Perinatal hepatitis B virus transmission in the United States. Prevention by passive-active immunization

Among infants born to women in whom sera are positive for both the hepatitis B surface antigen and the e antigen, 85% to 90% are infected with hepatitis B virus and become chronic hepatitis B surface antigen carriers. In a study to assess the effectiveness of passive-active prophylaxis (hepatitis B immune globulin and hepatitis B vaccine) of such infants, we screened 18,842 pregnant Asian-American women: 8.7% were positive for hepatitis B surface antigen and 3.0% were also positive for hepatitis B e antigen. Thus far, 113 infants have received hepatitis B immune globulin (0.5 mL at birth) and hepatitis B vaccine (three 20-micrograms doses beginning at birth or at 1 month) and have been followed up for nine to 18 months. Among these infants, 16 have become chronic carriers, an incidence of only 14.2%. All of the uninfected infants have retained high levels of antibody to surface antigen, suggesting that they have had an active immune response to the vaccine and should have long-term protection against hepatitis B virus.     

A mass vaccination program in Taiwan against hepatitis B virus infection in infants of hepatitis B surface antigen-carrier mothers

To combat hepatitis B virus (HBV) infection in Taiwan, a mass immunoprophylaxis program was launched on July 1, 1984, aiming first at prevention of chronic HBV carriage from perinatal mother-to-infant infection. In the first 15-month period, 352,721 (78%) of 450,585 pregnant women were screened for hepatitis B surface antigen (HBsAg); HBsAg was present in 62,359 (18%), with 50% of them categorized as highly infectious. Infants born to HBsAg-positive women were given 5 micrograms of a plasma-derived hepatitis B vaccine at ages 1, 5, and 9 weeks, with a booster at age 12 months. Infants of highly infectious carrier mothers received an additional 0.5 mL of hepatitis B immune globulin within 24 hours after birth. The coverage rate of the hepatitis B immune globulin was 77% in 27,375 infants born to highly infectious mothers, and that of the first, second, third, and the fourth doses of vaccine was 88%, 86%, 84%, and 71%, respectively, in infants of 55,620 carrier mothers. The reported untoward reactions to immunization were negligible. We conclude that a mass hepatitis B vaccination program is feasible in hyperendemic areas such as Taiwan; this should be a significant step toward the effective control of HBV infection in these areas.     

乙型肝炎疫苗预防效果研究

乙型肝炎是我国重大传染病,乙肝疫苗是预防和控制乙肝病毒感染的流行和传播最有效措施."九五"期间"乙肝疫苗预防效果研究"证实我国低剂量单纯乙肝血源疫苗的长期预防效果(新生儿免疫后15年内)持续为90%,新生儿完成全程免疫后无需加强免疫可有效预防乙肝病毒慢性感染而终生受益;乙肝疫苗明显具有免疫选择表面抗原基因变异株的作用;表面抗原基因变异株在未免疫携带者中主要是弱势准种;中国乙肝病毒基因型和血清型的分布有明显的地区性;我国乙肝基因工程疫苗(酵母、CHO)大面积推广使用安全、有效和可行;乙肝基因苗表面抗体阳转率和近期保护效果与相当剂量的血源疫苗效果相似;乙肝基因工程疫苗与50IU乙肝免疫球蛋白联合应用,可将母婴阻断效果提高到90%;我国目前推广乙肝疫苗的成本效益至少为135.     

Efficacy of a mass hepatitis B vaccination program in Taiwan. Studies on 3464 infants of hepatitis B surface antigen-carrier mothers

To evaluate the efficacy of the mass hepatitis B vaccination program in Taiwan in interrupting perinatal hepatitis B virus transmission, 3464 randomly selected 18-month-old infant vaccinees born to hepatitis B surface antigen-carrier mothers were recruited from 9697 eligible infants during a six-month period of the program. They were divided into ten groups according to maternal infectivity and compliance with the vaccination schedule. Serum samples were tested for hepatitis B surface antigen, antibody to hepatitis B surface antigen, and antibody to hepatitis B core antigen. In 786 infants who had highly infectious mothers and who received hepatitis B immune globulin and vaccine on schedule, the protective efficacy was about 85%. The efficacy seemed to be slightly lower in those immunized off schedule. Overall, 11% of infants still carried hepatitis B surface antigen, and 81% of the infants had antibody to hepatitis B surface antigen that exceeded 10 mIU/mL in more than 90% of them. The geometric mean titers of antibody to hepatitis B surface antigen were more than 200 mIU/mL in every group of infants. We conclude that the mass vaccination program is efficacious in preventing perinatal hepatitis B virus transmission and the chronic carrier state; most infant vaccinees have adequate levels of protective antibody at 18 months of age. This program is extremely significant in the control of hepatitis B virus infection in Taiwan.     

Protective efficacy of a recombinant DNA hepatitis B vaccine in neonates of HBe antigen-positive mothers

We have assessed the protective efficacy of a recombinant DNA hepatitis B vaccine alone in infants of women who were positive for the surface antigen and the e antigen. The infants received a 10-micrograms dose of the vaccine within 12 hours of birth and additional doses 1, 2, and 12 months later. No significant adverse reactions to vaccination were observed and the vaccine was highly immunogenic. Only 2 (3.6%) of the 55 infants followed up to 13 months became chronically infected with the hepatitis B virus, as evidenced by the persistent presence of hepatitis B surface antigen in serum samples. Without immunoprophylaxis, 65% to 90% of such infants would become chronic carriers. Immunization with a recombinant vaccine without concomitant administration of hepatitis B immunoglobulin, therefore, considerably decreased the incidence of the carrier state.     

181例全程联合免疫阻断hBV母婴传播效果观察

目的：观察乙型肝炎人免疫球蛋白与乙肝疫苗全程联合应用对乙型肝炎表面抗原（ hbsAg）携带者母亲所生的婴儿（以下指高危人群）阻断乙肝病毒（ hBV）母婴传播,提高高危人群免疫效果。方法：181例hBsAg携带者母亲分娩的婴儿,根据自愿接种的原则分成两组。观察组出生后4h内婴儿大腿前部外侧肌注乙型肝炎人免疫球蛋白100 IU,并分别于出生后24 h内、1个月和6个月三角肌肌注重组乙肝疫苗（酵母）10μg。对照组于出生后24 h内、1个月、6个月分别三角肌肌注重组乙肝疫苗（酵母）10μg。婴儿7月龄时检测hBsAg。结果：观察组血清hBsAg阳性率为4.63％,明显低于单独使用乙肝疫苗的对照组17.81％。结论：采用乙型肝炎人免疫球蛋白与乙肝疫苗全程联合应用,对阻断hBsAg携带者母亲分娩的婴儿hBV母婴传播,提高高危人群免疫效果明显。     

Perinatal transmission of hepatitis B virus.

Transmission of hepatitis B virus from carrier mothers to their infants seems most likely to occur during birth. Both cord blood and breast milk have been found to be positive (in 35% and 72% of cases respectively) for hepatitis B surface antigen (HBsAg), but they do not appear to play an important role in transmission. To control this problem high-risk women should be tested during pregnancy for HBsAg. The infants of infected women should be given several doses of hepatitis B immunoglobulin starting at birth. In less developed regions, where hepatitis B is endemic, administration of the immunoglobulin in combination with vaccine, or even the vaccine alone, may be preferable in order to provide infants with lasting protection.     

Vaccination against hepatitis B: the Chinese experience

Objective To review the implementation of mass vaccination of hepatitis B vaccine and its critical role in prevention of hepatitis B virus infection in China.
Data sources The data were mainly from PubMed, China Hospital Knowledge Database, and other popular Chinese journals published from 1980 to 2008. The search term was ＂hepatitis B vaccine＂.
Study selection Original studies conducted in China and critical reviews authored by principal investigators in the field of hepatology in China were selected.
Results Chinese investigators started to develop hepatitis B vaccine in late 1970s. The first home-made plasma-derived vaccine became available in 1986, which has been completely replaced by the domestically produced recombinant （yeast or Chinese hamster ovary cell） vaccine since 2001. China health authority recommended vaccinating all infants in 1992. From then on, China has put tremendous efforts in implementation of mass vaccination. The overall coverage of hepatitis B vaccine in infants has increased steadily and reached more than 95.0% in urban and 83.0%-97.0% in rural areas. The chronic HBV carrier rate in children 〈10 years of age decreased from 10.0% before the mass vaccination to 1.0%-2.0% in 2006, and that in general population decreased from 10.0% to 7.2%; overall, the nationwide mass hepatitis B vaccination has reduced more than 30 million of chronic HBV infections and HBV related severe sequlae.
Conclusion The Chinese successful experience in control of hepatitis B by mass vaccination offers an example for any unindustrialized country whoever is committed to control this disease.     

乙肝免疫球蛋白和乙肝疫苗联合阻断宫内感染的疗效观察

目的: 探讨不同方法阻断母婴垂直传播的效果.方法: 将120例HBsAg和(或)HBeAg阳性的孕妇分成3组,A组42例给予乙肝免疫球蛋白和乙肝疫苗治疗,B组40例给予乙肝疫苗治疗,C组38例,未给任何治疗.A组和B组均在孕20 wk时开始注射,用ELISA检测孕妇HBV血清标志物和新生儿的血清HBsAg.结果: 新生儿A组感染率为7%(3/42).B组感染率为30%(12/40).C组感染率为37%(14/38).A组HBV感染率明显低于B组与C组(P<0.01).结论: 携带乙肝病毒孕妇于孕晚期给乙肝免疫球蛋白和乙肝疫苗联合治疗可有效地降低婴儿HBV感染率,表明干预性治疗可有效阻断HBV宫内传播.     

Vertical transmission of hepatitis B virus: propositions and future directions

Chronic hepatitis B virus (HBV) infection due to vertical transmission remains a critical concern with regards to eliminating HBV infection. Implementation of hepatitis B vaccine, the foundation to prevent perinatal and horizontal transmission, has reduced the prevalence of HBV by >80%. In countries where the hepatitis B immune globulin (HBIG) is available, such as China and the United States, the administration of HBIG and hepatitis B vaccine to the infants of mothers who are positive for hepatitis B surface antigen has become a standard practice and is effective in preventing vertical transmission. Accumulating evidence on the efficacy and safety of antiviral prophylaxis during pregnancy indicates the probability of attaining the goal of the World Health Organization to eliminate hepatitis by 2030. In this review, we discuss the transmission routes, diagnostic criteria, and preventive strategies for vertical transmission. A preventive program that includes screening before pregnancy, antiviral prophylaxis during pregnancy, and postpartum immunoprophylaxis provides “perfect strategies” to eliminate vertical transmission. However, there is still a notable gap between “perfect strategies” and real-world application, including insufficient coverage of timely birth dose vaccine and the efficacy and necessity of HBIG, especially in mothers who are negative for hepatitis B envelope antigen. In particular, there is a clear need for a comprehensive long-term safety profile of antiviral prophylaxis. Therefore, feasible and cost-effective preventive strategies need to be determined across regions. Access also needs to be scaled up to meet the demands for prophylaxis and prevalence targets.     

Prevention of vertical transmission of hepatitis B. The place of routine screening in antenatal care, and the case for immunization of infants at risk

Many chronic carriers of hepatitis B virus acquire the infection from their mothers at birth; the risk is greatest if the mother either has acute hepatitis B or is a hepatitis Be antigen (HBeAg)-positive HBsAg carrier, but there is some risk also to the infants of mothers who do not carry HBeAg. At the Royal Women's Hospital, Melbourne, nearly 2% of women attending antenatal clinics are found to be carriers and, without immunization, approximately five infants per 1000 infants delivered (up to 15 infants annually) would also become carriers. Vertical transmission of hepatitis B can be prevented by a combination of passive and active immunization if infants at risk can be identified at or before birth. Routine screening for hepatitis B surface antigen in pregnant women is recommended, at least in institutions in which the patient population includes a high proportion of migrants, in whom the prevalence of hepatitis B carriage is relatively high.     

Absence of antibodies to HTLV-III in health workers after hepatitis B vaccination

A proportion of the plasma for the triply inactivated, plasma-derived hepatitis B vaccine produced in the United States is obtained from homosexual men. Because homosexual men are a high-risk group for the acquired immunodeficiency syndrome (AIDS), concern has emerged that the vaccine could harbor the AIDS agent. To evaluate this risk, we tested 15-month postvaccination serum samples for antibodies to human T-cell lymphotropic virus type III in 100 health care workers who had received inactivated hepatitis B vaccine lots made from plasma collected between 1977 and 1979 and 100 who had received placebo injections. None of the 200 health workers had serological evidence of human T-cell lymphotropic virus type III infection. These serological findings lend additional support to earlier epidemiologic and immunologic observations suggesting that hepatitis B vaccine does not transmit infection with an AIDS virus.     

Detection and significance of anti-pre S2 in patients with hepatitis B and HBsAg carriers

We studied anti-Pre S2 by ELISA incorporating a synthetic peptide corresponding to the pre S2 (120-150) sequence and a monoclonal anti-human IgG, conjugated with peroxidase in 139 patients with hepatitis B and HBsAg carriers. The positive rate was 90% inpatients with acute-hepatitis 6.7% in chronic active hepatitis and 2.5% in persistent hepatitis. No positive case was seen in the HBsAg carriers. These findings indicate that anti-pre S2 may contribute to virus clearance and early diagnosis. The coexistence of anti-pre S2 with pre-S2 antigen was found only in patients with acute hepatitis, and anti-pre S2 may be coexistent with HBeAg in acute hepatitis, whereas all HBeAg positive patients with chronic hepatitis and HBsAg carriers lacked anti-pre S2. Comparing with anti-HBc IgM, anti-HBs and anti-HBe, anti-pre S2 is an earlier antibody in humoral immune response to HBV infection during the acute phase of hepatitis.     

正常人与乙型肝炎病毒慢性携带者中乙型肝炎疫苗的血清学效果的观察

给61例正常人和33例HBV慢性携带者接种乙肝疫苗,后半年内检测了一些血清学指标。正常人接种疫苗后1,3,6个月时抗—HBs阳性率分别为27.8％,85.2％和90.1％。HBV携带者接种疫苗后6个月HBsAg滴度上升者8例,下降者4例,仅有1例抗—HBs阳性,12例HBeAg阳性者中仅有1例抗—HBe阳性。所有病例接种疫苗后无明显不良反应。结果说明本疫苗抗原性良好,但对HBsAg携带者无效。     

A six-year survey of immunogenicity and efficacy of hepatitis B vaccine in infants born to HBsAg carriers.

Although the efficacy of hepatitis B vaccine is well documented, the duration of immunity of healthy infants after vaccination is unknown. 99 infants born to hepatitis B surface antigen (HBsAg)-carrier mothers were studied and found to have positive anti-HBs (titer: greater than or equal to 10 mIU/mL) after a first injection of vaccine at the ages of 1 to 6 years. The infants were randomly divided into four groups of recipients treated with the vaccine of the National Institute of Allergy and Infectious Diseases (NIAID), U.S.A. or that of the Beijing Biological Products Research Institute (BBPRI), BBPRI vaccine in combination with hepatitis B immune globulin (HBIG) and placebo. The results showed that the protective efficacy dropped considerably after 5 years with NIAID vaccine, after 3 years with BBPRI vaccine and after 4 years with BBPRI vaccine plus HBIG. This suggests that a booster injection is needed 5 years after the first injection of NIAID vaccine, 3 years after BBPRI vaccine, and 4 years after BBPRI vaccine plus HBIG.

     

国产乙型肝炎疫苗和HBIG联合阻断乙型肝炎母婴传播效果研究

本文采用乙型肝炎疫苗和HBIG,经3种不同的联合免疫方案,对阻断乙型肝炎母婴传播的效果进行了研究。结果证明,3个组联合免疫后12个月的抗-HBs阳转率为75%～90%;抗-HBs平均浓度(mIU/ml)为32.55～42.93;阻断率为80.00%～93.3%。联合免疫的效果是满意的。     

Duration of immunogenicity and efficacy of hepatitis B vaccine in a Yupik Eskimo population

In 1981, a hepatitis B virus vaccine demonstration project was conducted in 1630 Yupik Eskimos in southwest Alaska. Levels of antibody to hepatitis B surface antigen and markers for hepatitis B virus infection in vaccinees were monitored yearly for 5 years. After 5 years of follow-up, 19% of those who initially had an immune response to vaccine of 10 sample ratio units or greater subsequently had levels of antibody to hepatitis B surface antigen lower than 10 sample ratio units. During the 5 years after the first dose of vaccine, in three responders and one person with an antibody to hepatitis B surface antigen response lower than 10 sample ratio units, antibody to hepatitis B core antigen developed, and the level of antibody to hepatitis B surface antigen was boosted. Hepatitis B surface antigen did not develop in any subjects, and none had clinical hepatitis. In the 5 years following the demonstration project, the annual incidence of hepatitis B virus infection decreased from 50 cases per 1000 population before the vaccine trial to 0.45 per 1000.     

Passive-active immunisation of neonates of HBsAg positive carrier mothers: preliminary observations

Screening of pregnant women for hepatitis B surface antigen (HBsAg) in three areas of Holland led to the identification of HBsAg carriers, 20 of whom were subsequently delivered. Within two hours after birth all infants received hepatitis B immune globulin (0.5 ml/kg body weight) and, after randomisation, hepatitis B vaccine (10 micrograms) was given either at 0, 1, and 2 months of age or at 3, 4, and 5 months of age, the latter concomitantly with DPTP vaccination. Eighteen infants complying with the protocol were followed up for at least six months. No side effects were observed after either passive or active immunisation. All infants developed high concentrations of anti-HBs antibodies; no interference of high dose passive immunisation with active immunisation was observed. Concentrations of anti-HBs at three months were significantly lower in infants given delayed active immunisation than in those given early active immunisation. These data suggest that passive-active immunisation against hepatitis B virus infection is well tolerated by neonates under 3 months of age and that both early and late active immunisation in combination with passive immunisation will result in excellent anti-HBs production.     

Detection of core antibody in hepatitis B infection.

Hepatitis B core antigen (HBcAg) is found on the decoated Dane particle and on a morphologically similar particle detected mainly in the nucleus of hepatocytes of patients with hepatitis B. HBcAg prepared from the liver of a chimpanzee infected with hepatitis B virus was used to test human serum for core antibody (anti-HBc) by complement fixation. Anti-HBc was found in serum collected from patients with hepatitis B in both the acute and convalescent stages, from carriers of hepatitis B surface antigen (HBsAg) and from patients with chronic liver or renal disease who were carriers of HBsAg. It was not found in patients with hepatitis A or infectious mononucleosis, or in healthy persons who were not carriers of HBsAg.