- Email: [email protected]
Comparison of results of recombinant and plasma-derived hepatitis B vaccines in Japanese nursery-school children
Journal of Infection (I988) I7, 49-55
Comparison of results of recombinant and plasma-derived h e p a t i t i s B v a c c i n e s in Japanese n u r s e r y - s c h o o l c h i l d r e n j. Hayashi, S. Kashiwagi, W. Kajiyama, H. Ikematsu, A. Noguchi, H. Nomura and K. Ikeda First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka 812, Japan Accepted for publication ~7 November I987
Summary Results obtained with a recombinant hepatitis B vaccine were compared with those obtained with a plasma-derived hepatitis B vaccine in separate studies conducted in nursery schools in which at least one child had hepatitis B e antigen associated with surface antigen. Recombinant vaccine (5 #g), made in Japan and prepared from antigen expressed in yeast, was given to i 18 children (aged 0-5 years of age, mean age 2'9 years). Plasma-derived vaccine (~o #g) was given to 243 children. Side-reactions were not observed with either vaccine. Seroconversion rates for the recombinant vaccine group were 8"5 % after I month, 98"3 % after 9 months and lOO % after I2 months, For the plasma-derived vaccine group, the rate after x month was 26"3 % after 9 months 82"3 %, and after I2 months 77"9 %- Although in the recombinant vaccine group the immune response developed more slowly during the early phase, seroconversion rates were significantly higher than in the plasma-derived vaccine group after 6 months. Titres of antibodies also were significantly higher in the recombinant vaccine group after the third injection. None of the children in either group became infected with hepatitis B virus. These results confirm the high immunogenicity, safety and efficacy of the recombinant vaccine given to these nursery school children.
Introduction Hepatitis B vaccines derived f r o m plasma of h u m a n carriers of hepatitis B virus (HBV) are n o w used world-wide. In Japan, such vaccines have been licensed since I985 and have proved to be safe, i m m u n o g e n i c and effective in preventing H B V infection. 1-a Even so, plasma-derived vaccines have the drawbacks o f limited availability of the raw material, the risk of containing u n k n o w n pathogenic substances and high cost. Problems with such vaccines have been largely overcome by the development of hepatitis B recombinant D N A vaccine. 4 M o s t H B V carriers acquire H B V infection in the neonatal period or in infancy. 5-7 W e have reported on the transmission of H B V a m o n g children in n u r s e r y schools s and have d e m o n s t r a t e d the efficacy of plasma-derived vaccine for preventing hepatitis B virus infection in this group. 9 In Japan as well as in the U . S . A . , hepatitis B r e c o m b i n a n t D N A vaccine is available. 1° MacAleer et al. n f o u n d that chimpanzees i m m u n i s e d with r e c o m b i n a n t vaccine were fully protected w h e n challenged with HBV. In order to determine the safety, i m m u n o g e n i c i t y and efficacy of this type of vaccine, we compared it with plasma-derived vaccine a m o n g n u r s e r y school children in Japan. oI63-4453/88/o4oo49+o 7 $o2.o0/0
© I988 The British Society for the Study of Infection
5o
J. HAYASHI ET AL. Materials and m e t h o d s
Study population
This consisted of children from o-5 years of age in nursery schools in Okinawa, Japan where there was at least one carrier with hepatitis B e antigen (HBeAg). T h o s e included in the trial fulfilled the following criteria: (a) serum negative for hepatitis B surface antigen (HBsAg), antibody to HBsAg (anti-HBs) and antibody to hepatitis B core antigen (anti-HBc); (b) serum glutamic oxaloacetic transaminase ( S G O T ) and serum glutamic pyruvic transaminase ( S G P T ) values < 40 K a r m e n U n i t s ; (c) absence of serious systemic illness or allergy; (d) informed written consent from the parents. Protocol
G r o u p I included 243 children (124 boys and 119 girls, mean age 2-7 years) in six nursery schools. These children were given IO #g plasma vaccine in August 1983 and again I and 6 m o n t h s later. Group II included 118 children (56 boys and 62 girls, mean age 2"9 years) in three nursery schools. These children were given 5/tg recombinant vaccine in February 1986 and again I and 6 m o n t h s later. T h e vaccines were administered subcutaneously. Blood samples were taken from children in both groups before the inoculation and again I, 6, 9 and 12 m o n t h s after the first inoculation. We investigated vaccine-related adverse reactions as ascertained from reports of the parents. Twelve m o n t h s after the first inoculation, 12 children left group I and 4 group II. T h e reasons for leaving the study included graduation from school, change of schools and change of place of residence. Vaccines
T w o plasma-derived vaccines were used for group I. One was prepared in the Kitazato Laboratories (Tokyo, Japan), the other in the Chemo-SeroTherapeutic Research Institute (Kumamoto, Japan) by treating the plasma of HBsAg carriers with heat and formalin. These vaccines contained 40 mg/1 of HBsAg protein, subtype adr, with an aluminium hydroxide adjuvant. T h e recombinant vaccine used for Group II was prepared by the Chemo-SeroTherapeutic Research Institute. Hepatitis B surface antigen in the vaccine was produced from a strain of the yeast Saccharomyces cerevisiae with a plasmid carrying the gene for the adr subtype of HBsAg. 1° This vaccine contained 2o mg/1 HBsAg with an aluminium hydroxide adjuvant. Laboratory m e t h o d s
All serum samples were tested for HBsAg, anti-HBs, and anti-HBc by means of commercially available radioimmunoassay (RIA) reagents (AUSRIA II, A U S U B , and CORAB, Abbott Laboratories, N o r t h Chicago, IL). Titration of anti-HBs was performed by passive haemagglutination (PHA) (Eisaikit, Eisai, Tokyo, Japan). Serum samples were also tested for serum transaminase. T h e XZ-squared test was applied to the results.
Recombinant and plasma-derived l i b vaccine
51
Results
T h e anti-HBs response in children receiving plasma-derived vaccine is shown in Table I. One month after the first vaccination, 26"3 % acquired antibodies. After 6 months, before the third injection, the rate rose to 70"8 %. T h e third injection increased the antibody-response rate to 82- 3 %. T h e antibodyresponse rate decreased to 77"9 % I2 months after the first injection. T h e rate of acquiring anti-HBs was higher in girls than in boys, but the difference was not statistically significant. (P < o" i). T h e anti-HBs response in children given recombinant vaccine is shown in Table II. One month after the first vaccination, 8"5 % had acquired antibodies. After 6 months the rate rose to 94"9 %. T h e third injection increased the antibody response rate to IOO %. T h e r e was no difference in the response rate between sexes. One month after the first injection, the anti-HBs response was significantly higher in plasma-derived vaccinees than in recombinant vaccinees (P < o'ooi). After 6, 9 and I2 months, however, the anti-HBs response was signficantly higher in recombinant vaccinees than in the plasma-derived vaccinees (P <
O'OOI). Samples of serum from both plasma-derived vaccines and recombinant vaccines, were found to contain anti-HBs by RIA, quantitatively by PHA. P H A titres of 8 or less were considered to indicate a low response, those of I6-64 an intermediate response, and t28 or more, a high response. T h e percentage of plasma-derived vaccinees with an intermediate or high response was 5"3 % after I month, 50"6% after 6 months, 71.6% after 9 months and 67"5 % after I2 months (Fig. i). T h e percentage of vaccines with an intermediate or high response to the recombinant vaccine was 0"8 % after I month, 67"8 % after 6 months, 89"0 % after 9 months and 84"2 % after x2 months (Fig. 2). Thus, recombinant vaccine resulted in higher antibody titres. Notably, the number of children with a high response was significantly greater in the recombinant vaccines after 9 and I2 months (P < o'oI). Adverse side-effects were not reported by the parents of children inoculated with either the plasma-derived or the recombinant vaccine. All vaccinated children remained negative for HBsAg and anti-HBc during the study. Serum transaminase values did not rise above 40 IU/1 in any of the vaccinated children. None had hepatitis. Discussion
It is desirable to vaccinate children in order to prevent infection from HBV because children are prone to become carriers. In Okinawa, Japan, where the rate of infection is higher than the national average, 1~ we found that children became infected with HBV from HBeAg-positive carrier children attending nursery schools. 8 For these reasons, we vaccinated children in nursery schools. T o our knowledge, this is the first report of vaccination of children with recombinant hepatitis B vaccine made in Japan. Recombinant hepatitis B vaccine appears to be as safe as plasma-derived
52
J. H A Y A S H I
ET,,'tL.
t,.I
7
888
-~, .~
o
B 0 ~
~-~
'~
0 ~2
(xI
~-~ ~
O
",:t"
oc
t'~
0
~-(
~-I
6 Z
(xI
',~
rq
o0
O',
O~
O",
.~ "~. ~-~
',~
cq
oo
ON
~
t¢~
i
6o6o6o
N
o~
@ 0
E
O
53
Recombinant and plasma-derived H B vaccine
o u ~
o
~u
o
co 0~_
I00
50 I
I
o
I
6
9
12
Time after first injection (months) Fig. I. Antibody response of children to plasma-derived hepatitis B vaccine (IO #g/dose). Arrows indicate w h e n vaccine was given. T h e ordinate indicates the percentage of vaccinees with anti-HBs detectable by P H A after vaccination. Shaded areas show the proportion of the children with various titres of anti-HBs, [], ~< 8; [], I6-64; k~, >/ I28.
vaccine already in use.l-~ Reports of some other studies on recombinant vaccine described local pain and low-grade fever, 13-16 the frequency of side-effects being similar to that reported for the plasma-derived vaccine. 13-1~ In the present study, none of the children had side-effects, regardless of the type of vaccine given. As a result of this observation and those in other reports 9'~7'18 we conclude that children are not likely to develop significant side-effects from either plasma-derived or recombinant vaccine. Jilg et a l . 16 reported a slower development of anti-HBs with recombinant vaccine than with the plasma-derived vaccine. We also found that the i m m u n e response to the recombinant vaccine was less during the first m o n t h than that to the plasma-derived vaccine. After 6 months, however, the seroconversion rate was significantly higher in those given the recombinant vaccine. It is worth noting that antibodies developed in all children given the recombinant vaccine. Other investigators ~4'~6 have reported lower geometric mean titres of anti-HBs in persons given recombinant compared with those given plasma-derived vaccine. We found the anti-HBs titres obtained by passi;ce haemagglutination to be significantly higher in the recombinant vaccines. Yamamoto et al. ~9 reported that, for Japanese adults, the anti-HBs seroconversion rate in respect of recombinant vaccine did not differ from that
54
J. H A Y A S H I
o-~
=,3
q~ o
c(3
no
~
s~>
ET AL.
to.c_
oo> xzo,_
~o
0 I
i
I
6
9
12
Time after first injection (months)
Fig. 2. Antibody response of children to recombinant hepatitis B vaccine (5 #g/dose). Arrows indicate when vaccine was given. T h e ordinate indicates the percentage of vaccinees with antiHBs detectable by P H A after vaccination. Shaded areas show the proportion of children with various titres of anti-HBs, I7, ~< 8; D , I6--32; k~, /> I28.
of plasma-derived vaccine but that recombinant vaccine resulted in a lower antibody titre than that induced by plasma-derived vaccine. On the other hand, the recombinant vaccine used in the present study in children induced a higher anti-HBs seroconversion rate and higher antibody titres than the plasma-derived vaccine. Long-term surveillance of vaccine responders is needed since the anti-HBs sero-conversion rate and titres in respect of plasmaderived vaccine decline gradually with time. 9' 2o Plasma-derived vaccine has proved effective in preventing HBV infection in nursery schools. 9 None of the children in the recombinant vaccine group in our study were infected with HBV although they attended nursery schools where there were HBeAg-positive children. Thus, recombinant vaccine is also effective in such a population. In conclusion, our study shows that recombinant hepatitis B vaccine has greater immunogenic potency than does plasma-derived vaccine. Furthermore, it is as safe and effective as plasma-derived vaccine in children in nursery schools.
Recombinant and plasma-derived H B vaccine
55
References I. Szmuness W, Stevens CE, Harley EJ et al. Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States. New Engl J Med I98O; 303: 833-84I. z. Crosnier J, Jungers P, Courouce A M et al. Randomised placebo controlled trial of hepatitis B surface antigen vaccine in French haemodialysis units. I. Medical staff. Lancet I 9 8 I i: 455-459. 3. Heyword W L , Bender TR, McMahon BJ et al. T h e control of hepatitis B virus infection with vaccine in Yupik Eskimos: demonstration of safety, immunogenicity, and efficacy under field conditions. Am J Epidemiol I985 ; xzI : 914-923. 4. Valenzuela P, Medina A, Rutter WJ et al. Synthesis and assembly of hepatitis B virus surface antigen particles in yeast. Nature I982; I98: 347-35o. 5. Okada K, Kamiyama I, Inomata M et al. e antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to their infants. New Engl J Med I976; z94:746--749 • 6. Beasley RP, Hwang LY, Liu CC et al. Incidence of hepatitis B virus infections in preschool children in Taiwan. J Infect Dis I982 ; x46 : I98-2o4. 7. Kashiwagi S, Hayashi J, Ikematsu H et al. Transmission of hepatitis B virus among siblings. Am ff Epidemiol I984; IZO: 617-625. 8. Hayashi J, Kashiwagi S, Nomura H e t al. Hepatitis B virus transmission in nursery schools. Am J Epidemiol I987; x25: 492-498. 9. Hayashi J, Kashiwagi S, Nomura H et al. T h e control of hepatitis B virus infection with vaccine in Japanese nursery schools. A m J Epidemiol I987; ,26: 474-479. IO. Miyanohara A, Toh-e A, Nozaki C et al. Expression of hepatitis B surface antigen gene in yeast. Proc Natl Acad Sci U S A I983 ; 8o: I-5. I I. McAleer WJ, Buynak EB, Margetter RZ et al. Human hepatitis B vaccine from recombinant yeast. Nature 1984; 3o7: I78-I8O. i2. Kashiwagi S, Hayashi J, Ikematsu H et al. An epidemiologic study of hepatitis B virus in Okinawa and Kyushu, Japan. Am ff Epidemiol 1983; xx8: 787-794. I3. Dandolos E, Roumeliotou-Karayannis A, Richardson SC et al. Safety and immunogenicity of a recombinant hepatitis B vaccine. J Med Virol I985 ; x7 : 57-62. I4. Scolnick EM, McLean AA, West DJ et al. Clinical evaluation in healthy adults of a hepatitis B vaccine made by recombinant D N A . J A M A I984; aS*: 2812-2815. I5. Zahradnik JM, Couch RB, Gerin JL. Safety and immunogenicity of a purified hepatitis B virus vaccine prepared by using recombinant D N A technology. J lnfect Dis I987; x55: 9o3-9o8. i6. Jilg W, Lorbeer B, Shmidt M et al. Clinical evaluation of a recombinant hepatitis B vaccine. Lancet I984: ii, I I 7 4 - I I75. I7. Barin F, Goudean A, Denis F et al. Immune response in neonates to hepatitis B vaccine. Lancet I982; i: 251-253. 18. Lee GC-Y, Hwang L-Y, Beasley RP et al. Immunogenicity of hepatitis B virus vaccine in healthy Chinese neonates. J Infect Dis I983 ; I 4 8 : 5 3 6 - 5 3 9 • I9. Yamamoto S, Kuroki T , Kurai K et al. Comparison of results for phase I studies with recombinant and plasma-derived hepatitis B vaccines, and controlled study comparing intramuscular and subcutaneous injections of recombinant hepatitis B vaccine. J Infect I986; x3: 53-60. 20. McLean AA. Hepatitis B vaccine : a review of the clinical data to data. J Am Dent Assoc 1985; IIO: 624-628.
Comparison of results of recombinant and plasma-derived h e p a t i t i s B v a c c i n e s in Japanese n u r s e r y - s c h o o l c h i l d r e n j. Hayashi, S. Kashiwagi, W. Kajiyama, H. Ikematsu, A. Noguchi, H. Nomura and K. Ikeda First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka 812, Japan Accepted for publication ~7 November I987
Summary Results obtained with a recombinant hepatitis B vaccine were compared with those obtained with a plasma-derived hepatitis B vaccine in separate studies conducted in nursery schools in which at least one child had hepatitis B e antigen associated with surface antigen. Recombinant vaccine (5 #g), made in Japan and prepared from antigen expressed in yeast, was given to i 18 children (aged 0-5 years of age, mean age 2'9 years). Plasma-derived vaccine (~o #g) was given to 243 children. Side-reactions were not observed with either vaccine. Seroconversion rates for the recombinant vaccine group were 8"5 % after I month, 98"3 % after 9 months and lOO % after I2 months, For the plasma-derived vaccine group, the rate after x month was 26"3 % after 9 months 82"3 %, and after I2 months 77"9 %- Although in the recombinant vaccine group the immune response developed more slowly during the early phase, seroconversion rates were significantly higher than in the plasma-derived vaccine group after 6 months. Titres of antibodies also were significantly higher in the recombinant vaccine group after the third injection. None of the children in either group became infected with hepatitis B virus. These results confirm the high immunogenicity, safety and efficacy of the recombinant vaccine given to these nursery school children.
Introduction Hepatitis B vaccines derived f r o m plasma of h u m a n carriers of hepatitis B virus (HBV) are n o w used world-wide. In Japan, such vaccines have been licensed since I985 and have proved to be safe, i m m u n o g e n i c and effective in preventing H B V infection. 1-a Even so, plasma-derived vaccines have the drawbacks o f limited availability of the raw material, the risk of containing u n k n o w n pathogenic substances and high cost. Problems with such vaccines have been largely overcome by the development of hepatitis B recombinant D N A vaccine. 4 M o s t H B V carriers acquire H B V infection in the neonatal period or in infancy. 5-7 W e have reported on the transmission of H B V a m o n g children in n u r s e r y schools s and have d e m o n s t r a t e d the efficacy of plasma-derived vaccine for preventing hepatitis B virus infection in this group. 9 In Japan as well as in the U . S . A . , hepatitis B r e c o m b i n a n t D N A vaccine is available. 1° MacAleer et al. n f o u n d that chimpanzees i m m u n i s e d with r e c o m b i n a n t vaccine were fully protected w h e n challenged with HBV. In order to determine the safety, i m m u n o g e n i c i t y and efficacy of this type of vaccine, we compared it with plasma-derived vaccine a m o n g n u r s e r y school children in Japan. oI63-4453/88/o4oo49+o 7 $o2.o0/0
© I988 The British Society for the Study of Infection
5o
J. HAYASHI ET AL. Materials and m e t h o d s
Study population
This consisted of children from o-5 years of age in nursery schools in Okinawa, Japan where there was at least one carrier with hepatitis B e antigen (HBeAg). T h o s e included in the trial fulfilled the following criteria: (a) serum negative for hepatitis B surface antigen (HBsAg), antibody to HBsAg (anti-HBs) and antibody to hepatitis B core antigen (anti-HBc); (b) serum glutamic oxaloacetic transaminase ( S G O T ) and serum glutamic pyruvic transaminase ( S G P T ) values < 40 K a r m e n U n i t s ; (c) absence of serious systemic illness or allergy; (d) informed written consent from the parents. Protocol
G r o u p I included 243 children (124 boys and 119 girls, mean age 2-7 years) in six nursery schools. These children were given IO #g plasma vaccine in August 1983 and again I and 6 m o n t h s later. Group II included 118 children (56 boys and 62 girls, mean age 2"9 years) in three nursery schools. These children were given 5/tg recombinant vaccine in February 1986 and again I and 6 m o n t h s later. T h e vaccines were administered subcutaneously. Blood samples were taken from children in both groups before the inoculation and again I, 6, 9 and 12 m o n t h s after the first inoculation. We investigated vaccine-related adverse reactions as ascertained from reports of the parents. Twelve m o n t h s after the first inoculation, 12 children left group I and 4 group II. T h e reasons for leaving the study included graduation from school, change of schools and change of place of residence. Vaccines
T w o plasma-derived vaccines were used for group I. One was prepared in the Kitazato Laboratories (Tokyo, Japan), the other in the Chemo-SeroTherapeutic Research Institute (Kumamoto, Japan) by treating the plasma of HBsAg carriers with heat and formalin. These vaccines contained 40 mg/1 of HBsAg protein, subtype adr, with an aluminium hydroxide adjuvant. T h e recombinant vaccine used for Group II was prepared by the Chemo-SeroTherapeutic Research Institute. Hepatitis B surface antigen in the vaccine was produced from a strain of the yeast Saccharomyces cerevisiae with a plasmid carrying the gene for the adr subtype of HBsAg. 1° This vaccine contained 2o mg/1 HBsAg with an aluminium hydroxide adjuvant. Laboratory m e t h o d s
All serum samples were tested for HBsAg, anti-HBs, and anti-HBc by means of commercially available radioimmunoassay (RIA) reagents (AUSRIA II, A U S U B , and CORAB, Abbott Laboratories, N o r t h Chicago, IL). Titration of anti-HBs was performed by passive haemagglutination (PHA) (Eisaikit, Eisai, Tokyo, Japan). Serum samples were also tested for serum transaminase. T h e XZ-squared test was applied to the results.
Recombinant and plasma-derived l i b vaccine
51
Results
T h e anti-HBs response in children receiving plasma-derived vaccine is shown in Table I. One month after the first vaccination, 26"3 % acquired antibodies. After 6 months, before the third injection, the rate rose to 70"8 %. T h e third injection increased the antibody-response rate to 82- 3 %. T h e antibodyresponse rate decreased to 77"9 % I2 months after the first injection. T h e rate of acquiring anti-HBs was higher in girls than in boys, but the difference was not statistically significant. (P < o" i). T h e anti-HBs response in children given recombinant vaccine is shown in Table II. One month after the first vaccination, 8"5 % had acquired antibodies. After 6 months the rate rose to 94"9 %. T h e third injection increased the antibody response rate to IOO %. T h e r e was no difference in the response rate between sexes. One month after the first injection, the anti-HBs response was significantly higher in plasma-derived vaccinees than in recombinant vaccinees (P < o'ooi). After 6, 9 and I2 months, however, the anti-HBs response was signficantly higher in recombinant vaccinees than in the plasma-derived vaccinees (P <
O'OOI). Samples of serum from both plasma-derived vaccines and recombinant vaccines, were found to contain anti-HBs by RIA, quantitatively by PHA. P H A titres of 8 or less were considered to indicate a low response, those of I6-64 an intermediate response, and t28 or more, a high response. T h e percentage of plasma-derived vaccinees with an intermediate or high response was 5"3 % after I month, 50"6% after 6 months, 71.6% after 9 months and 67"5 % after I2 months (Fig. i). T h e percentage of vaccines with an intermediate or high response to the recombinant vaccine was 0"8 % after I month, 67"8 % after 6 months, 89"0 % after 9 months and 84"2 % after x2 months (Fig. 2). Thus, recombinant vaccine resulted in higher antibody titres. Notably, the number of children with a high response was significantly greater in the recombinant vaccines after 9 and I2 months (P < o'oI). Adverse side-effects were not reported by the parents of children inoculated with either the plasma-derived or the recombinant vaccine. All vaccinated children remained negative for HBsAg and anti-HBc during the study. Serum transaminase values did not rise above 40 IU/1 in any of the vaccinated children. None had hepatitis. Discussion
It is desirable to vaccinate children in order to prevent infection from HBV because children are prone to become carriers. In Okinawa, Japan, where the rate of infection is higher than the national average, 1~ we found that children became infected with HBV from HBeAg-positive carrier children attending nursery schools. 8 For these reasons, we vaccinated children in nursery schools. T o our knowledge, this is the first report of vaccination of children with recombinant hepatitis B vaccine made in Japan. Recombinant hepatitis B vaccine appears to be as safe as plasma-derived
52
J. H A Y A S H I
ET,,'tL.
t,.I
7
888
-~, .~
o
B 0 ~
~-~
'~
0 ~2
(xI
~-~ ~
O
",:t"
oc
t'~
0
~-(
~-I
6 Z
(xI
',~
rq
o0
O',
O~
O",
.~ "~. ~-~
',~
cq
oo
ON
~
t¢~
i
6o6o6o
N
o~
@ 0
E
O
53
Recombinant and plasma-derived H B vaccine
o u ~
o
~u
o
co 0~_
I00
50 I
I
o
I
6
9
12
Time after first injection (months) Fig. I. Antibody response of children to plasma-derived hepatitis B vaccine (IO #g/dose). Arrows indicate w h e n vaccine was given. T h e ordinate indicates the percentage of vaccinees with anti-HBs detectable by P H A after vaccination. Shaded areas show the proportion of the children with various titres of anti-HBs, [], ~< 8; [], I6-64; k~, >/ I28.
vaccine already in use.l-~ Reports of some other studies on recombinant vaccine described local pain and low-grade fever, 13-16 the frequency of side-effects being similar to that reported for the plasma-derived vaccine. 13-1~ In the present study, none of the children had side-effects, regardless of the type of vaccine given. As a result of this observation and those in other reports 9'~7'18 we conclude that children are not likely to develop significant side-effects from either plasma-derived or recombinant vaccine. Jilg et a l . 16 reported a slower development of anti-HBs with recombinant vaccine than with the plasma-derived vaccine. We also found that the i m m u n e response to the recombinant vaccine was less during the first m o n t h than that to the plasma-derived vaccine. After 6 months, however, the seroconversion rate was significantly higher in those given the recombinant vaccine. It is worth noting that antibodies developed in all children given the recombinant vaccine. Other investigators ~4'~6 have reported lower geometric mean titres of anti-HBs in persons given recombinant compared with those given plasma-derived vaccine. We found the anti-HBs titres obtained by passi;ce haemagglutination to be significantly higher in the recombinant vaccines. Yamamoto et al. ~9 reported that, for Japanese adults, the anti-HBs seroconversion rate in respect of recombinant vaccine did not differ from that
54
J. H A Y A S H I
o-~
=,3
q~ o
c(3
no
~
s~>
ET AL.
to.c_
oo> xzo,_
~o
0 I
i
I
6
9
12
Time after first injection (months)
Fig. 2. Antibody response of children to recombinant hepatitis B vaccine (5 #g/dose). Arrows indicate when vaccine was given. T h e ordinate indicates the percentage of vaccinees with antiHBs detectable by P H A after vaccination. Shaded areas show the proportion of children with various titres of anti-HBs, I7, ~< 8; D , I6--32; k~, /> I28.
of plasma-derived vaccine but that recombinant vaccine resulted in a lower antibody titre than that induced by plasma-derived vaccine. On the other hand, the recombinant vaccine used in the present study in children induced a higher anti-HBs seroconversion rate and higher antibody titres than the plasma-derived vaccine. Long-term surveillance of vaccine responders is needed since the anti-HBs sero-conversion rate and titres in respect of plasmaderived vaccine decline gradually with time. 9' 2o Plasma-derived vaccine has proved effective in preventing HBV infection in nursery schools. 9 None of the children in the recombinant vaccine group in our study were infected with HBV although they attended nursery schools where there were HBeAg-positive children. Thus, recombinant vaccine is also effective in such a population. In conclusion, our study shows that recombinant hepatitis B vaccine has greater immunogenic potency than does plasma-derived vaccine. Furthermore, it is as safe and effective as plasma-derived vaccine in children in nursery schools.
Recombinant and plasma-derived H B vaccine
55
References I. Szmuness W, Stevens CE, Harley EJ et al. Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States. New Engl J Med I98O; 303: 833-84I. z. Crosnier J, Jungers P, Courouce A M et al. Randomised placebo controlled trial of hepatitis B surface antigen vaccine in French haemodialysis units. I. Medical staff. Lancet I 9 8 I i: 455-459. 3. Heyword W L , Bender TR, McMahon BJ et al. T h e control of hepatitis B virus infection with vaccine in Yupik Eskimos: demonstration of safety, immunogenicity, and efficacy under field conditions. Am J Epidemiol I985 ; xzI : 914-923. 4. Valenzuela P, Medina A, Rutter WJ et al. Synthesis and assembly of hepatitis B virus surface antigen particles in yeast. Nature I982; I98: 347-35o. 5. Okada K, Kamiyama I, Inomata M et al. e antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to their infants. New Engl J Med I976; z94:746--749 • 6. Beasley RP, Hwang LY, Liu CC et al. Incidence of hepatitis B virus infections in preschool children in Taiwan. J Infect Dis I982 ; x46 : I98-2o4. 7. Kashiwagi S, Hayashi J, Ikematsu H et al. Transmission of hepatitis B virus among siblings. Am ff Epidemiol I984; IZO: 617-625. 8. Hayashi J, Kashiwagi S, Nomura H e t al. Hepatitis B virus transmission in nursery schools. Am J Epidemiol I987; x25: 492-498. 9. Hayashi J, Kashiwagi S, Nomura H et al. T h e control of hepatitis B virus infection with vaccine in Japanese nursery schools. A m J Epidemiol I987; ,26: 474-479. IO. Miyanohara A, Toh-e A, Nozaki C et al. Expression of hepatitis B surface antigen gene in yeast. Proc Natl Acad Sci U S A I983 ; 8o: I-5. I I. McAleer WJ, Buynak EB, Margetter RZ et al. Human hepatitis B vaccine from recombinant yeast. Nature 1984; 3o7: I78-I8O. i2. Kashiwagi S, Hayashi J, Ikematsu H et al. An epidemiologic study of hepatitis B virus in Okinawa and Kyushu, Japan. Am ff Epidemiol 1983; xx8: 787-794. I3. Dandolos E, Roumeliotou-Karayannis A, Richardson SC et al. Safety and immunogenicity of a recombinant hepatitis B vaccine. J Med Virol I985 ; x7 : 57-62. I4. Scolnick EM, McLean AA, West DJ et al. Clinical evaluation in healthy adults of a hepatitis B vaccine made by recombinant D N A . J A M A I984; aS*: 2812-2815. I5. Zahradnik JM, Couch RB, Gerin JL. Safety and immunogenicity of a purified hepatitis B virus vaccine prepared by using recombinant D N A technology. J lnfect Dis I987; x55: 9o3-9o8. i6. Jilg W, Lorbeer B, Shmidt M et al. Clinical evaluation of a recombinant hepatitis B vaccine. Lancet I984: ii, I I 7 4 - I I75. I7. Barin F, Goudean A, Denis F et al. Immune response in neonates to hepatitis B vaccine. Lancet I982; i: 251-253. 18. Lee GC-Y, Hwang L-Y, Beasley RP et al. Immunogenicity of hepatitis B virus vaccine in healthy Chinese neonates. J Infect Dis I983 ; I 4 8 : 5 3 6 - 5 3 9 • I9. Yamamoto S, Kuroki T , Kurai K et al. Comparison of results for phase I studies with recombinant and plasma-derived hepatitis B vaccines, and controlled study comparing intramuscular and subcutaneous injections of recombinant hepatitis B vaccine. J Infect I986; x3: 53-60. 20. McLean AA. Hepatitis B vaccine : a review of the clinical data to data. J Am Dent Assoc 1985; IIO: 624-628.