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Prevention of hepatitis B infection in infants born to hepatitis B carrier mothers: low dosage vaccination
353
Int. J. Gynecol. Obstet., 1990,32: 353-357 International Federation of Gynecology and Obstetrics
Prevention of hepatitis B infection in infants born to hepatitis B carrier mothers: low dosage vaccination U. Theppisai”,
C. Thanuntaseth”,
P. Chiewsilpb
and P. Siripoonya”
Departments of YObstetrics and Gynecology, bPathology and =Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400 (Thailand) (Received February 24th, 1989) (Revised and accepted May 3Oth, 1989)
Abstract
Two groups of newborn infants born to HBeAg positive carrier mothers were given HBIG (200 IU) immediately after birth. Subsequently, at age 2 days and at 1, 2 and 12 months, the first group received 5 pg and the second group 2 pg of HBV vaccines. There was no significant difference in the anti-HBs seroconversion rate (SR), and the protective efficacy rate (PER) at the age of 13 months in either group. The SR and PER of group I were 91.7% and 90.18%, and group II were 92.9% and 91.01%, respectively. Although the significant differences were observed in the geometric mean titers of anti-HBs in group I (526.3 mIU/ml) and group II (371.4 mIU/ml), both were above the protective level. The immune responses to the reduced dosage of HBV vaccines are satisfactory in preventing HBV in the newborn infants of HBeAgpositive carrier mothers.
Keywords: Hepatitis B virus; Hepatitis B vaccine; Hepatitis B surface antigen; Hepatitis B e antigen; Antibody to hepatitis B surface antigen. Introduction
In Thailand, the association of hepatitis B 0020-7292/90/$03.50 @ 1990 International Federation of Gynecology and Obstetrics
Published and Printed in Ireland
(HBV) with chronic hepatitis, cirrhosis and hepatocellular carcinoma has been well documented [l-3]. The prevalence of hepatitis B surface antigen (HBsAg) in three separate studies conducted in different groups of normal population yielded a high carriage rate (5-10%) [4--51. Transmission of HBV from carrier mothers to their infants is considered the most important means of transmitting HBV infection in most endemic areas [6--81. Maternal transmission occurs during labor and delivery [9]. One study reported 34% of infants born of carrier mothers developed HBsAg. Hepatitis B e antigen (HBeAg) positive carrier mothers are more likely to transmit HBV to their newborn infants than those who are HBeAg negative [lo]. Mother to infant transmission has been documented in 84.6% of HBeAg positive mothers, in contrast to 19% in HBeAg negative mothers. HBV immunization currently represents the only way to interrupt the transmission of HBV infection from carrier mothers. Safe and effective hepatitis vaccines have been available for several years [ 11,121. In many endemic areas, the widespread use of HBV vaccines is limited by their cost. Decreasing the antigen content per dose may allow a reduction in cost. The purpose of this study was to assess the immunogenicity and efficacy of a reduced dose of vaccine with reference to the standard dose in a population of neonates at risk. virus
Clinical and Clinical Research
354
Theppisai et al.
Materials and methods
Since December 1983, all pregnant women attending the antenatal clinic of Ramathibodi Hospital have been routinely screened for HBsAg by reverse passive hemagglutination test (RPHA). A total of 6.7% of the mothers were HBsAg positive. Of these, 41.2% were also HBeAg positive by RIA [lo] (AbbottHBe). From March 1986 to September 1986, 60 newborn infants from HBeAg positive carrier mothers were randomized to enter the immunization program. They were divided into two groups (1,II). Each group was composed of 30 infants. The following schedule and vaccines were used: HBV vaccine, Hevac B Pasteur vaccines (plasma derived vaccines) contained 5 pg and 2 pg of HBsAg per dose; hepatitis B immunoglobin (HBIG), anti-hepatitis B specific immunoglobin (Centre National de Transfusion Sanguine, France) containing 200 IU of antibody specific to hepatitis B surface antigen (anti-HBs) per ml. Active and passive immunizations were given to both groups of infants. HBIG (200 IU per dose) was injected intramuscularly to each infant within 3 h after delivery. Infants were immunized with 5 pg HBsAg per dose, and 2 pg HBsAg per dose in groups I and II, respectively. In both groups, the immunization protocol consisted of four intramuscular injections, at the age of 2 days and 1,2 and 12 months. Follow-up and laboratory tests Blood samples were drawn from umbilical veins of the infants at birth prior to immunization, and venous blood samples were taken again at 4,6, 12 and 13 months of age. Additional samples were obtained at 2 and 3 years of age. Samples were tested for HBsAg and antibody to HBsAg (anti-HBs) by RIA (Ausria-Abbott, Ausab-Abbott Kit). Anti-HBs titers were expressed in milliinternational units/ml (mIU/ml). A historical control group was constituted consisting of 34 infants of HBsAg carrier Int J Gynecol Obstet 32
mothers (born during May 1984 to January 1985) who failed to enter the immunization program due to misunderstanding of the parents . Statistical method The geometric mean was used to describe the average individual titer. The differences between groups were tested for statistical significance by x2-test and the Student’s t-test for discrete observation or analysis of variance for continuous data. The protective efficacy (PER) was assessed with reference to the historical control group. It was defined as follows (AR = attack rate): AR controls - AR vaccinated group x loo AR controls Results
Between March 1986 and September 1987, the 60 infants who participated in the immunization program were followed for 13 months; 6 infants in group I and 2 infants in group II, respectively, were lost to follow-up after 1 month of age. The historical control group Thirty-four infants of HBsAg positive mothers, were seen from the age of l-12 months. Eleven (84.6%) of the 13 infants born to HBeAg positive mothers were HBsAg positive, in contrast to 4 (19%) of the 21 infants born to HBeAg negative mothers. Vaccinated groups Before the immunizations, blood samples were taken from umbilical veins for HBsAg detection. Twenty-six (43.3%) were found to be positive. At 13 months of age, the HBsAg carrier rate was 8.3% (2/24) in group I and 7.6% (2/28) in group II. These infected infants of both groups had antigenemia at 6 months of age and became chronic HBV carriers. The anti-HBs level of these infected infants in both groups was below 50 mIU/ml
Low dosage of HBV immunization Table I.
Seroconversion rate in infants of 5 pg and 2 pg vaccines.
Study groups
% seroconversion rate(n) at the age of 4 months
I (5 Pg) (n = 30) II (2 Pg) (n = 30)
6 months
12 months
13 months
82.70 (23)
91.7 (24)
91.7 (24)
100 (25)
89.3 (28)
88.9 (27)
92.7 (28)
> 0.2
> 0.5
> 0.7
> 0.8
95.5 (22)
P values
at 4 months of age (2 months following the three injections). There was no correlation between the development of persistent HBsAg and the initial presence of HBsAg in the umbilical veins. The protective efficacy rates (PER) among these high risk infants were 90.18% and 91.01% in group I and The anti-HBs group II, respectively. positivity rate or seroconversion rate (SR) in both groups at 4, 6, 12 and 13 months of age are shown in Table I. There was no significant difference in the SR and PER of both groups. Anti-HBs geometric mean titers of infants at 4, 6, 12 and 13 months of age in both groups are shown in Table II. The level of antibody titers in group II with low dose (2 pg), were lower than the group I infants with standard dose (5 pg) (P < 0.0005). The minimal level of antibody response in this study for a small dose of vaccine was 38.25 mIU/ml, higher than the protective level (10 mIU).
Table II.
Discussion Combined passive-active immunization had been proven to be highly efficient in preventing transmission of HBV from carrier mothers to their infants [10,13-151. However, the high cost of HBV immunization in developing countries has limited its use for high risk infants. Simply stated, many countries in endemic areas cannot afford HBV immunization unless the current prices of vaccine are considerably lower. The ability to reduce per capita by dosage reduction represents another approach to cost containment. Our study showed no difference in the anti-HBs seroconversion rate and PER between two groups of vaccinated infants with differing vaccine doses. At 13 months of age, the seroconversion rate exceeded 90% in both groups. The increase in geometric mean titers of antiHBs between 6 and 12 months was observed
Geometric mean of anti-HBs titer (mIU/ml) in infants of 5 pg and 2 pg vaccines. P value < 0.0005.
Study groups
I (5 w) (n = 30) II (2 ccg) (n = 30)
355
Geometric mean titers (mIU/ml) of anti-HBs at age of (X f S.D.) 4 months
6 months
12 months
13 months
111.30 + 2.691
123.54 f 3.090
188.93 f 3.388
526.39 2 1.479
75.95 f 1.955
56.83 + 3.235
116.36 f 3.981
371.47 f 2.691
Clinical and Clinical Research
356
Theppisai et al.
in both vaccinated groups without boostering. This may be explained by the hypothesis that some infants had natural booster as a result of infection due to contact with HBV in the absence of or with a very short virus replication. Therefore, they remained HBsAg negative with an increase of anti-HBs level. This phenomenon was also observed in our previous study [ 161 which was similar to a report from Senegal [17]. Although the HBV vaccine containing 2 pg of HBsAg per dose induced lower anti-HBs titers than standard dose of vaccine, anti-HBs titer was sufficient to sustain a high level of protection (> 10 mIU/ml). This finding provides evidence that immune response in infants to the low dosage of vaccine was satisfactory and no significant loss of immunogenicity occurred within 13 months. The HBsAg carrier rates in both study groups were similar. All infected infants had the anti-HBs level below 50 mIU/ml following the third injection (4 months of age) and developed antigenemia at 6 months of age. This finding suggests that these infants were poor responders or non-responders to the vaccine, and that they became subceptible to HBV infection from their carrier mothers after the disappearance of HBIG. This may explain why these infants failed hepatitis B immunization. In order to achieve high PER, all vaccinated infants should be tested for anti-HBs titers l-2 months after the third vaccination. Additional doses of vaccine should be given immediately to those who have anti-HBs level below 50 mIU/ml. The overall immune response rate was over 90% and 4-6070 of them had absent or poor antibody responses [11,18,19]. However, the additional doses of vaccine or revaccination produced adequate antibody in only 30-50% of non-responders or poor-responders [20]. This is another reason why a number of the high-risk infants failed hepatitis B immunization. The high percentage of HBsAg positivity in the umbilical cord blood of infants born to HBsAg and HBeAg positive mothers does not Int J Gynecol Obstet 32
indicate that transmission has already occurred in utero. The HBsAg in the cord blood was not detected in all of HBsAg infected infants. The absence of correlation between HBsAg in cord blood and the subsequent development of antigenemia has been previously described [21J. The presence of HBsAg in cord blood may be due to the leakage of maternal blood via the placenta during delivery or the contamination of maternal blood during the collection. For more reliable results, it is important to draw the blood directly from the neonate to be tested. The present study provides evidence that HBV vaccine containing 2 I.cgof HBsAg per dose may be used without significant loss of immunogenicity compared to the current 5 pg per dose of vaccine. This is one way of economizing on vaccines as well as reducing expenses. The cost saving on a national scale is obvious. In addition, the infants who are poor responders or non-responders to three doses of vaccines should receive the additional doses of vaccine or revaccination. References Chainuvati T, Viranuvati V, Pongpipat D: Relationship of hepatitis B antigen in cirrhosis and hepatoma in Thailand. Gastroenterology 68: 1261, 1975. Bunyaratvej S, Rochanawutanon M, Chaimuangraj S: Hepatitis B surface antigen in liver tissue and primary liver carcinoma in Thailand. J Med Assoc Thailand 62: 414,1979. Bunyaratvej S, Meenakanit V, Tantachamrun T, Srinawat P, Susilaworn P, Chongchitnan N: Nationwide survey of major liver diseases in Thailand analysis of 3305 biopsies as to year-end 1978. J Med Assoc Thailand 64: 430, 1981. Punyagupta S, Olson LC, Harinasuta U, Akarawong, K, Varawidhya W: The epidemiology of hepatitis B antigen in a high prevalence area. Am J Epidemio197: 349, 1973. Thongcharoen P, Panpatana P, Wasi C et al: The incidence of hepatitis B surface antigen in tropical infections and liver diseases in Thailand. J Med Assoc Thailand 59: 546, 1976. Stevens, CE, Beasley RP, Taui J, Lee WC: Vertical transmission of hepatitis B antigen in Taiwan. N Engl J Med292: 771, 1975. Beasley RP: Hepatitis B virus as the etiologic agent in hepatocellular carcinoma epidemiologic considerations. HepatologyZ(suppl): 21, 1982.
LOW dosage of HBV immunization 8
9
10
11
12
13
14
15
Szmuness W: Hepatocellular carcinoma and the hepatitis B virus: evidence for a causal association. Prog Med Viral 24: 40, 1978. Theppisai U, Chiewsilp P, Bunyaratvej S, Siripoonya P, Varawidhya W: Hepatitis B surface antigen in asymptomatic carrier mothers and vertical transmission of hepatitis B virus. J Med Assoc Thailand 67(Supp12): 90, 1984. Theppisai U, Chiewsilp P, P: A comparison between and active immunization transmission of hepatitis B
Thanuntaseth C, Siripoonya the efficacy of passive-active for prevention of perinatal virus. J Med Assoc Thailand
70: 459, 1987. Szmuness W, Stevens CE, Zang EA. Harley EJ, Kellner A: A controlled clinical trial of the efficacy of the hepatitis B vaccine (Heptavax B): a final report. Hepatology I: 377, 1981. Desmyter J, Colaert J, De Groote G et al: The Leuven renal transplantation collaborative group: Efficacy of heat-inactivated hepatitis B vaccine in hemodialysis
16
17
18 19
20
are chronic carriers of HBsAg and HBeAg by administration of hepatitis B vaccine and hepatitis B immunoglobulin. Lancet 2: 921, 1984. Theppisai U, Thanuntaseth C, Chiewsilp P, Siripoonya P: Long-term immunoprophylaxis of hepatitis B surface antigen carrier in infants born to hepatitis B surface antigen positive mothers using plasma derived vaccine. Asia Oceania J Obstet Gynaecol (in press). Coursaget P, Yvonnet B, Chotard J et al: Seven-year study of hepatitis B vaccine efficacy in infants from an endemic area (Senegal). Lancet 2: 1143, 1986. Barin, F, Goudeau A, Denis F et al: Immune response in neonates to hepatitis B vaccine. Lancet I: 251, 1982. Dienstag JL, Werner BG, Polk BF et al: Hepatitis B vaccine in health care personel: safety, immunogenicity and indicators of efficacy. Ann Intern Med 101: 34, 1984. Hadler SC, Francis DP, Maynard JE et al: Long-term immunogenicity and efficacy of hepatitis B vaccine in homosexual men. N Engl J Med 315: 209, 1986. Lee AKY, Ip HMP, Wong VCW: Mechanisms of mater-
patients and staff. Lancet 2: 1323, 1983. Beasley RP, Hwang LY, Lee GC et al: Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 2:
21
1099, 1983. Lo KJ, Tsai YT, Lee SD, et al: Combined passive and active immunization for interruption of perinatal transmission of hepatitis B virus in Taiwan. Hepato-gastroen-
Address for reprints:
tero132: 65, 1985. Wong VCW, Ip HMH, Reesink HW, Nco Lelie P, Reerink-Brongers EE, Young CY, Ma HK: Prevention of the HBsAg carrier state in new born infants of mothers who
357
nal-fetal transmission 138: 668,1978.
of hepatitis
B virus.
J Infect
Dis
U. Theppisai Department of Obstetrics and Gynecology Rnmathibodi Hospital M&idol University Bangkok 10400 Thailand
ClinicalandClinicalResearch
Int. J. Gynecol. Obstet., 1990,32: 353-357 International Federation of Gynecology and Obstetrics
Prevention of hepatitis B infection in infants born to hepatitis B carrier mothers: low dosage vaccination U. Theppisai”,
C. Thanuntaseth”,
P. Chiewsilpb
and P. Siripoonya”
Departments of YObstetrics and Gynecology, bPathology and =Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400 (Thailand) (Received February 24th, 1989) (Revised and accepted May 3Oth, 1989)
Abstract
Two groups of newborn infants born to HBeAg positive carrier mothers were given HBIG (200 IU) immediately after birth. Subsequently, at age 2 days and at 1, 2 and 12 months, the first group received 5 pg and the second group 2 pg of HBV vaccines. There was no significant difference in the anti-HBs seroconversion rate (SR), and the protective efficacy rate (PER) at the age of 13 months in either group. The SR and PER of group I were 91.7% and 90.18%, and group II were 92.9% and 91.01%, respectively. Although the significant differences were observed in the geometric mean titers of anti-HBs in group I (526.3 mIU/ml) and group II (371.4 mIU/ml), both were above the protective level. The immune responses to the reduced dosage of HBV vaccines are satisfactory in preventing HBV in the newborn infants of HBeAgpositive carrier mothers.
Keywords: Hepatitis B virus; Hepatitis B vaccine; Hepatitis B surface antigen; Hepatitis B e antigen; Antibody to hepatitis B surface antigen. Introduction
In Thailand, the association of hepatitis B 0020-7292/90/$03.50 @ 1990 International Federation of Gynecology and Obstetrics
Published and Printed in Ireland
(HBV) with chronic hepatitis, cirrhosis and hepatocellular carcinoma has been well documented [l-3]. The prevalence of hepatitis B surface antigen (HBsAg) in three separate studies conducted in different groups of normal population yielded a high carriage rate (5-10%) [4--51. Transmission of HBV from carrier mothers to their infants is considered the most important means of transmitting HBV infection in most endemic areas [6--81. Maternal transmission occurs during labor and delivery [9]. One study reported 34% of infants born of carrier mothers developed HBsAg. Hepatitis B e antigen (HBeAg) positive carrier mothers are more likely to transmit HBV to their newborn infants than those who are HBeAg negative [lo]. Mother to infant transmission has been documented in 84.6% of HBeAg positive mothers, in contrast to 19% in HBeAg negative mothers. HBV immunization currently represents the only way to interrupt the transmission of HBV infection from carrier mothers. Safe and effective hepatitis vaccines have been available for several years [ 11,121. In many endemic areas, the widespread use of HBV vaccines is limited by their cost. Decreasing the antigen content per dose may allow a reduction in cost. The purpose of this study was to assess the immunogenicity and efficacy of a reduced dose of vaccine with reference to the standard dose in a population of neonates at risk. virus
Clinical and Clinical Research
354
Theppisai et al.
Materials and methods
Since December 1983, all pregnant women attending the antenatal clinic of Ramathibodi Hospital have been routinely screened for HBsAg by reverse passive hemagglutination test (RPHA). A total of 6.7% of the mothers were HBsAg positive. Of these, 41.2% were also HBeAg positive by RIA [lo] (AbbottHBe). From March 1986 to September 1986, 60 newborn infants from HBeAg positive carrier mothers were randomized to enter the immunization program. They were divided into two groups (1,II). Each group was composed of 30 infants. The following schedule and vaccines were used: HBV vaccine, Hevac B Pasteur vaccines (plasma derived vaccines) contained 5 pg and 2 pg of HBsAg per dose; hepatitis B immunoglobin (HBIG), anti-hepatitis B specific immunoglobin (Centre National de Transfusion Sanguine, France) containing 200 IU of antibody specific to hepatitis B surface antigen (anti-HBs) per ml. Active and passive immunizations were given to both groups of infants. HBIG (200 IU per dose) was injected intramuscularly to each infant within 3 h after delivery. Infants were immunized with 5 pg HBsAg per dose, and 2 pg HBsAg per dose in groups I and II, respectively. In both groups, the immunization protocol consisted of four intramuscular injections, at the age of 2 days and 1,2 and 12 months. Follow-up and laboratory tests Blood samples were drawn from umbilical veins of the infants at birth prior to immunization, and venous blood samples were taken again at 4,6, 12 and 13 months of age. Additional samples were obtained at 2 and 3 years of age. Samples were tested for HBsAg and antibody to HBsAg (anti-HBs) by RIA (Ausria-Abbott, Ausab-Abbott Kit). Anti-HBs titers were expressed in milliinternational units/ml (mIU/ml). A historical control group was constituted consisting of 34 infants of HBsAg carrier Int J Gynecol Obstet 32
mothers (born during May 1984 to January 1985) who failed to enter the immunization program due to misunderstanding of the parents . Statistical method The geometric mean was used to describe the average individual titer. The differences between groups were tested for statistical significance by x2-test and the Student’s t-test for discrete observation or analysis of variance for continuous data. The protective efficacy (PER) was assessed with reference to the historical control group. It was defined as follows (AR = attack rate): AR controls - AR vaccinated group x loo AR controls Results
Between March 1986 and September 1987, the 60 infants who participated in the immunization program were followed for 13 months; 6 infants in group I and 2 infants in group II, respectively, were lost to follow-up after 1 month of age. The historical control group Thirty-four infants of HBsAg positive mothers, were seen from the age of l-12 months. Eleven (84.6%) of the 13 infants born to HBeAg positive mothers were HBsAg positive, in contrast to 4 (19%) of the 21 infants born to HBeAg negative mothers. Vaccinated groups Before the immunizations, blood samples were taken from umbilical veins for HBsAg detection. Twenty-six (43.3%) were found to be positive. At 13 months of age, the HBsAg carrier rate was 8.3% (2/24) in group I and 7.6% (2/28) in group II. These infected infants of both groups had antigenemia at 6 months of age and became chronic HBV carriers. The anti-HBs level of these infected infants in both groups was below 50 mIU/ml
Low dosage of HBV immunization Table I.
Seroconversion rate in infants of 5 pg and 2 pg vaccines.
Study groups
% seroconversion rate(n) at the age of 4 months
I (5 Pg) (n = 30) II (2 Pg) (n = 30)
6 months
12 months
13 months
82.70 (23)
91.7 (24)
91.7 (24)
100 (25)
89.3 (28)
88.9 (27)
92.7 (28)
> 0.2
> 0.5
> 0.7
> 0.8
95.5 (22)
P values
at 4 months of age (2 months following the three injections). There was no correlation between the development of persistent HBsAg and the initial presence of HBsAg in the umbilical veins. The protective efficacy rates (PER) among these high risk infants were 90.18% and 91.01% in group I and The anti-HBs group II, respectively. positivity rate or seroconversion rate (SR) in both groups at 4, 6, 12 and 13 months of age are shown in Table I. There was no significant difference in the SR and PER of both groups. Anti-HBs geometric mean titers of infants at 4, 6, 12 and 13 months of age in both groups are shown in Table II. The level of antibody titers in group II with low dose (2 pg), were lower than the group I infants with standard dose (5 pg) (P < 0.0005). The minimal level of antibody response in this study for a small dose of vaccine was 38.25 mIU/ml, higher than the protective level (10 mIU).
Table II.
Discussion Combined passive-active immunization had been proven to be highly efficient in preventing transmission of HBV from carrier mothers to their infants [10,13-151. However, the high cost of HBV immunization in developing countries has limited its use for high risk infants. Simply stated, many countries in endemic areas cannot afford HBV immunization unless the current prices of vaccine are considerably lower. The ability to reduce per capita by dosage reduction represents another approach to cost containment. Our study showed no difference in the anti-HBs seroconversion rate and PER between two groups of vaccinated infants with differing vaccine doses. At 13 months of age, the seroconversion rate exceeded 90% in both groups. The increase in geometric mean titers of antiHBs between 6 and 12 months was observed
Geometric mean of anti-HBs titer (mIU/ml) in infants of 5 pg and 2 pg vaccines. P value < 0.0005.
Study groups
I (5 w) (n = 30) II (2 ccg) (n = 30)
355
Geometric mean titers (mIU/ml) of anti-HBs at age of (X f S.D.) 4 months
6 months
12 months
13 months
111.30 + 2.691
123.54 f 3.090
188.93 f 3.388
526.39 2 1.479
75.95 f 1.955
56.83 + 3.235
116.36 f 3.981
371.47 f 2.691
Clinical and Clinical Research
356
Theppisai et al.
in both vaccinated groups without boostering. This may be explained by the hypothesis that some infants had natural booster as a result of infection due to contact with HBV in the absence of or with a very short virus replication. Therefore, they remained HBsAg negative with an increase of anti-HBs level. This phenomenon was also observed in our previous study [ 161 which was similar to a report from Senegal [17]. Although the HBV vaccine containing 2 pg of HBsAg per dose induced lower anti-HBs titers than standard dose of vaccine, anti-HBs titer was sufficient to sustain a high level of protection (> 10 mIU/ml). This finding provides evidence that immune response in infants to the low dosage of vaccine was satisfactory and no significant loss of immunogenicity occurred within 13 months. The HBsAg carrier rates in both study groups were similar. All infected infants had the anti-HBs level below 50 mIU/ml following the third injection (4 months of age) and developed antigenemia at 6 months of age. This finding suggests that these infants were poor responders or non-responders to the vaccine, and that they became subceptible to HBV infection from their carrier mothers after the disappearance of HBIG. This may explain why these infants failed hepatitis B immunization. In order to achieve high PER, all vaccinated infants should be tested for anti-HBs titers l-2 months after the third vaccination. Additional doses of vaccine should be given immediately to those who have anti-HBs level below 50 mIU/ml. The overall immune response rate was over 90% and 4-6070 of them had absent or poor antibody responses [11,18,19]. However, the additional doses of vaccine or revaccination produced adequate antibody in only 30-50% of non-responders or poor-responders [20]. This is another reason why a number of the high-risk infants failed hepatitis B immunization. The high percentage of HBsAg positivity in the umbilical cord blood of infants born to HBsAg and HBeAg positive mothers does not Int J Gynecol Obstet 32
indicate that transmission has already occurred in utero. The HBsAg in the cord blood was not detected in all of HBsAg infected infants. The absence of correlation between HBsAg in cord blood and the subsequent development of antigenemia has been previously described [21J. The presence of HBsAg in cord blood may be due to the leakage of maternal blood via the placenta during delivery or the contamination of maternal blood during the collection. For more reliable results, it is important to draw the blood directly from the neonate to be tested. The present study provides evidence that HBV vaccine containing 2 I.cgof HBsAg per dose may be used without significant loss of immunogenicity compared to the current 5 pg per dose of vaccine. This is one way of economizing on vaccines as well as reducing expenses. The cost saving on a national scale is obvious. In addition, the infants who are poor responders or non-responders to three doses of vaccines should receive the additional doses of vaccine or revaccination. References Chainuvati T, Viranuvati V, Pongpipat D: Relationship of hepatitis B antigen in cirrhosis and hepatoma in Thailand. Gastroenterology 68: 1261, 1975. Bunyaratvej S, Rochanawutanon M, Chaimuangraj S: Hepatitis B surface antigen in liver tissue and primary liver carcinoma in Thailand. J Med Assoc Thailand 62: 414,1979. Bunyaratvej S, Meenakanit V, Tantachamrun T, Srinawat P, Susilaworn P, Chongchitnan N: Nationwide survey of major liver diseases in Thailand analysis of 3305 biopsies as to year-end 1978. J Med Assoc Thailand 64: 430, 1981. Punyagupta S, Olson LC, Harinasuta U, Akarawong, K, Varawidhya W: The epidemiology of hepatitis B antigen in a high prevalence area. Am J Epidemio197: 349, 1973. Thongcharoen P, Panpatana P, Wasi C et al: The incidence of hepatitis B surface antigen in tropical infections and liver diseases in Thailand. J Med Assoc Thailand 59: 546, 1976. Stevens, CE, Beasley RP, Taui J, Lee WC: Vertical transmission of hepatitis B antigen in Taiwan. N Engl J Med292: 771, 1975. Beasley RP: Hepatitis B virus as the etiologic agent in hepatocellular carcinoma epidemiologic considerations. HepatologyZ(suppl): 21, 1982.
LOW dosage of HBV immunization 8
9
10
11
12
13
14
15
Szmuness W: Hepatocellular carcinoma and the hepatitis B virus: evidence for a causal association. Prog Med Viral 24: 40, 1978. Theppisai U, Chiewsilp P, Bunyaratvej S, Siripoonya P, Varawidhya W: Hepatitis B surface antigen in asymptomatic carrier mothers and vertical transmission of hepatitis B virus. J Med Assoc Thailand 67(Supp12): 90, 1984. Theppisai U, Chiewsilp P, P: A comparison between and active immunization transmission of hepatitis B
Thanuntaseth C, Siripoonya the efficacy of passive-active for prevention of perinatal virus. J Med Assoc Thailand
70: 459, 1987. Szmuness W, Stevens CE, Zang EA. Harley EJ, Kellner A: A controlled clinical trial of the efficacy of the hepatitis B vaccine (Heptavax B): a final report. Hepatology I: 377, 1981. Desmyter J, Colaert J, De Groote G et al: The Leuven renal transplantation collaborative group: Efficacy of heat-inactivated hepatitis B vaccine in hemodialysis
16
17
18 19
20
are chronic carriers of HBsAg and HBeAg by administration of hepatitis B vaccine and hepatitis B immunoglobulin. Lancet 2: 921, 1984. Theppisai U, Thanuntaseth C, Chiewsilp P, Siripoonya P: Long-term immunoprophylaxis of hepatitis B surface antigen carrier in infants born to hepatitis B surface antigen positive mothers using plasma derived vaccine. Asia Oceania J Obstet Gynaecol (in press). Coursaget P, Yvonnet B, Chotard J et al: Seven-year study of hepatitis B vaccine efficacy in infants from an endemic area (Senegal). Lancet 2: 1143, 1986. Barin, F, Goudeau A, Denis F et al: Immune response in neonates to hepatitis B vaccine. Lancet I: 251, 1982. Dienstag JL, Werner BG, Polk BF et al: Hepatitis B vaccine in health care personel: safety, immunogenicity and indicators of efficacy. Ann Intern Med 101: 34, 1984. Hadler SC, Francis DP, Maynard JE et al: Long-term immunogenicity and efficacy of hepatitis B vaccine in homosexual men. N Engl J Med 315: 209, 1986. Lee AKY, Ip HMP, Wong VCW: Mechanisms of mater-
patients and staff. Lancet 2: 1323, 1983. Beasley RP, Hwang LY, Lee GC et al: Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 2:
21
1099, 1983. Lo KJ, Tsai YT, Lee SD, et al: Combined passive and active immunization for interruption of perinatal transmission of hepatitis B virus in Taiwan. Hepato-gastroen-
Address for reprints:
tero132: 65, 1985. Wong VCW, Ip HMH, Reesink HW, Nco Lelie P, Reerink-Brongers EE, Young CY, Ma HK: Prevention of the HBsAg carrier state in new born infants of mothers who
357
nal-fetal transmission 138: 668,1978.
of hepatitis
B virus.
J Infect
Dis
U. Theppisai Department of Obstetrics and Gynecology Rnmathibodi Hospital M&idol University Bangkok 10400 Thailand
ClinicalandClinicalResearch