Low-dose vaccination against hepatitis B in children: one-year follow-up

Six hundred forty-three children, negative for markers of hepatitis B virus (HBV) infections, were given three X 2-micrograms doses of Merck, Sharp and Dohme (MSD) plasma derived hepatitis B vaccine (H-B-Vax) at monthly intervals. Twelve months after the first dose of vaccine, antibody to hepatitis B surface antigen (anti-HBs) was detected in 89% of children by radioimmunoassay (RIA) and in 83% by enzyme immunoassay (EIA). Seroconversion rates and anti-HBs titres were significantly greater in 1-4-year-olds than in older children (p less than 0.01). Eighteen children with no anti-HBs or other markers of HBV at this time were given 10 micrograms of vaccine and tested one month later. Seventeen developed anti-HBs, 12 at levels consistent with an anamnestic response. Forty-nine HBV-marker-negative children seroconverted for antibody to hepatitis B core antigen (anti-HBc) in the 8-month period before or the 12-month period following vaccination. Forty-six of these children were positive for anti-HBs, and one has been confirmed as a chronic carrier of hepatitis B surface antigen (HBsAg). Three cases of clinical hepatitis B in children have been seen in the community since the vaccination programme began. Two of these were amongst the estimated 5% of children who were not vaccinated. The third was in a vaccinee and occurred 4 1/2 months after the last dose of vaccine.(ABSTRACT TRUNCATED AT 250 WORDS)     

国产乙型肝炎疫苗不同剂量免疫效果的研究

本文报道应用上海生物制品研究所生产的乙型肝炎(血源)疫苗对上海、山东8～11岁的血清乙肝标志均阴性的学龄儿童,随机分至5μg、10μg和 20μg三组,按0、1、6月免疫程序接种,全程后 3月(即首针后 9月)三组的 Anti-HBs阳转率分别为 94.4％、99.1％和 90.4％。GMT(几何均数滴度)RIA S/N 在107.1～140.6之间;24月时阳转率仍在90.9～96.5％之间,S/N 在89.1～118.8之间。S/N≥10 者5μg、10μg和 20μg各为 90.0％、94.0％和 86.4％,无显著性差异。     

Comparison of the immunogenicity of reduced doses of two recombinant DNA hepatitis B vaccines in New Zealand children

A group of 201 hepatitis B virus (HBV) sero-negative children 1-12 years of age received either three 2 micrograms doses of Merck Sharp and Dohme (MSD) or Smith Kline and French (SKF) recombinant DNA (rDNA) hepatitis B vaccine I.M. at monthly intervals. Each recipient was tested 4-6 weeks later for antibody to hepatitis B surface antigen (anti-HBs) by enzyme immunoassay (EIA) and radioimmunoassay (RIA). Ninety-six 4-5-year-old children, given 2 micrograms doses of a plasma-derived vaccine (MSD, H-B-Vax) I.M. at 0, 1, 2 months, were tested at the same time with the same assays for comparison. Anti-HBs responses and geometric mean titres (GMT) were significantly higher with the MSDrDNA vaccine (96% and 338.9 IU/liter) than with the SKF/r DNA vaccine (82.3% and 69.4 IU/liter). We conclude that for the protection of young children, 2 micrograms doses of the MSD rDNA hepatitis B vaccine may be used under similar circumstances in which 2 micrograms of the MSD plasma-derived vaccine was used. Further studies are needed before the other rDNA hepatitis B vaccine may be used in lower than the 10 micrograms dose recommended in children.     

Significance of isolated anti-HBc seropositivity by ELISA: implications and the role of radioimmunoassay.

Hepatitis B virus (HBV) surface antigen (HBsAg) and antibody to HBsAg (anti-HBs) are excellent markers for HBV infection and its immunity. The significance of isolated antibody to HBV core antigen (anti-HBc) seropositivity is not certain. To elucidate this, sera from 638 Chinese adult subjects, aged 18-52 years, seronegative for both HBsAg and anti-HBs, were tested for anti-HBc. Fifty-one (8%) were found to have an isolated anti-HBc seropositivity by ELISA, and all were negative for IgM-anti-HBc. The anti-HBc persisted in all subjects who attended follow-up for hepatitis B vaccination (n = 48) for a period of 8 months. These 48 subjects received 3 doses of hepatitis B vaccine (HB-VAX, 10 micrograms or 20 micrograms) at 0, 1, and 6 months: 72.9% developed a primary anti-HBs response (suggestive of a false-positive anti-HBc seropositivity), 4.2% developed an anamnestic or secondary anti-HBs response, and 22.9% did not develop an anti-HBs response. Increasing the cutoff point of the ELISA or reconfirmation with radioimmunoassay (RIA) reduced only a minor half of the false positives. This low specificity of anti-HBc ELISA/RIA, together with the high rate of anti-HBs response to hepatitis B vaccine, indicates that subjects with isolated anti-HBc seropositivity should be included in vaccination programs.     

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.     

Antibody responses of adults, adolescents, and children to a plasma-derived hepatitis B vaccine in a rural African setting

A field trial of a plasma-derived hepatitis B vaccine in five rural villages in Zambia was analyzed to determine if adults in a rural African setting respond to this vaccine as well as adults in Western countries and to determine the immunogenicity of fewer than the recommended three doses; 255 residents, including 171 who were susceptible to hepatitis B, were vaccinated. Among those who received three vaccine doses, protective levels of antibody to hepatitis B surface antigen (anti-HBs) developed in 67% of adults (ages 21 to 70 years), 87% of adolescents (ages 12 to 19 years), and 100% of children (ages 0 to 11 years). The 67% of vaccinated adults who developed anti-HBs at the protective level was lower than the 96% reported among adults receiving the same vaccine at the same dose and dosage schedule in studies in Western countries. No difference was seen in the response of those receiving two doses compared with those receiving three doses among adults and adolescents, suggesting that a two-dose regimen may be acceptable in these age groups in developing countries to reduce costs and improve compliance. Use of hepatitis B vaccine in a region where prevaccination hepatitis B serologic screening was not available did not appear to increase the number of severity of adverse reactions.     

Long-term follow-up of Hepatitis B Surface antibody levels in subjects receiving universal Hepatitis B vaccination in infancy in an area of hyperendemicity: correlation between radioimmunoassay and enzyme immunoassay

The aims of the present study were to determine (i) the long-term immunogenicity and the decay rate of hepatitis B virus (HBV) surface antibody (anti-HBs) from universal hepatitis B vaccination at infancy for a healthy population in an area of hyperendemicity and (ii) whether the anti-HBs levels measured by enzyme immunoassay (EIA) were closely correlated with those assayed by radioimmunoassay (RIA) methods during long-term monitoring. A total of 1,337 apparently healthy children (696 boys and 641 girls) who were vaccinated against HBV at infancy and monitored for anti-HBs annually from 7 to 16 years of age entered the study. Serum samples were analyzed for anti-HBs by RIA at 7 to 15 years of age and were also analyzed by EIA at 13 to 16 years of age. Antibody titers were quantified in mIU/ml by EIA as well as by the ratio of the count in the sample to the count for a negative control (S/N) by RIA. In non-boosted children, the average decay of anti-HBs from 7 to 16 years of ages indicated that approximately 20% of the geometric mean titer decays per year. There was a good correlation between serum anti-HBs levels measured by the RIA and the EIA methods (r=0.91; P<0.0001). An equation for RIA to EIA level conversion was established: log EIA titer=-0.12+ (1.31 . log RIA S/N). The anti-HBs titers measured by EIA correlate well with the S/N assayed by RIA. The annual decay rate of the log anti-HBs level may help in planning booster immunizations for hypo-responders or individuals at risk in adolescence.     

Active pre-exposure immunisation against hepatitis B virus: immunogenicity of hepatitis B vaccine in healthy Thai adults and children

The immunogenicity of plasma derived hepatitis B vaccine (Hevac B) was studied for active pre-exposure immunisation in 176 healthy volunteer adults and 162 randomised children who had no hepatitis B virus markers. All subjects received three injections of 5 micrograms of hepatitis B vaccine intramuscularly at one month intervals. Seroconversion at 2 months after the third dose of vaccine was 96.30 percent in the children and 92.00 percent in the adults with mean anti-HBs titres of 800 mlU/ml and 353 mlU/ml respectively. The difference of anti-HBs levels between these two groups was statistically significant (p less than 0.05). Female adults had exhibited higher immune response to HB vaccine than male adults but there was no seroconversion difference between boys and girls. There were no serious local or systemic side effects of hepatitis B vaccination. It was concluded that active immunisation with plasma derived hepatitis B vaccine in non-immune children and adults is highly effective without any serious side effects or complications. The prevention of horizontal transmission of hepatitis B virus should be done by vaccination in children since they have a much better immune response to hepatitis B vaccine than adults.     

Very low dose hepatitis B vaccination in the newborn: anamnestic response to booster at four years

Seventy-eight children who had received three very low doses (1 or 2 microg) of Merck, Sharp and Dohme (MSD) plasma-derived vaccine (PDV) in early infancy were followed to approximately four years of age. Of the 70 who had responded to the initial course of vaccine with measurable anti-HBs, levels had fallen to below 10 mlU/ml in 38% of subjects given 1 microg doses and in 17% of those who had been given 2 microg doses. None of the children were positive for anti-HBc. Two weeks after 2 microg dose of MSD recombinant DNA (rDNA) vaccine all subjects had more than 10 mlU/ml of anti-HBs, with 90% exceeding 1,000 mlU/ml. A response to hepatitis B vaccine in infancy is followed by an effective immunological memory for several years, even if anti-HBs falls to low levels. The rDNA hepatitis B vaccine (MSD) in 2 microg doses is an effective booster following a primary course of plasma derived vaccine.     

Hepatitis B vaccine: immunogenicity and follow-up including two year booster doses in high-risk health care personnel in a London teaching hospital

One hundred forty-four adult health care personnel (aged 18-62 years, median 33 years) considered at high risk of future HBV infection were vaccinated with a plasma-derived hepatitis B vaccine (20 micrograms HBVax at 0, 1, and 6 months) and followed-up for 2 years. Anti-HBs was present in only 6.9% prior to vaccination, and prescreening to detect this group would not have been cost-effective. At 9 months, 8.3% were nonresponders and a further 9% had anti-HBs levels less than 50 mIU/ml. Multivariate analysis showed that age was the single most important determinant of a poor response. In 47 of 52 individuals retested 2 years later, anti-HBs levels had fallen by 80% or more, and in four it had become undetectable. Response to a booster dose at this stage was excellent, with anti-HBs levels 3 months later much higher than at the end of the initial course. Additional booster doses of vaccine in two of the initial nonresponders at 14 and 22 months, respectively, also led to seroconversion. Although a significant proportion of health care workers in this study did not make a satisfactory response to the hepatitis B vaccine, later booster doses were very effective in subsequently increasing anti-HBs levels.     

Comparison of two testing methods to determine hepatitis B surface antibody response to hepatitis B vaccine among health-care workers

Because of variations in reported seroconversion rates and to compare enzyme-linked immunoassay (EIA) and radioimmunoassay (RIA) methods to assess hepatitis B vaccine response, hepatitis B surface antibody (anti-HBs) was tested in 116 of 174 high-risk hospital employees enrolled in a hepatitis B vaccine program. All individuals were vaccinated with three injections of Heptavax-B, 1.0 ml containing 20 micrograms of HBsAg intramuscularly in the deltoid. The same lot of appropriately stored vaccine was used. Of the 41 individuals tested within zero to six months postvaccination, 35 (85%) and 38 (93%) were positive by EIA and RIA, respectively. Of the 75 individuals tested 7-24 months postvaccination, 61 (81%) and 71 (95%) were positive by EIA and RIA, respectively. Results of EIA tests performed at two laboratories were similar. Of 109 individuals positive by RIA, 13 did not have protective antibody levels. In contrast, of 96 individuals positive by EIA, only one did not have a protective antibody level. RIA may be a more sensitive test for anti-HBs, but a positive EIA result correlates better with protective antibody levels.     

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.     

Diminished response to recombinant hepatitis B vaccine in homosexual men with HIV antibody: an indicator of poor prognosis

Three doses of a recombinant DNA HBV vaccine (MSD) were given to healthy male homosexuals. Seventy-eight out of 104 (77.6%) participants had detectable antibody (anti-HBs) two months after the third dose. Seroconversion occurred in only 9 out of 27 subjects (33.3%) who were anti-HIV positive compared with 69 out of 77 (89.6%) who were negative (chi 2 = 30.8; P less than .001). Fifteen of the 18 anti-HIV positive who did not mount an antibody response to the hepatitis B vaccine (anti-HBs) later progressed to persistent generalised lymphadenopathy syndrome (5), AIDS-related complex (5), and AIDS (5). Only one of the nine anti-HIV positive anti-HBs responders developed PGL (chi 2 = 10.14; P less than .005). Our results show that anti-HIV positive homosexuals are poor responders to the recombinant hepatitis B vaccine and anti-HIV positive non-responders are more likely to develop clinically apparent HIV infection.     

Nine-year follow-up study of a plasma-derived hepatitis B vaccine in a rural African setting

One hundred and one of 255 recipients of a plasma-derived hepatitis B vaccine were evaluated in 1990, 9 years after the first vaccine dose in a study in Zambia to evaluate the efficacy of one, two, or three doses. In 1983, 2 years after the first vaccine dose, antibody to the hepatitis B surface antigen (anti-HBs) had been detectable in 90 of these 101 participants (89%). In 1990, anti-HBs was still detectable in 72 of 101 (71%), and was present at a protective level ( ≥ 10 mlU ml) in 68 of 101 (67%). Although the original vaccine study elicited a protective level of antibody in a greater percentage of children and adolescents than in adults, there were no significant differences among the three groups at 9 years. (In 1990, anti-HBs was still detectable in 52 of 70 [74%] who had had no serologic markers of the hepatitis B virus in 1981, and a protective level was detected in 47 of 70 [67%].) A protective level of anti-HBs was detected in 1990 in 26 of 36 (72%) recipients of three doses and in 23 of 31 (74%) recipients of two doses; the slightly lower prevalence among recipients of one dose (19 of 34 [56%]) was not statistically significant. However, between the years 1983–1990, hepatitis B virus infections had occurred in one of 36 (3%) of those who had been vaccinated with three doses, one of 31 (3%) vaccinated with two doses, and eight of 34 (24%) of those vaccinated with one dose (P < .02 for either two or three doses compared with one dose). These data support the long-term immunogenicity and protective efficacy of a two- or three-dose regimen of the hepatitis B vaccine in a rural African setting. © 1993 Wiley-Liss, Inc.     

Field evaluation of the efficacy and immunogenicity of recombinant hepatitis B vaccine without HBIG in newborn Vietnamese infants

A study involving more than 2,000 infants was conducted in Vietnam to assess the field effectiveness and immunogenicity of recombinant hepatitis B vaccine given at birth, 1 month, 2 months, without concomitant hepatitis B immune globulin (HBIG). All received a 5 microg dose of H-B-VAX II at birth. Infants born to non-carrier mothers (Group 1; N = 1798) then received 2.5 microg doses at 1 and 2 months of age, while infants of HBeAg-negative (Group 2; N = 125) or HBeAg-positive (Group 3; N = 88) carrier mothers received 5 microg doses. No Group 1 or 2 vaccinees were infected. In Group 3, 12 (14.6%) of 82 infants did become infected (estimated efficacy 84%). 98.0-98.6% of uninfected infants who were tested for anti-HBs developed a seroprotective concentration > or = 10 IU/L. In hyperendemic Vietnam, where routine maternal screening and passive-active prophylaxis of high-risk infants with vaccine plus HBIG is not feasible, administration of vaccine alone to all newborns may control effectively HBV infection.     

The immune response of healthy Nigerian adults to small doses of hepatitis B vaccine: comparison of 10- and 20-micrograms doses

The immunogenic effect of hepatitis B vaccine (H-B-vax) was evaluated in 120 seronegative healthy Nigerians. Three doses of the vaccine were given at 0, 1, and 6 months. Serial blood samples were tested 1 month after each vaccination for hepatitis B surface antibody (anti-HBs) and antibody to hepatitis B core antigen (anti-HBc). Of 60 vaccines given 20 micrograms of the vaccine, 40% had significant anti-HBs response 1 month after the first dose, 70% after the second dose, and 91.7% after the third dose. In the 60 vaccines given 10-micrograms doses, the seroconversion rates were 35, 73.3, and 90%, respectively. It is concluded that this vaccine in 10-micrograms doses is as effective as the larger doses in producing anti-HBs. The administration of small doses would reduce the cost of large-scale vaccination programs in developing countries.     

Hepatitis B vaccination of immunosuppressed heart transplant recipients with the vaccine Hepa Gene 3 containing pre-S1, pre-S2, and S gene products

The antibody response of immunosuppressed heart transplant recipients to vaccination with the hepatitis B (HB) virus vaccine Hepa Gene 3 (HG-3), containing HB virus pre-S1, pre-S2, and S gene products, was examined. Three heart transplant recipients who had been vaccinated preoperatively against HB responded well to the vaccination. Five of 38 patients (13.2%) vaccinated postoperatively before HG-3 vaccination with the second-generation vaccine Gen-H-B-Vax-D (37 without and 1 with detectable anti-HBs response) and 3 of 24 (12.5%) without previous HB vaccination developed protective anti-HBs titers (greater than 10 U/1) after immunization with the HG-3 vaccine. The l low response rate (8/62, 12.9%) found for postoperatively vaccinated patients indicates that heart transplant recipients should be vaccinated against HB before immunosuppressive medication.Abbreviations HB hepatitis B - HG-3 Hepa gene 3     

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.     

乙型肝炎病毒母婴阻断长期效果的随访研究

目的观察乙型肝炎病毒母婴阻断长期效果,探讨HBsAg阳性孕妇生产儿童发生慢性HBV感染的相关影响因素。方法随访和收集于2004--2006年在北京地坛医院出生的HBsAg阳性母亲所生,并在出生时进行200单位乙肝免疫球蛋白（HBIG）注射和经过乙肝疫苗10μg,0、1和6个月的完整免疫接种程序的儿童静脉血,采用Abbott微粒子化学发光法检测其HBsAg、抗-HBs抗体、抗-HBc抗体,分析母婴阻断和乙肝疫苗接种的长期效果及其影响因素。结果收集和调查306名儿童年龄3—6（4．84）岁,其母亲生产时HBeAg阳性198人,HBeAg阴性92人。10（3．27％）名儿童发生慢性HBV感染。除慢性HBV感染者外,其余296名儿童,20．27％抗-HBs〈10mlU／ml;44．26％抗-HBs≥10—100mlU／ml;27．03％抗-HBs≥100～1000mlU／ml和8．45％抗-HBs≥1000mlU／m,抗-HBs保护率为79．73％（236／296）。抗-HBc阳性率为7．43％（22／296）。10例感染儿童的母亲生产时HBeAg均为阳性,HBVDNA均在10。拷贝／ml以上,其中8例超过10^8拷贝／ml。结论在进行乙肝疫苗加HBIG注射的HBV母婴传播阻断措施下,HBV母婴阻断失败和慢性H13V感染发生在HBeAg阳性和高病毒载量产妇所生婴儿,在有效阻断后仍需进行抗HBs监测并加强免疫接种。     

Quantitation of hepatitis B surface antibody by an automated microparticle enzyme immunoassay

A fully automated microparticle enzyme immunoassay, IMx AUSAB, was developed for the detection and quantitation of antibody against hepatitis B surface antigen (anti-HBs). The IMx AUSAB assay can complete 24 tests in less than 45 minutes. Anti-HBs concentrations in specimens are calculated automatically by comparison of the specimen rate to values determined from a stored standard curve. IMx AUSAB sensitivity is 2-3 mIU/ml, equivalent in sensitivity to AUSAB RIA or EIA. Specimens from blood donors, diagnostic and hospital patients, hepatitis B vaccinees, and individuals with a variety of infectious and autoimmune diseases tested in parallel by IMx AUSAB and AUSAB RIA or IMx AUSAB and EIA gave overall qualitative agreement of 97.8% (1265/1293) and 99.1% (1281/1293), respectively. The prevalence of anti-HBs ranged from 5.9% in volunteer blood donors to 47.0% of specimens from a sexually transmitted disease clinic. Most discordant specimens (18/34) were low level reactive (less than 10 mIU/ml) by AUSAB RIA, but negative by IMx AUSAB and AUSAB EIA. These specimens were also negative for antibodies to hepatitis B core antigen (anti-HBc). Six discordants were low level reactive by IMx but negative by RIA and EIA. Three of these six specimens were also reactive for anti-HBc suggesting that the IMx AUSAB reactivity resulted from the presence of low level anti-HBs. Quantitative agreement between IMx AUSAB and RIA or IMx and EIA for 106 specimens ranging in anti-HBs concentration from 1 to 30,000 mIU/ml gave linear correlation coefficients of 0.91 and 0.96, respectively. The IMx test was useful for monitoring hepatitis B vaccine response and seroconversion levels after hepatitis B infection.