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.     

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.     

Safety and immunogenicity of a recombinant hepatitis B vaccine

A hepatitis B vaccine produced in yeast by recombinant DNA technology was evaluated using 5-micrograms and 10-micrograms doses in a randomized trial lasting 7 months in 110 male armed forces recruits aged 17-19 years. Results were compared to those of an identical trial of a plasma-derived vaccine. No allergic reactions were observed, and the rate of mild side effects was similar to the plasma-derived vaccine. Seroconversion rates in the first month were 60% (33/55) and 67% (37/55) with the 5-micrograms and 10-micrograms doses of the recombinant vaccine, respectively. All participants seroconverted by 3 months, and none lost antibody. These results are very similar to those for plasma-derived vaccine. Comparison of titres of antibody to hepatitis B surface antigen (anti-HBs) showed a slightly higher level with the 10-micrograms than with the 5-micrograms dose of the recombinant vaccine. Geometric mean titres of anti-HBs after the booster dose were similar in the 5-micrograms and 10-micrograms dose recombinant vaccine groups (2,620 and 2,748 IU/l, respectively) and in the 5-micrograms plasma-derived vaccine group (3,591 IU/l) but significantly higher (9,227 IU/l) with the 10-micrograms dose of the plasma-derived vaccine. These results confirm the safety and immunogenicity of the recombinant vaccine, although further study is needed on the duration of immunity.     

Molecular analysis of hepatitis B virus associated with vaccine failure in infants and mothers: a case-control study in Thailand

Perinatal transmission of hepatitis B virus (HBV) has been controlled incompletely despite adequate immunoprophylaxis in infants. The aim of this study was to characterize virological factors of HBV associated with vaccine failure in Thailand. Sera of 14 infected infants (13 HBeAg‐positive and one HBeAg‐negative) with vaccine failure and their respective mothers (group M1) were tested quantitatively for HBV DNA by real‐time PCR, HBV genotypes and mutations were characterized by direct sequencing. Sera collected from 15 HBeAg‐positive (group M2) and 15 HBeAg‐negative (group M3) mothers whose infants had been vaccinated successfully served as controls. The results showed that group M1 and group M2 mothers had equal titers of HBV DNA but higher titers than group M3. All infected infants and their respective mothers had the same HBeAg status and HBV genotypes. DNA analysis in a pair of HBeAg‐negative infant and mother revealed that both were infected with an HBV precore mutant (G1896A). Escape mutants in the “a” determinant region (residues 144 and 145) were detected in two (14%) infected infants. The prevalence of BCP mutations/deletions in groups M2 and M3 was higher significantly than in group M1 (P = 0.022 and P < 0.001, respectively). In conclusion, instead of the HBeAg status, a high titer of HBV DNA in mothers was the major contributor to perinatal transmission of HBV. Escape mutants might be associated with vaccine failure in some infants. BCP mutations/deletions in mothers might contribute to the prevention of mother‐to‐infant transmission of HBV. J. Med. Virol. 84: 1177–1185, 2012. © 2012 Wiley Periodicals, Inc.     

Prevention of perinatal transmission of hepatitis B virus (HBV): a comparison of two prophylactic schedules

Perinatal transmission of hepatitis B virus (HBV) from HBsAg carrier mothers who were HBeAg+, antiHBe+, or negative for both HBe markers, was interrupted using either 4 doses of vaccine, or one dose of hepatitis B immunoglobulin (HBIG) at birth, combined with 4 doses of vaccine. In those infants who received HBIG at birth, the antiHBs titre was significantly higher at 1 and 2 months old, but at 6, 9, and 18 months old, there was no significant difference. Among the infants of carrier mothers who did not display HBeAg (i.e., were antiHBe+, or negative for both HBe markers), a transient subclinical infection would have been expected in around 10% had there been no intervention. No evidence of such infection was detected, and no difference in outcome was found between the two treatment groups. Amongst infants born to HBeAg+ carrier mothers, infection occurred in 1 out of 8 who had received HBIG and vaccine, and in 3 of 8 who had received vaccine only. The difference in outcome was not statistically significant, but the numbers analysed were small. The infections which occurred in spite of prophylaxis may be attributable to in utero infection, poor response to vaccine by the infant, or to the mother having a particularly high HBV-DNA level. HBIG given at birth to infants of HBeAg+ carrier mothers may enhance the protection of infants who are destined to be poor responders to vaccine.     

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.     

乙型肝炎疫苗长期免疫效果评价及免疫持久性研究

目的 评价我国新生儿乙型肝炎(乙肝)疫苗免疫后的长期保护效果,为乙肝防控和乙肝疫苗HepB免疫策略提供参考.方法 用横断面调查和分层整群抽样的方法,在乙肝疫苗免疫效果观察监测点收集1987-1996年出生(13～22岁)、全程接种乙肝血源疫苗的人群,以及1997-2008年出生(1 ～ 12岁)、全程接种乙肝重组酵母疫苗人群的血清样本和资料;用微粒子酶免疫法检测HBV感染指标,结合本底资料和乙肝疫苗免疫史进行分析.结果 在河北正定、广西隆安、上海黄浦、青海同德和湖南湘潭5个监测点共收集1～12岁重组酵母疫苗免疫人群样本8133例,13 ～22岁血源疫苗免疫人群样本4848例,5个监测点的HBsAg平均阳性率均显著低于本底值,疫苗总体保护效果分别为86.04％～96.14％;河北正定、青海同德和湖南湘潭的年龄分布差异无统计学意义,广西隆安和上海黄浦的结果显示19～22岁人群HBsAg阳性率偏高;Anti-HBs阳性率随免疫年龄增长而下降,重组疫苗免疫人群从1～2岁组的86.84％下降至11～12岁组的46.40％,17 ～18岁组的Anti-HBs阳性率处于较低水平,而19～22岁组出现升高;几何平均浓度(GMC) ＜10 mIU/ml(Anti-HBs阴性)的比例随着年龄增长逐渐升高,100～999.99 mIU/ml和≥1000 mIU/ml的比例随着年龄的增长呈现下降趋势.结论 血源疫苗免疫后13～ 22年、重组酵母疫苗免疫后1～12年的总体保护效果良好;不必开展加强免疫,建议加强监测18岁以上人群的Anti-HBs水平,对GMC＜10 mIU/ml者开展加强免疫.     

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.     

Low-cost hepatitis B vaccine improves uptake among self-paying health-care students.

Advisory committees recommend hepatitis B (HBV) immunization for professional and student health-care workers. However, the currently licensed vaccines are expensive, and previous surveys have shown that few students (14%) have been immunized in Canada. A low-cost immunization program was offered to health-care students in order to determine whether the effectiveness of HBV immunization could be improved by substantially reducing the vaccine cost to recipients. The immunogenicity, side effects, and 3-dose completion rate of a low-cost Korean HBV vaccine were compared with a similar U.S.-made vaccine. A total of 922 postsecondary students enrolled in 6 health-care disciplines in Ottawa, Canada were surveyed for hepatitis-B immunization status. Nonimmunized students were subsequently offered HBV vaccine at total cost of $15 (Canadian), randomly allocated to receive 3 intramuscular doses of either Korean or U.S.-made plasma-derived HBV vaccine in a double-blind fashion, surveyed about side effects, and tested for hepatitis B surface antibody seroconversion. Only 12% of the 922 surveyed students had been previously immunized when vaccine was obtainable only at high cost. However, 66% of those not immunized participated in the vaccine trial and paid the $15 fee. Hepatitis-B surface antibody seroconversion (greater than or equal to 10 sample ratio units by radioimmunoassay) occurred in 291/311 (93.6%) and 299/310 (96.5%) of recipients of 3 doses of the Korean and U.S. vaccines, respectively (P = 0.10). There were no meaningful differences in vaccine adverse effects, and 92.6% of recipients of either vaccine completed 3 doses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Response to a hepatitis B polypeptide vaccine in micelle form in a young adult population

Polypeptide micelles with relative molecular weights of 25,000 (p25) and 30,000 (gp30) daltons were prepared from native 22-nm hepatitis B surface antigen (HBsAg) particles. This p25/gp30 complex was alum-adsorbed, and three dosage levels (20 micrograms, 4 micrograms, and 0.8 micrograms) were administered at 0, 1, and 6 months to 51 human volunteers. Local and systemic reactions were clinically insignificant, and all vaccinees seroconverted, regardless of dose. As anticipated, antibody responses diminished as the dosage was reduced. Seroconversion rates and geometric mean antibody levels for the 20 micrograms dosage group were significantly better than those observed with a commercial vaccine and were comparable to those achieved after immunization with 40 micrograms of the intact 22-nm particles used to prepare the polypeptides. By 2 weeks, an anti-HBs response was elicited in 80% of the group receiving 20 micrograms of the polypeptide vaccine. This rapid response to immunization may be particularly beneficial for postexposure prophylaxis where the early development of immunity is advantageous.     

HBIG联合HBVac阻断HBV宫内感染的研究

目的探讨孕期多次联合注射乙型肝炎免疫球蛋白 (HBIG)和乙型肝炎疫苗(HBVac )阻断乙型肝炎病毒HBV)宫内感染效果.方法对30例HBsAg阳性孕妇从孕20周开始联合注射HBIG和HBVac,另23 例未行注射的HBsAg阳性孕妇作对照.采用敏感特异的套式聚合酶链反应检测孕妇及新生儿血清及外周血单个核细胞(PBMC)中HBV DNA.结果阻断组和对照组新生儿血清HBV DNA检出率分别为10%(3/30)和34.8%(8/23),二组差异显著,而PBMC中HBV DNA检出率二组无显著性差异;阻断组孕妇血清 HBV DNA水平下降率38.5 %(10/26),而对照组10.5%(2/19),差异显著, PBMC中HBV DNA水平二组无显著性差异.结论孕期多次联合注射HBIG 和 HBVac 可有效降低孕妇体内HBV DNA水平,从而降低HBV宫内感染率,但对孕妇PBMC中 HBV 影响不大, 并不降低新生儿 PBMC 中HBV DNA的检出率.     

不同剂量乙肝疫苗与HBIG联合免疫阻断HBV母婴传播的效果对比

目的 探讨10 μg和20 μg乙肝疫苗与HBIG联合免疫阻断HBV母婴传播的效果.方法 124例HBsAg阳性孕妇所生的婴儿随机分为两组,即10 μg乙肝疫苗组和20 μg乙肝疫苗组.婴儿于出生6h内及30 d分别注射200 IU HBIG,同时分别于出生24 h内、1个月及6个月注射3次10 μg或20 μg重组酵母乙肝疫苗.检测婴儿出生时以及1岁时血清HBV标志物.结果 两组新生儿血清HBsAg、HBeAg及抗-HBe阳性率与滴度之间差别均无统计学意义（P＞0.05）.所有新生儿血清HBV DNA水平均小于检测下限（500 U/ml）.出生12个月时,所有124例婴儿血清HBsAg和HBeAg检测结果均为阴性;血清HBV DNA水平均在检测下限以下;10 μg和20 μg乙肝疫苗组血清抗-HBs阳性率分别为90.3％和96.8％,差异无统计学意义（P＞0.05）;抗-HBs水平分别为325.5±342.2 mIU/ml和463.7±353.3 mIU/ml,后者显著高于前者（P=0.01）.而且,20 μg乙肝疫苗组产生高应答抗-HBs（＞ 100 mIU/ml）的比例显著高于10μg乙肝疫苗组（P =0.035）.结论 20 μg乙肝疫苗联合HBIG方案阻断HBV母婴传播的效果优于10 μg乙肝疫苗联合HBIG方案.     

Comparison of safety and immunogenicity of adw and ayw hepatitis b vaccines

The safety and immunogenicity of adw and ayw hepatitis B vaccines were compared in a double-blind randomized trial in Greek Air Force recruits. One hundred and ten out of 240 eligible nonimmune recruits were randomly selected and allocated to thc two vaccine treatment groups. Two 20-m?g doses 1 month apart and a third 20-m?g booster dose, at 6 months, were given intramuscularly. Severe local or general side effects were not observed. The frequency of mild side effects (local discomfort or pain, fever less than 37.5°C, and malaise) was slightly higher with the adw than with the ayw vaccine. Antibodies developed earlier and in higher titers in adw vaccinees. However, after the booster dose all ayw and all but one adw vaccinees developed anti-HBs in almost similar titers. It is concluded that both vaccines are equally safe and immunogenic after administration of two doses at a 1-month interval followed by a booster dose at 6 months.     

Recombinant-yeast-derived hepatitis B vaccine in healthy adults: safety and two-year immunogenicity of early investigative lots of vaccine

We tested the safety and long-term immunogenicity of two of the early investigative lots of a recombinant-yeast-derived hepatitis B vaccine in immunocompetent adults. Three 10-micrograms doses of recombinant hepatitis B vaccine (Merck Sharp & Dohme Research Laboratories, West Point, PA) were administered by deltoid intramuscular injection at time 0, 1, and 6 months to 65 seronegative adult health workers. Following a complete three-injection course, 98% of vaccinees acquired anti-HBs, 97% at levels greater than 10 mlU/ml, and 95% maintained such "protective" antibody levels at 1 year. At 2 years, 93% retained antibody, but only 68% had levels greater than 10 mlU/ml. In those who responded to vaccination by achieving any detectable level of antibody, the peak geometric mean titer of anti-HBs, measured at 9 months, was 741 +/- 6 mlU/ml; the geometric mean titer fell to 348 +/- 6 at 1 year and to 66 +/- 7 at 2 years. Side effects were trivial, and levels of yeast antibody, as measured by radioimmunoassay, were not changed from prevaccine levels. No serious adverse effects were encountered, and neither type B nor non-B hepatitis occurred in any vaccine. These findings demonstrate that the recombinant yeast hepatitis B vaccine is safe and immunogenic but that 10 micrograms of the early investigative lots of the recombinant vaccine is less immunogenic than 20 micrograms of the plasma-derived vaccine. Recipients of early investigative vaccine lots should be considered for booster vaccination with currently available, more immunogenic vaccine lots.     

Immunogenicity of a five-microgram dose of hepatitis B vaccine

The immunogenicity of a 5-μg dose of vaccine (H-B-Vax, MSD) was evaluated in 50 young adults (17–19 years). Results were compared to our previous studies using similarly prepared vaccines using 20 μg and 10 μg per dose with the same trial protocol in a comparable population. Seroconversion rates for the 5-μg doses of vaccine were 80% after the first dose and 98% after the second dose. The remaining participants did not develop anti-HBs in the course of the trial. These results are not significantly different from those observed in the 10-μg and 20-μg studies. The increase of anti-HBs titers was slower for the 5-μg group. High geometric mean titers were observed after booster vaccination, but lower for the 5μg (3,591 mIU/ml) than for 10 μg (9,277 mIU/ml) and 20 μg (12,975mIU/ml) doses. It is concluded that 5-μg dose of the vaccine is effectively immunogenic for young adults.     

Immunogenicity of a yeast-recombinant hepatitis B vaccine in high-risk children

Horizontal transmission of hepatitis B virus (HBV) from illicit drug users to their contacts, including young children, can be prevented by active immunization against HBV. Yeast-recombinant hepatitis B vaccines are now available for this purpose, but their potential efficacy in such high-risk contacts has not yet been evaluated. Therefore we gave 20 mcg of a recombinant yeast-derived hepatitis B vaccine to 38 children who were at high risk for HBV infection because they had been institutionalized in a community for drug users in which 8.7% of the occupants are carriers. After third dose of vaccine (at 0, 1, and 6 months), all children had anti-HBs responses with titers of 10 mIU/ml or more, with 81% showing responses greater than 1,000 mIU/ml. At 12 months, the percentage of anti-HBs-positive children was 100%, and the percentage of children with anti-HBs higher than 1,000 mIU/ml was 56%. None of the children developed HBV infection during follow-up. Hence the recombinant vaccine was immunogenic, with percentages of seroconversion and anti-HBs titers comparable with those attained in other categories of high-risk children with plasma-derived vaccines.     

Immunogenic effect of hepatitis B vaccine in children: comparison of two- and three-dose protocols

The immunogenic effect of hepatitis B vaccine was evaluated in 183 seronegative infants from Senegal. Seventy-two seronegative infants received two 5-micrograms doses of vaccine at a two-month interval and 111 seronegative infants received three 5-micrograms doses at one-month intervals. All the children had a booster dose one year after the first injection of vaccine. No difference between the two groups was observed in the seroconversion rate (93.1% and 94.6%, respectively); in the proportion of high anti-HBs titer; or in the anti-HBs geometric mean titer (82 and 92 mIU/ml, respectively). These results demonstrate that two doses of 5 micrograms of hepatitis B vaccine are sufficient in infants to obtain a high immunogenic effect.     

HBIG阻断HBV母婴垂直传播的疗效观察

目的：观察评价外源性注射HBIG对HBV母婴垂直传播的阻断效果和安全性。方法：选取2006年7月2007年7月在我院产前检查和分娩的阳性孕妇200例作为对象。根据知情同意原则,分为三组,HBIG 1组：同意孕期及产后注射HBIG者75例;HBIG 2组,同意产后注射HBIG者85例;非HBIG组不同意或因经济原因无法注射HBIG者40例。凡新生儿HBV-DNA（＋）,即表示胎儿宫内感染HBV;婴儿出生后6个月HBV-DNA（＋）,亦表示母婴垂直传播HBV。结果：孕28周时孕妇乙肝标志物各指标检测结果三组间比较,差异无统计学意义（P〉0.05）,而HBIG1组经过产前3次HBIG注射之后,HBsAg、HBeAg、HBsAb阳性率与HBIG2组和非HBIG组间比较,有显著性差异（P〈0.01,P〈0.05）。三组孕妇在孕28周和产前血清中的HBV-DNA阳性率间比较,差异无统计学意义（P〉0.05）;三组产后乳汁中HBV-DNA阳性率间比较,差异有统计学意义（P〈0.05,P〈0.01）。新生儿和6个月婴儿HBV感染率HBIG 1组〈HBIG 2组〈非HBIG组（P〈0.05,P〈0.01）。结论：肌注HBIG可对HBV母婴垂直传播的阻断效果明显,并可降低母乳喂养感染的风险,且孕晚期孕妇和新生儿均使用HBIG优于仅产后新生儿肌注。孕晚期孕妇肌注HBIG可降低HBV的传染力。     

孕期不同阶段应用HBIG阻断乙肝母婴传播效果初探

目的探讨孕期不同阶段应用HBIG阻断乙肝病毒宫内感染的效果。方法设计自孕20周起,给予乙肝孕妇每四周免疫HBIG一次,共5次。对比常用的孕晚期3次免疫方法及孕期无干预措施的乙肝孕妇,在脐血、新生儿外周血及羊膜、胎盘感染方面进行比较。结果20周免疫组新生儿宫内感染率与28周免疫组相比无明显减少,同时新生儿抗体产生率也无明显增加。但是在胎盘感染的微观方面,20周免疫组明显低于28周免疫组。两个干预组较未干预组相比宫内感染率都有明显降低。结论孕期应用HBIG阻断乙肝母婴传播可有效的减少宫内感染率;20周开始免疫和28周开始免疫相比,在临床上,未见明显的优势,但是胎盘感染的微观方面,有明显低的感染率,新生儿外周血能比脐血更准确的诊断乙肝感染情况;羊膜的感染率与胎盘相同。     

Response to hepatitis B vaccine in family members of HBsAg carriers

The family members of HBsAg carriers have an increased risk of hepatitis B virus (HBV) infection. 214 subjects from 98 families with no HBV markers were randomized to receive hepatitis B vaccine: HEVAC B (Institute Pasteur) or GCC VAC (Green Cross Corporation) at 0, 1, and 5 months. Of those who completed the course, 87.8% had an anti-HBs response of greater than 10 mIU/ml at 6 months. The response rate was similar for both sexes. There was a decrease in response rate and anti-HBs titre with age. The response rate for HEVAC B was 92.5% and GCC VAC 84.3%. The offspring had comparable response to the spouses who were not blood relatives of the index carriers, but this could be related to their younger age. Discriminant analysis showed that a higher anti-HBs titre was associated with HEVAC B, younger age, and less direct relationship with the index carrier.