Journal of Infection (x989) xg, II9-I25

I n t r a d e r m a l hepat i t i s B vacc inat ion for m e n t a l l y re tarded pat ients

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 low- dose (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

Hepat i t is B presents particular problems in insti tutions for the mentally re tarded due to the aberrant social behaviour of the patients, unique medical problems such as bleeding gums and drooling as well as c rowded living conditions. I-3 Patients in such insti tutions seem to respond unconvent ional ly to infection with hepatitis B virus (HBV). Fur thermore , patients with D o w n ' s syndrome usually have an impaired immune response. 4, 5 Hence, they are more susceptible to infection and eventually become chronic carriers. Mental ly re tarded patients, therefore, need to be vaccinated against hepatitis B. Studies on active immunisat ion against this disease were initiated by Krugman et al. f rom I97o to I97I in an insti tution for the mentally retarded where hepatitis B was highly endemic. 6' 7

Our previous studies showed the safety, immunogenic i ty and efficacy of p lasma-der ived hepatitis B vaccine given in three subcutaneous doses of Io or 2o #g of antigen protein. 8' 9 T h e limitations of widespread use of hepatitis B vaccine in insti tutions include its relatively high cost. Low-dose intradermal inoculations of hepatitis B vaccine were therefore given in order to assess the cost effectiveness. We have already repor ted the safety and immunogenic i ty 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

I20 J. HAYASHI ET AL.

Table I Prevalence of hepatitis B virus markers in institutionalised patients with Down's syndrome and others forms of mental retardation

Institution Disease Sex Patients HBsAg Anti-HBs Anti-HBc Susceptible

A Down's Males 9 3 (3) I 4 5 syndrome

Females 6 o 2 2 4 Males 33 0 IO I0 23

Females 22 o 5 5 I7 Males I7 7 (3) 6 13 4

Males 53 6 (I) 29 35 IS

Total

Other mentally retarded Down's syndrome Other mentally retarded

Males I I2 I6 (7) 46 62 50 Females 28 o 7 7 2I Total i4o i6 (7) 53 69 71

Figures in parenthesis = HBeAg-positive.

Materials and methods

Populat ion studied

In November I986, we screened I4o of the mental ly retarded patients residing in two institutions in Okinawa, Japan, for hepatitis B surface antigen (HBsAg), ant ibody to HBsAg (anti-HBs), ant ibody to hepatitis B core antigen (anti- HBc) and serum transaminase. HBsAg was detected in I6 patients ( I I ' 4 %) seven of whom were positive for hepatitis B e antigen. Ant i -HBs was detected in 53 patients (37"9 %) and ant ibody to (anfi-HBc) hepatitis in 69 patients (49"3 %). A total of 7I patients who were negative for all HBV markers were considered to be susceptible (Table I). The relatives of these susceptible patients gave permission' for vaccination but, since serum transaminase values were raised in eight of them only 63 patients, 43 men and 2o women, aged 20-50 years, (mean age 29"3 years) were vaccinated. Twelve patients had Down 's syndrome and 5I were otherwise mental ly retarded.

Vaccine

The vaccine used for this project was prepared by the Chemo-Sero- Therapeut ic Research Inst i tute (Kumamoto , Japan) by treating the plasma of HBsAg carriers with heat and formalin. The vaccines contained 4o # g / m l HBsAg protein, subtype adr with an a luminum hydroxide adjuvant. To avoid inactivation by overheating or freezing, the vaccine was t ransported in an insulated box and stored in a refrigerator with the temperature maintained at 2-8 °C.

Hepatitis B vaccine for mentally retarded patients I2I

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 6 9 12

Sex

Anti-HBs Anti-HBs Anti-HBs Anti-HBs Number positive Number positive Number positive Number positive

tested (%) tested (%) tested (%) tested (%)

Males 42 33'3 42 95.2* 42 IOO 42 Ioo Females 20 15 20 7 ° 20 80 20 80

Total 62 27" 4 62 85"5 62 93"5 62 93"5

P < o ' o 5 males v s . females.

Protocol

The vaccine was administered in three doses, the first of which was given in March I987. The 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 (AUSRIA II, AUSAB, and CORAB, Abbott Laboratories, North Chicago, IL). The anti- HBs 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. The X 2 (chi squared) test was applied to the results.

Results

Of the 63 mentally retarded patients given plasma-derived vaccine intra- dermally, 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.

The anti-HBs responses are shown in Table II. We excluded from this table

122 J. H A Y A S H I E T AL.

8

i ,

Ioo

8

~0 "I"

I

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/ml; [], > ioo ml U/ml.

data on the patient who became infected with HBV. One month after the first vaccination, 27"4 % patients acquired antibodies. After 6 months and before the third injection, the rate rose to 85"5 %. The third injection increased the ant ibody response rate to 93"5 %. The rate of acquiring an t i -HBs was significantly higher in men than women from 6 months to 12 months after the first injection. There were no significant differences be tween those with D o w n ' s syndrome and other mental ly re tarded patients or be tween those in the younger and older age groups. Four women given plasma-der ived vaccine intradermally were ant i -HBs-negat ive within 12 months. One of these had D o w n ' s syndrome, the remaining three were otherwise mentally retarded. T w o of the three have diabetes mellitus treated with insulin.

Hepatitis B vaccine for mentally retarded patients I23

The 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. The 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.). There were no systemic side effects or skin ulcerations. Local reactions were limited to transient soreness at the sites of inoculation.

Discuss ion

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 reposed 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 plasma- derived 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~ They 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 mIU/ml ) 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.

The phenomenon of a sex-dependent antibody response to HBsAg is poorly understood. The 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 anti- HBs-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

124 j. HAYASHI ET AL.

age g roups . I n any even t , s u p p l e m e n t a r y vacc ina t i on is n e e d e d for pa t i en t s wi th a low r e s p o n s e in o r d e r to ob 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 in jec t ion o f hepa t i t i s B vacc ine is safe a n d effect ive, the smal l dose i n t e n d e d for i n t r a d e r m a l use m u s t be in jec ted i n t e r d e r m a l l y . A c c i d e n t a l in jec t ion into s u b c u t a n e o u s t i s sue m a y be s igni f icant ly less i m m u n o g e n i c .

T h i s s t u d y r evea l ed t ha t the r e s p o n s e ra te fo r hepa t i t i s B vacc ine in the m e n t a l l y r e t a r d e d was s imi la r to tha t o f n o r m a l p e r s o n s a n d tha t i n t r a d e r m a l in jec t ion o f the vacc ine was sa t i s fac to ry 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 inocu la t ion . O n e o f o u r pa t i en t s w h o d e v e l o p e d a low t i t re o f a n t i b o d y a f t e r vacc ina t i on b e c a m e in fec t ed w i th 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 the vacc ine n e e d to be 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 the i r p r o t e c t i o n aga ins t hepa t i t i s B.

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