, they are m o r e susceptible to infection and eventually b e c o m e chronic carriers. Mentally retarded patients, therefore, need to be vaccinated against hepatitis B. Studies on active immunisation against this disease were initiated by K r u g m a n et al. from I97o to I97I in an institution for the mentally retarded where hepatitis B was highly endemic. 6' 7 O u r previous studies showed the safety, immunogenicity and efficacy of plasma-derived hepatitis B vaccine given in three s u b c u t a n e o u s doses of Io or 2o # g of antigen protein. 8' 9 T h e limitations of widespread use of hepatitis B vaccine in institutions include its relatively high cost. L o w - d o s e intradermal inoculations of hepatitis B vaccine were therefore given in order to assess the cost effectiveness. W e have already reported the safety and immunogenicity of intradermal inoculation of this vaccine. I°' ix oi63-4453/89/o5oi I9 + 07 $o2.oo/o

© I989 The British Society for the Study of Infection

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T a b l e I Prevalence of hepatitis B virus markers in institutionalised patients

with Down's syndrome and others forms of mental retardation Institution

Disease

A

Down's Males syndrome Females Other Males mentally retarded Females Down's Males syndrome Other Males mentally retarded Males Females Total

Total

Sex

Patients 9

HBsAg Anti-HBs Anti-HBc Susceptible 3 (3)

I

4

5

2 IO

2 I0

4 23

6 33

o 0

22 I7

o 7 (3)

5 6

5 13

I7 4

53

6 (I)

29

35

IS

I I2 28 i4o

I6 (7) o i6 (7)

46 7 53

62 7 69

50 2I 71

Figures in parenthesis = HBeAg-positive.

Materials and m e t h o d s Population studied In N o v e m b e r I986, we screened I4o of the mentally retarded patients residing in two institutions in Okinawa, Japan, for hepatitis B surface antigen (HBsAg), antibody to H B s A g (anti-HBs), antibody to hepatitis B core antigen (antiHBc) and serum transaminase. H B s A g was detected in I6 patients ( I I ' 4 %) seven of w h o m were positive for hepatitis B e antigen. A n t i - H B s was detected in 53 patients (37"9 %) and antibody to (anfi-HBc) hepatitis in 69 patients (49"3 %). A total of 7I patients who were negative for all H B V markers were considered to be susceptible (Table I). T h e relatives of these susceptible patients gave permission' for vaccination but, since serum transaminase values were raised in eight of t h e m only 63 patients, 43 m e n and 2o women, aged 20-50 years, (mean age 29"3 years) were vaccinated. Twelve patients had D o w n ' s s y n d r o m e and 5I were otherwise mentally retarded. Vaccine T h e vaccine used for this project was prepared by the C h e m o - S e r o T h e r a p e u t i c Research Institute ( K u m a m o t o , Japan) by treating the plasma of H B s A g carriers with heat and formalin. T h e vaccines contained 4o # g / m l H B s A g protein, subtype adr with an a l u m i n u m h y d r o x i d e adjuvant. T o avoid inactivation by overheating or freezing, the vaccine was transported in an insulated box and stored in a refrigerator with the temperature maintained at 2-8 °C.

Hepatitis B vaccine for mentally retarded patients

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Table II Immune response of patients to hepatitis B vaccine, by sex in

institutions in Okinawa, Japan, z987-I988 Months after the first injection i

Sex Males Females Total

Number tested 42 20 62

P < o ' o 5 males

6

12

Anti-HBs Anti-HBs Anti-HBs Anti-HBs positive N u m b e r positive Number positive Number positive (%) tested (%) tested (%) tested (%) 33'3 15 27"4

vs.

9

42 20 62

95.2* 7° 85"5

42 20 62

IOO 80 93"5

42 20 62

Ioo 80 93"5

females.

Protocol

T h e vaccine was administered in three doses, the first of which was given in March I987. T h e second dose was administered I month later and the third dose was given 6 months after the first. On each occasion, a dose of 4 #g (o'I ml) was given intradermally. Blood samples from the vaccinated patients were taken before the first inoculation and again I, 6, 9 and I2 months later. Laboratory methods

All samples of serum were tested for HBsAg, anti-HBs, and anti-HBc by means of commercially available radioimmunoassay reagents ( A U S R I A II, AUSAB, and CORAB, Abbott Laboratories, North Chicago, IL). T h e antiHBs titres were expressed in m I U according to the method described by Hollinger.12 Serum samples from the vaccinated patients were tested also for transaminase. Analysis

In order to evaluate age-dependence in the results of the two groups, vaccines were assigned to younger or older age groups separated by an arbitrarily chosen border line of age 30 years. T h e X2 (chi squared) test was applied to the results. Results

Of the 63 mentally retarded patients given plasma-derived vaccine intradermally, a 34-year-old man with Down's syndrome was infected with HBV during the period of this study. He became anti-HBs-positive (RIA-= I-9 m I U / m l ) without anti-HBc within I month after the first dose of vaccine. He was first found to be positive for anti-HBc, however, within 6 months after the first injection but before the third injection. T h e anti-HBs responses are shown in Table II. We excluded from this table

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ET AL.

8 8 i,

Ioo

"I" I

~0

c

I

6

9

12

Time after first injection (months)

Fig. ~. Immunogenic response of mentally retarded patients to hepatitis B vaccine (4/~g per dose). Arrows indicate time of intradermal administration of vaccine. The ordinate indicates the percentage of vaccinees with anti-HBs detectable by radioimmunoassay. Shaded areas show the proportion of patients with various concentrations of anti-I-IBs, [], I-9 ml U/ml; [], lO-99 ml U / m l ; [], > ioo ml U/ml.

data on the patient who became infected with H B V . O n e m o n t h after the first vaccination, 27"4 % patients acquired antibodies. After 6 m o n t h s and before the third injection, the rate rose to 85"5%. T h e third injection increased the antibody response rate to 93"5 %. T h e rate o f acquiring a n t i - H B s was significantly higher in m e n than w o m e n from 6 m o n t h s to 12 m o n t h s after the first injection. T h e r e were no significant differences b e t w e e n those with D o w n ' s s y n d r o m e and other mentally retarded patients or b e t w e e n those in the y o u n g e r and older age groups. F o u r w o m e n given plasma-derived vaccine intradermally were anti-HBs-negative within 12 months. O n e of these had D o w n ' s syndrome, the remaining three were otherwise mentally retarded. T w o o f the three have diabetes mellitus treated with insulin.

Hepatitis B vaccine for mentally retarded patients

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T h e RIA value of I-9 m I U / m l was considered to be a low response, that of Io--99 m I U / m l a normal response and that of Ioo m I U / m l or more a higher response. T h e percentage of vaccinated patients with normal and high responses was 22.6 % after I month, 75"8 % after 6 months, 83"9 % after 9 months and 82"3 % after I2 months (Fig.). T h e r e were no systemic side effects or skin ulcerations. Local reactions were limited to transient soreness at the sites of inoculation. Discussion

HBV infection is common among mentally retarded patients confined to an institution. Those with Down's syndrome in particular are especially predisposed to develop chronic hepatitis B infection following exposure to the virus. 13 For them vaccination is therefore particularly important. Hepatitis B vaccine is expensive and clinical trials have demonstrated that low doses of vaccine given intramuscularly to children and newborn infants were immunogenic and effective. 14 It has been r e p o s e d also that intradermal administration of vaccine was immunogenic and safe. 15-19 Among mentally retarded patients, seroconversion rates in Down's syndrome has been shown to be high (9o-90-8 %) and almost the same as in normal adults. ~°'21 In contrast, Warl et al. 22 noted a reduced seroconversion rate (75 %). After three intradermal vaccinations with 4 #g doses of plasmaderived hepatitis B vaccine made in Japan, we found a 93"5 % seroconversion rate in the mentally retarded patients as well as in normal children and adults, given the same vaccine, subcutaneously. This result was similar to that observed by Heijtink et al. 2~ T h e y also vaccinated mentally retarded patients intradermally. It has been reported that hepatitis B or inapparent infection developed in homosexuals, despite administration of the vaccine. 24 One of our male patients with Down's syndrome who acquired antibody (RIA = I-9 m I U / m l ) was found to be infected with HBV within 6 months after the first injection, although it was uncertain, whether he had been already infected at the time he was given the vaccine. It is important to know the degree of the immune response that protects against infection. An RIA antibody value of I-9 m I U / m l may not protect patients with Down's Syndrome against HBV infection. T h e phenomenon of a sex-dependent antibody response to HBsAg is poorly understood. T h e same bias has been observed in HBV infections in which males seem to be more susceptible to carriage of the virus. ~ In general, the response to hepatitis B vaccine has been higher in females than males. 9,z6 It was of interest in our study that, 12 months after the first injection, all the antiHBs-negative patients were females. Since two had diabetes mellitus, it may be that mentally retarded patients being treated with insulin do not respond well to the hepatitis B vaccine. Nine months after vaccination 83"9 % our patients were normal or high responders, a value about equal to that of our previous studies. It has been reported that geometric mean titres of anti-HBs were lower in older mentally retarded patients and in male patients with Down's syndrome, s° In our present study, however, we did not find any differences between types of disease and

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age g r o u p s . I n a n y e v e n t , s u p p l e m e n t a r y v a c c i n a t i o n is n e e d e d f o r p a t i e n t s w i t h a l o w r e s p o n s e in o r d e r to o b t a i n p r o t e c t i v e c o n c e n t r a t i o n s o f a n t i - H B s . A l t h o u g h i n t r a d e r m a l i n j e c t i o n o f h e p a t i t i s B v a c c i n e is safe a n d effective, the small dose intended for intradermal use m u s t be injected interdermally. A c c i d e n t a l i n j e c t i o n into s u b c u t a n e o u s t i s s u e m a y b e s i g n i f i c a n t l y less immunogenic. T h i s s t u d y r e v e a l e d t h a t t h e r e s p o n s e r a t e f o r h e p a t i t i s B v a c c i n e in t h e m e n t a l l y r e t a r d e d was s i m i l a r to t h a t o f n o r m a l p e r s o n s a n d t h a t i n t r a d e r m a l i n j e c t i o n o f t h e v a c c i n e was s a t i s f a c t o r y a n d c h e a p e r t h a n s u b c u t a n e o u s inoculation. One of our patients who developed a low titre of a n t i b o d y after v a c c i n a t i o n b e c a m e i n f e c t e d w i t h H B V . T h o s e w h o r e s p o n d p o o r l y to t h e v a c c i n e n e e d to b e r e v a c c i n a t e d in o r d e r to e n s u r e t h e i r p r o t e c t i o n a g a i n s t h e p a t i t i s B.

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