乙型肝炎血源疫苗与卡介苗的联合应用

本文观察HBsAg阳性孕妇77例,其新生儿生后当天接种乙肝疫苗,次日接种卡介苗;同期HBsAg阴性孕妇的新生儿8,289例,单接种卡介苗。3个月时结核菌素试验阳转率分别为92.2％、93.4％。卡介苗在乙肝疫苗后接种无干扰作用。     

Hepatitis B vaccine: further studies in children with previously acquired hepatitis B surface antigenemia.

Three doses of inactivated hepatitis B vaccine were given at 1-month intervals to 31 hepatitis B surface antigen (HBsAg)-positive Senegalese children aged between 3 and 24 months. A control group of 18 HBsAg-positive Senegalese children received diphtheria-tetanus-polio vaccine. Immunization of HBsAg-positive infants with hepatitis B vaccine was safe but inefficient. After a 12-month follow-up, the prevalence of HBsAg chronic carriers was not significantly reduced in the hepatitis B vaccine group as compared with the control group: 48.4 and 66.7%, respectively. The presence of hepatitis B antigen was found to be a major risk factor for HBsAg-positive children to develop a chronic carrier state. The risk of developing an HBsAg chronic carrier state was also related to advancing age at time of enrollment in the study.     

Seroprevalence of Hepatitis-B infection amongst Taiwanese university students 18 years following the commencement of a national Hepatitis-B vaccination program

In Taiwan, the nation-wide Hepatitis-B virus (HB) vaccination program was first launched in July 1984 and was directed to those infants born to hepatitis B surface antigen (HBsAg) carrier mothers in Taiwan. From July 1986 onwards, all infants born in Taiwan were immunized against HB. This study examined the HB-infection status amongst students at a Taiwanese university 18 years subsequent to the implementation of universal HB vaccination. A total of 1,969 new university entrants in 2005 were grouped into 1 of 3 distinct birth cohorts according to their HB-vaccination schedule (cohort-1 students born prior to July 1, 1984; cohort-3 students born subsequent to June 30, 1986) and were examined for their serum HBsAg, antibody to hepatitis B surface antigen (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc) status. Immunity arising from vaccination was defined as an anti-HBs level 10 mIU/ml. We observed a trend toward a decreasing anti-HBc-positive rate and a decreasing HBsAg carrier rate from, respectively, 26.5 and 8.7% for cohort-1 to 4.7 and 1.7% for cohort-3 students. The prevalence of students featuring seronegativity for all three HB markers increased from 12.3% for cohort-1 to 48.8% for cohort-3 individuals. Amongst the 1,695 subjects revealing seronegativity for HBsAg and anti-HBc, their anti-HBs level was analyzed according to their birth year. The prevalence of students featuring a non-protective anti-HBs level increased from 11.9% for birth-year 1984 individuals to 48.2% for birth-year 1987 students. The introduction of HB vaccine has effectively reduced the transmission of HBV infection in Taiwan, 18 years subsequent to the commencement of the universal HB-vaccination program. A "waning-off" effect of anti-HBs seropositivity acquired from the HB vaccination program has also been observed.     

Multicenter trial on the efficacy of HBIG and vaccine in preventing perinatal hepatitis B. Final report

In an attempt to interrupt perinatal transmission of hepatitis B, 92 infants born to HBsAg carrier mothers (49 to HBeAg-positive mothers, 30 to anti-HBe-positive with abnormally elevated ALT levels, and 13 to HBeAg/anti-HBe-negative mothers) received 0.5 ml/kg BW of HBIG at birth and at 1 month of age. Three IM injections of hepatitis B vaccine were given at 3, 4, and 9 months of life. All babies who were given the three doses of vaccine developed an active anti-HBs response: of these, 53 (62.3%) had antibody titers higher than 1,000 mIU/ml, 29 (34.2%) had levels between 100 and 1,000 mIU/ml, and the other three (3.5%) were below 100 mIU/ml. At the end of the 2-year follow-up, these three poor responders became anti-HBs negative, whereas the others still had antibody. All but three babies were protected by HBIG plus vaccine treatment. Two chronic HBV infections occurred within 6 months of life presumably because the babies were already infected when prophylaxis started. The third baby became an HBsAg carrier at 9 months of age in spite of a previous response to the vaccine. Simultaneous presence of HBsAg of y specificity and anti-HBs (anti-a) was still detectable at 24 months of age. The vaccine was well tolerated. Passive plus active immunization is an effective procedure for preventing perinatally transmitted HBV infection.     

Markers of hepatitis-viral infection in children born of mothers with hepatitis B

Sixty-two women suffering from hepatitis B (HB) and their newborn babies were examined by a highly sensitive radioimmunoassay (RIA). The fluorescent antibody technique was also used to examine autopsy specimens of livers of 7 fetuses, 1 stillborn, and 3 babies dying in the first days of life whose mothers during pregnancy or delivery had experienced HB. Frequent infection of babies (77.8%) was observed at high concentrations of HBsAg in mothers in labor with subsequent development of persisting HBs-antigenemia, and in half of the babies of chronic hepatitis. HBsAg was detected in the first days of life not only in the blood serum, but also in the liver tissue which may be explained by intrauterine infection. At low concentrations of HBsAg in mothers the babies were infected less frequently (26.1%) and half of them were shown to have anti-HBs in the umbilical blood and blood serum in the first days and months of life. Anti-HBc transmission from mothers was also demonstrated. In babies born to convalescents after HB in the absence of HBsAg, anti-HBs in combination with anti-HBc were determined.     

Epidemiology of hepatitis B infection in Liberian infants.

To provide background for a hepatitis B vaccine efficacy trial, sera were collected from 0- to 4-year-old Liberian infants and their mothers, on two occasions an average of 14.75 months apart, and tested for serological markers of hepatitis B virus infection. The prevalence of the hepatitis B surface antigen (HBsAg) was 2.9% in the 0- to 6-month age group and 23% in infants 3 to 4 years of age. HBsAg persisted for the 14.75-month average follow-up period in 80.8% of the infants tested. The annual incidence of development of HBsAg was 18.9% for infants less than 1 year of age and 13.6% in infants 3 to 4 years of age. Infants born to HBsAg carrier mothers had significantly higher age-specific prevalence and incidence of hepatitis B virus infection. However, it was estimated that only a minor proportion of hepatitis B infections in Liberia are derived by vertical transmission from carrier mothers.     

Screening of pregnant women and hepatitis B prophylaxis in newborns

Prevention of perinatal hepatitis B includes: (1) screening ol pregnant women for hepatitis B surface antigen, and (2) immunoprophylaxis of babies at risk. HBIG treatment seems to be of some efficacy in preventing the HBsAg carrier state while it permits passive active immunization to occur. The disadvantage of HBIG is that it confers only temporary immunity. Therefore, it infection does not occur, babies will still be susceptible to the virus when passively administered anti-HBs will no longerbe circulating. On the other hand, vaccine provides a long term but not immediate protection. Therefore the ideal approach in post-exposure prophylaxis is a combination of passive plus active immunization. The aim is to provide an immediate protection, with the HBIG, and a long term immunity, with the vaccine, to babies born to HBsAg carrier mothers.     

Markers of hepatitis B virus infection in infants born of mothers who are HBs-antigen carriers with anti-HBe present and the problems of passive immunoprophylaxis

In December, 1983 to December, 1985, blood sera of 14,603 pregnant women were tested for the detection of HBsAg carriers among them. A low level (1.1%) of HBsAg carrier state was demonstrated. HBeAg was detected in 5.2% of women-carriers of HBsAg, anti-HBe in 68.8%. The follow-up observations involved 59 babies born to the mothers HBsAg-carriers. The babies were divided into an experimental and a control group. The experimental group consisted of 22 babies who were given specific anti-HBs immunoglobulin, 37 babies of the control group did not receive this preparation. In the experimental group, 3 babies were found to be infected, all of them at the age of 9-12 months. In the control group the infection was detected in 9 babies, among them in 5 the markers of hepatitis B virus were detected at the age of 1-2 months. Based on these data, the efficacy of using anti-HBs immunoglobulin for prevention of neonatal hepatitis B is discussed.     

Quantitative analysis of HBV DNA level and HBeAg titer in hepatitis B surface antigen positive mothers and their babies: HBeAg passage through the placenta and the rate of decay in babies

It is well documented that perinatal transmission is the major cause of chronic HBV infection in China. However, the mechanisms of HBV perinatal transmission are not defined clearly. It is not known whether hepatitis B e antigen can cross the human placenta, and the rate of HBeAg decay in babies with and without HBV breakthrough has not been studied. In this study, HBV serological markers were investigated in 95 hepatitis B surface antigen positive pregnant women. These markers were also studied in the babies at birth and at the age of 6 months and 12 months. The data show that 7.4% (7/95) children were infected with HBV during the first year after birth despite receiving passive-active immunoprophylaxis with hepatitis B immune globulin and hepatitis B vaccine. The surface gene fragment of HBV DNA was cloned and sequenced following PCR amplification in 7 cases of HBsAg positive babies and their mothers. All babies had the same sequences as their mothers, although two babies also had sequences that would produce an amino acid substitution within the "a" determinant. Furthermore, we measured HBeAg titers and HBV DNA levels by using Abbott AxSYM system and LightCycler-based real-time fluorescence quantitative PCR in 54 mother-infant pairs. Thirty-three mothers were HBeAg positive, and 21 mothers were HBeAg negative. Seventy percent (23/33) of neonates from HBeAg-positive mothers were HBeAg positive at birth compared with 0% (0/21) of neonates from HBeAg negative mothers. HBeAg was present at higher titer in the birth sera of the babies with HBV breakthrough than in babies without breakthrough. HBeAg was cleared from the serum in all 19 babies without breakthrough. In 17 of these 19 babies, the HBeAg was cleared within 6 months, and in two babies clearance took 12 months. The mean serum HBV DNA level in the mothers of the 4 infants with HBV breakthrough was significantly higher than in the mothers of babies who did not become infected. In conclusion, this data suggests that HBeAg can cross the human placenta, and disappears from serum within 6 months in most babies. HBV DNA levels in hepatitis B carrier mothers are associated with the failure of HBIG and vaccine immunization, and the additional influence of transmitted HBeAg cannot be excluded.     

乙肝疫苗联合乙肝免疫球蛋白对阻断母婴垂直传播乙型肝炎病毒的临床分析

目的探讨孕妇产前用乙肝免疫球蛋白（HBIG）与乙型肝炎疫苗联合免疫阻断母婴传播的效果。方法将504例HBsAg（＋）孕妇分为A（预防组）,B（对照组）两组。A组：246名HBsAg阳性孕妇孕晚期每月分别注射基因重组型乙肝疫苗10μg、HBIG200IU（200IU/ml）,新生儿出生后采股静脉血,同时在出生后24h内注射HBIG200IU,然后在0、1、6月龄接种基因重组型乙肝疫苗,每次10μg。B组：258例产前未注射HBIG和基因重组型乙肝疫苗的HBsAg阳性孕妇,其所生新生儿在0、1、6（30μg、30μg、30μg）月龄只用基因重组型乙肝疫苗免疫。A、B两组婴儿都分别在0、3、6、9、12、24月龄静脉采血,用酶联免疫吸附试验（ELISA）检测HBV标志物,同时随访。结果A组的宫内感染率为3.25%,B组为4.16%,差异无统计学意义（χ^2=1.43,P〉0.05）。A组没有发生慢性HBV感染的婴儿,而B组中有7例婴儿发生慢性HBV感染,B组婴儿发生慢性HBV的感染率显著高于A组（χ^2=4.41,P〈0.05）。结论产前用HBIG和新生儿HBIG联合免疫可降低慢性HBV感染率,阻断宫内感染的慢性化,提高产程感染的阻断效果。     

Hepatitis B vaccine in the prevention of perinatally transmitted hepatitis B virus infections: initial report of a study in the West Midlands of England

A study was carried out to evaluate the efficacy of hepatitis B vaccine in interrupting perinatal transmission of hepatitis B virus from carrier mothers to their babies. A four-dose schedule was used. Eight of nine babies of e antigen carrier mothers became actively immune when immunisations were started within 48 hr of birth. Effectiveness was reduced if immunisation was delayed. This report includes results from a total of 32 babies, the longest period of follow-up being 2 years. The success of this scheme is comparable to that of more intensive prophylaxis of immunoglobulin either alone or combined with vaccine and should be seriously considered for the babies of all hepatitis B carrier mothers.     

Reduced doses of hepatitis B immune globulin in the prevention of perinatal transmission of hepatitis B

From October 1982 to May 1983, newborn infants of 79 hepatitis B surface antigen (HBsAg)-positive women were enrolled in a study of the efficacy of hepatitis B immune globulin (HBIG) in the prophylaxis of perinatal transmission of hepatitis B virus (HBV) infection. HBIG 0.5 ml or 0.25 ml was given to the newborn within 15 minutes of birth and at 3 and 6 months. The mother-infant pairs were followed-up every 3 months for at least 9 months. Similar observations of untreated infants were used for comparison. Among infants of hepatitis B e antigen (HBeAg)-positive carrier mothers, the HBsAg carrier rates at 3 months were similar in the 0.5-ml and 0.25-ml HBIG dose groups. At 12 months the difference--17.7% of 17, 40% of 15--did not reach statistical significance, but the differences between these rates and that of the untreated control-85.7% of 35--did. Among infants of HBeAg-negative carrier mothers, HBV infection rates in both dose groups were similar to those of untreated infants. In the treated groups at 12 months about 45% of infants of HBeAg-positive mothers and 90% of infants of HBeAg-negative mothers were still negative for HBsAg and anti-HBs. Vaccination to induce active antibody is necessary to prevent postnatal infection and chronic carriage of HBV. To reduce the cost of combined passive and active hepatitis B immunoprophylaxis in children born to HBeAg-positive carrier mothers, 0.25 ml of HBIG could be used instead of the usually recommended 0.5 ml.     

Mother-to-infant transmission of hepatitis B virus: a Chinese experience

Over 90% of infants infected with hepatitis B virus (HBV) caused by mother-to-infant transmission will evolve to carrier status, and this cannot be prevented until widespread administration of the HB vaccine and hepatitis B immune globulin (HBIG) is implemented. This prospective study of 214 infants born to HBsAg-positive mothers was carried out to determine if either perinatal or intrauterine HBV transmission could be effectively prevented with HBIG and the HB vaccine. Peripheral blood was collected from mothers and from newborns before they received HBIG and the HB vaccine, as well as at 0, 1, 7, 24, and 36 months after birth. Infants born with an ratio of signal to noise(S/N) value of >5 for HBsAg (ABBOTT Diagnostic Kit) were defined as mother-to-infant transmission cases, those with an S/N between 5 and 50 were classified as perinatal transmission cases, and those with an S/N >50 were considered intrauterine transmission cases. Mother-to-infant transmission occurred in approximately 4.7% (10/214) of the infants; the perinatal transmission and intrauterine transmission rates were 3.7% (8/214) and 0.9% (2/214), respectively. The risk of mother-to-infant transmission increased along with maternal HBeAg or HBVDNA levels. After 36 months of follow-up, all perinatal cases became HBsAg-negative, whereas all intrauterine transmission cases evolved into carrier status. These results indicate that infants infected via intrauterine transmission cannot be effectively protected by HBIG and HB vaccine.     

Immunoprophylaxis of perinatal transmission of the hepatitis B virus: efficacy of hepatitis B immune globulin and hepatitis B vaccine in a low-prevalence area

One hundred eleven newborn infants born of Spanish hepatitis B surface antigen (HBsAg) carrier mothers were consecutively assigned to one of three treatment groups. Group A was treated with three or four doses of hepatitis B immune globulin (HBIG) in one of three different schedules. Group B received one dose of hepatitis B vaccine (Hevac-B, Pasteur) at birth and at 1, 2 and 12 months. Group C was treated with the same vaccination schedule as group B and in addition received a single dose of HBIG at birth. Comparisons were made in the 85 babies who had strictly completed the immunization schedule and had been followed for at least 12 months. The three immunization protocols were equally effective, since none of the children became a chronic HBsAg carrier or developed acute symptomatic infection. There were five transient and subclinical infections among children who received only HBIG (group A), one transient infection in group B, and one in group C. There seems to be some correlation between anti-HBs levels and degree of protection, since all transient infections in group A occurred in the subgroups who did not maintain protective antibodies during the first 6 months. Although the percentage of responders in the two vaccinated groups did not differ significantly, children who received only vaccine reached higher antibody levels than those who also received HBIG. Our results suggest that any immunization schedule able to maintain anti-HBs levels during the first 6 months of life would be useful to prevent mother-to-infant transmission of the hepatitis B virus in areas where most of the carrier women are expected to be anti-HBe positive and hence relatively less infectious.     

Comparative evaluation of the immunogenicity of yeast-derived (recombinant) and plasma-derived hepatitis B vaccine in infants.

The immunogenicity of plasma-derived (HB Vax,MSD) and recombinant hepatitis B virus (Engerix B, SK&F) vaccines was evaluated in infants born to hepatitis B virus carrier mothers. The vaccination was carried out at 1 day, 1 month, and 6 months of age using 10 micrograms of the vaccine given intramuscularly. A total of 83/88 (94.3%) and 74/79 (93.6%) of the infants receiving the plasma-derived vaccine and yeast-derived vaccine showed antibody to hepatitis B surface antigen (anti-HBs). None of the maternal factors studied apart from the HBeAg positivity corellated with vaccine failure. The yeast-derived vaccine gives marginally lower antibody titre than the plasma-derived vaccine. The group-specific anti-"a" antibody was less than 10% of the total anti-HBsAg titre. It was observed that the vaccine alone without prior administration of hepatitis B immunoglobulin is effective in perinatal infection.     

A low rate of hepatitis B virus vaccine breakthrough infections in Mongolia

A nation-wide hepatitis B virus (HBV) immunization program of all newborn babies was launched in Mongolia in 1991. However, the continuation of clinical icteric viral hepatitis infections in children led to the investigation to determine whether HBV breakthrough infections were occurring and if any were due to hepatitis B surface antigen (HBsAg) mutants. Hepatitis A virus (HAV) infections accounted for most of these cases with 3% of the jaundiced children shown to have acute hepatitis B. Hepatitis B vaccine protection was 93% against HBV infection and 97% against HBV carriage. A G145A "escape mutant" was found in one HBV carrier child only. Anti-HBs levels, however, were low with 85% having titers less than 100 IU/L, 46% of whom had levels less than 10 IU/L. The results from this study demonstrate that the HBV immunization program in Mongolia provides an effective level of protection. However, continued surveillance of breakthrough infections and close monitoring of "vaccine escape" mutants is required.     

Patterns in perinatal infection with the hepatitis B virus in areas contrasted by the level of HBsAg and HBeAg carriage

In 1984-1988, the levels of HBsAg carrier state and the status of the "e"-system components in pregnant women in Moscow and in the Uzbek SSR, as well as the rate of infection with hepatitis B virus (HBV) in babies born to women carriers of HBsAg in regions with different levels of HBsAg and HBeAg carrier state were studied. The levels of HBsAg carrier state among pregnant women were different in Moscow and Uzbekistan (1.1% and 6.9%, respectively). It was noted that in female HBsAg carriers in these regions the rate of HBeAg detection differed greatly: 5.2% in Moscow and 13.9% in Uzbekistan. The frequency of perinatal infection with HBV in Moscow was 26.1%, in Uzbekistan 40.0%, the frequency of persistent carrier state of HBsAg in the infected babies of Uzbekistan was 16.0%. The possibility of formation of HBsAg persistence in babies born to women with HBsAg and anti-HBe in the blood was demonstrated. The problem of the use of specific prophylaxis measures to prevent perinatal transmission of HBV is discussed.     

Perinatal transmission of the hepatitis b virus and of the hbv-associated delta agent from mothers to offspring in northern italy

We report a prospective study on infants born to hepatitis B surface antigen (HBsAg) carrier mothers to estimate the incidence of perinatal transmission of HBV and HBV-associated delta agent in Northern Italy. The risk of infection to the infant was related to the presence of the HBe antigen-antibody system, HBV-specific DNA polymerase activity and antibody to delta in maternal sera, and to the titer of anti-HBe in babies at birth. The data of this study indicate: 1. Babies born to HBsAg carrier mothers with HBeAg in serum are at extremely high risk of acquiring HBV infection and of developing a chronic carrier state, whereas those born to anti-HBe-positive mothers are at a lower (P <.01) yet consistent risk of infection. 2. HBs antigenernia is usually prolonged and symptomatic in babies born to HBeAg–positive mothers while being self-limited and asymptomatic in babies born to anti-HBe-positive mothers. 3. DNA polymerase activity in maternal serum appears to be the most sensitive marker predicting HBV transmission to the infant since it was detected in all the HBeAg-positive mothers and also in two anti-HBe-positive mothers and in one HBeAg/anti-HBe-negative mother who transmitted infection to their babies. 4. High titers of anti-HBe (up to 1:10³) do not prevent HBV infection. 5. Vertical transmission of delta infection seems to occur only in circumstances that permit perinatal transmission of HBV infection.     

Perinatal transmission of hepatitis B virus in high-incidence countries

Hepatitis B is a serious public health problem throughout the world. Hepatitis B virus (HBV) induces acute hepatitis with a case-fatality rate of about 1%. Even more important, 5-10% of patients infected with HBV become chronic carries and about 25% of these will die due to cirrhosis and hepatocellular carcinoma. The reservoir of HBV chronic carriers in the world is estimated at more than 200 million people and 80% of them reside in Asia and the western Pacific. In high-incidence areas, such as south-east Asia, perinatal transmission of HBV from carrier mothers to newborns appears to be the most important factor for the high prevalence of HBV infection and 70-90% of infants born to HBsAg/HBeAg-positive mothers become chronic carriers. Three possibilities of transmission of HBV from carrier mothers to newborns are suggested: (a) transplacental transmission in utero - it was estimated that such transmission occurred in 5-15% of newborns; (b) transmission during delivery, which is considered the main mode of perinatal transmission; (c) postnatal transmission from mother to newborn, which is not common. HBeAg is the main maternal factor in determining whether infection of newborns will occur; the expression of this antigen seems to be determined genetically. Recently it has shown that immunoprophylaxis is highly effective in preventing the development of the carrier state in infants born to HBsAg/HBeAg-positive mothers. Only 5-10% of high-risk infants are not protected by vaccination. If it becomes possible to immunize the entire world population including all babies born to carrier mothers at birth, and if our knowledge of the mechanisms of perinatal transmission of HBV is accurate, the carriers and acute cases of HB ought to disappear in two to three generations.     

Characterization of cell mediated immune responses to the hepatitis B core protein in man.

Eight donors immune to hepatitis B (HB) after natural infection were studied for their cell-mediated immune response to hepatitis B core (HBc) protein in vitro. Significant specific activation was observed in highly purified peripheral blood lymphocytes and T cells from these donors after 5-8 days of incubation with HBc protein. This in vitro response was modulated by monocytic cells and maximal 3H-thymidine incorporation was elicited with low concentrations of the antigen (0.1-10 ng/ml). The cell-mediated immune reactivity towards HBc-protein was significantly (P less than 0.005) elevated compared to the envelope material of the virus (HBsAg) when analysed in the same donor population. In contrast, donors with plasma-derived hepatitis B vaccine induced immunity to HB exhibited only specific lymphocyte activation to HBsAg. These data indicate that the composition of immune responses conferring protection against HBV after natural infection is far more complex than after immunization with the hepatitis B vaccine. Further characterization of the cell-mediated immune response to HBc protein and its relation to protection against HBV seems warranted when strategies for new HB-vaccines are being designed.