Immunogenicity of low doses of hepatitis B vaccine in children: a study in 650 New Zealand children

Six hundred and fifty New Zealand children from 2-12 years of age were vaccinated three times with 2 mcg intramuscular (IM) doses of Merck Sharp and Dohme plasma-derived hepatitis B vaccine (H-B-Vax), at 0, 1, and 6 months, and tested 2-3 months later for antibody to hepatitis B surface antigen (anti-HBs) by radioimmunoassay (RIA). Overall, 96.5% of the children seroconverted for anti-HBs by RIA, having levels greater than 2.1 RIA S/N units, with 91.2% having values greater than 10 S/N units. Anti-HBs levels were also determined by enzyme immunoassay (EIA), by which method a significantly better response was demonstrated in 2-4-year-olds than in older children. This study demonstrated that a satisfactory anti-HBs response was obtained using one-fifth of the recommended doses of hepatitis B vaccine.     

乙型肝炎病毒多表位抗原DNA疫苗的免疫原性

目的 :探讨HBV复合多表位DNA疫苗诱导体液及细胞免疫的可行性。方法 :将HBV多表位抗原基因BPT克隆到真核表达载体pcDNA3.1中 ,构建重组真核表达载体pcDNA3.1/BPT。将其通过肌肉注射免疫BALB/c小鼠 ,用间接免疫ELISA法、CTL杀伤功能检测和淋巴细胞增殖试验 ,检测特异性体液免疫和细胞免疫的水平 ,并观察其对免疫小鼠的毒副作用。结果 :用重组质粒pcDNA3.1/BPT免疫BALB/c小鼠后 ,在效靶比为 10 0∶1时 ,可诱导显著地特异性CTL应答 (P <0 .0 5 )。ELISA检测免疫小鼠血清特异性IgG的水平明显升高 (P <0 .0 5 )。在BPT基因原核表达蛋白的刺激下 ,免疫小鼠脾淋巴细胞增殖显著 (P <0 .0 5 )。RT PCR分析表明 ,IL 12mRNA的水平亦明显升高。结论 :HBV多表位基因疫苗可诱发特异性免疫应答 ,为预防、治疗性HBV疫苗的研制提供了一定的实验依据     

The immune response of healthy adults to a reduced dose of hepatitis B vaccine

Three hundred thirty-six medical personnel from hemodialysis centers were treated with three doses, 20 μg each, of the Merck hepatitis B vaccine (at 0, 1, and 6 months). Within 1 month after the first injection, 41% converted to anti-HBs positivity; after the second injection the conversion rate rose to 80–90%; and after the booster, to 96–98%. The later rate remained unchanged during the 18-month follow-up period. Only 2.8% of those vaccinated did not respond to the vaccine. The patterns of immune responses to 20-μg doses were found to be exactly the same as to 40-μg doses. It is suggested that reduced doses of vaccine should be as efficacious as the larger ones.     

不同剂量配比的实验性甲型肝炎戊型肝炎联合疫苗的免疫原性研究

目的研究实验性甲型肝炎(甲肝)戊型肝炎(戊肝)联合疫苗的免疫原性,探讨两种抗原组分间的相互作用。方法制备9种不同剂量配比的实验性甲戊肝联合疫苗,与单价疫苗对照一起免疫15组(共120只)小鼠,定时采血,以ELISA和中和试验检测抗HAV和抗HEV的抗体。结果高剂量的HAV抗原(5×105U/L)与不同剂量的HEV抗原(200、100、50mg/L)配制的联合疫苗,诱导的抗HAV中和抗体的滴度可达1∶1024,含25×104、125×103U/LHAV抗原的联合疫苗诱导的中和抗体滴度为1∶512,不同剂量的HEV抗原对抗HAV中和抗体的产生均无明显影响。与单价戊肝疫苗相比较,联合疫苗诱导的抗HEV抗体水平均有明显升高,且随联合疫苗中HAV抗原的含量(5×105、25×104、125×103U/L)的增加而升高,HEV抗原的剂量在一定范围内(200、100、50mg/L)与抗HEV抗体产生无明显关系。采用基于逆转录套式PCR的中和试验表明,各联合疫苗组的免疫血清均可中和HEV。结论实验性甲、戊肝联合疫苗内HAV抗原对HEV抗原的免疫原性具有增强作用,而HEV抗原对HAV抗原的免疫原性无明显影响。     

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.     

重组酵母乙肝疫苗免疫效果研究

目的研究重组酵母乙肝疫苗对青少年学生的免疫效果。方法同时对３６５名乙肝病毒血清学指标（ＨＢＶ－Ｍ）不同感染状况的学生进行免疫监测。随机分为两组，Ａ组：１８３人，接种剂量１０－５－５（μｇ），Ｂ组：１８２人，接种剂量５－５－５（μｇ），用ＥＬＩＳＡ法，在全自动酶标分析仪上测定。结果１．重组酵母乙肝疫苗对青少年免疫效果良好，抗－ＨＢｓ阳性率达９７％以上；２．对ＨＢＶ－Ｍ不同感染状况的学生，免疫后均无不良反应。结论ＨＢＶ易感者和感染者接种疫苗后免疫效果均好。在青少年中普种乙肝疫苗可不筛查ＨＢＶ－Ｍ。     

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.     

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.     

Subcutaneous administration of inactivated hepatitis B vaccine by automatic jet injection

To assess the feasibility of jet injection for mass immunization against hepatitis B virus, inactivated, alum-adsorbed hepatitis B vaccine (Merck, Sharp, and Dohme Research Laboratories, West Point, PA) was administered subcutaneously by automatic jet injection to 19 volunteers lacking antibody to hepatitis B surface antigen (anti-HBs). Three 20-μg doses were given at 0, 1, and 6 months. Of 19 volunteers, 5 (26%) developed anti-HBs by 1 month after the first injection, and 15 of 19 (79%) were anti-HBs-positive 6 to 8 weeks after the first booster administration. Following the second booster, 16 of 19 (84%) recipients had detectable anti-HBs. Possible systemic reactions were limited to low-grade fever (37.8°C) in one volunteer following one injection, and mild lethargy in a second recipient. Local reactions to jet injection of vaccine occurred more frequently, with indurated, nodular lesions 3–10 mm in diameter developing at the site of 19 of 57 (33%) vaccine injections, compared with 2 of 57 (3%) saline placebo injections. Such nodules were generally painless. Sore arms were noted in 11 of 57 (19%) vaccine injections. With the exception of frequent but minor local reactions, subcutaneous administration of inactivated hepatitis B vaccine by automatic jet injection is safe, and results in vaccine immunogenicity approximating that associated with intramuscular needle injection.     

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.     

Immunogenicity of a low dose recombinant DNA hepatitis B vaccine in healthy adults in Singapore

The immunogenicity and safety of a standard dose of 10 micrograms of a yeast derived recombinant DNA hepatitis B vaccine (B-Hepavac II) was compared with that of a reduced dose of 5 micrograms in 84 healthy adult volunteers with no previous exposure to hepatitis B. Each subject received either a 10 micrograms or 5 micrograms dose of vaccine intramuscularly at 0, 1 and 6 months. One month after the second injection of vaccine the seroconversion rate in the two groups were 85 and 86 percent respectively. Two months after the third injection 100 percent of participants had sero-converted; 95 percent of the 10 micrograms group and 91 percent of the 5 micrograms group had titres of anti-HBs greater than 10 IU/L. The geometric mean titres (GMT) of anti-HBs levels at 2, 6, 8, and 12 months were 34, 61, 811 and 188 IU/L in the 10 micrograms group and 26, 45, 836 and 304 IU/L in the 5 micrograms group respectively. Adverse effects were mild and transient. The vaccine was safe and immunogenic in the doses given. The reduced dose of 5 micrograms was as effective as the standard 10 micrograms dose.     

明胶微球乙肝疫苗动物免疫效果研究

目的 研究并优化微球乙型肝炎疫苗的配方,观察微球乙肝疫苗对温度的稳定性。方法 用明胶包裹ＨＢｓ制备微球,设计不同配方及不同粒径微球乙肝疫苗、冻干微球乙肝疫苗于不同温度放置一定时间,免疫动物观察免疫效果。结果 微球疫苗ＨＢｓ包裹率〉９０％,微球疫苗的免疫效果受佐剂配方及制备程序等因素影响,〈１０μｍ的微球（５．６μｍ）免疫效果明显优于〉１０μｍ的微球（２５．４μｍ）（Ｐ〈０．０２）及铝佐剂组（Ｐ〈０     

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.     

可生物降解高分子乙型肝炎疫苗微球的免疫原性研究

目的　研究聚乳酸 聚乙二醇共聚物 [poly dl lactide poly(ethyleneglycol) ,PELA]包被汉逊酵母表达的HBsAg制备所得乙型肝炎PELA疫苗微球 (PELA·HBsAg)的免疫原性。方法　应用PELA·HBsAg皮下免疫BALB c小鼠 ,在体液免疫方面 ,采用固相放免法测定抗 HBs的水平 ,对抗 HBs中IgG的亚类进行了ELISA测定。在细胞免疫方面 ,于免疫后用3H TdR法测定单个核细胞 (MNC)对ConA、LPS和HBsAg的增殖反应性 ;小鼠迟发型超敏反应 (DTH)的发生程度 ;淋巴细胞亚群分析 ;检测HBsAg特异性CTL活性等评价细胞免疫。结果　①免疫 4周后 ,PELA·HBsAg与HBsAg混合 ,产生抗 HBs的滴度高于铝佐剂的HBsAg[Al(OH) 3 HBsAg]的 2倍多 ;②PELA·HBsAg与HBsAg混合以及PELA·HBsAg产生的IgG2a与IgG的比例显著高于与铝佐剂的HBsAg ;③PELA·HBsAg免疫 2 5d小鼠脾细胞的MNC体外经ConA、LPS刺激后SI最高 ,达到 133.5 9、4 7.4 8,显著高于Al(OH) 3 HBsAg组 (2 8.98、2 1.81)和HBsAg组 (34.95、14 .75 ) ,P <0 .0 5 ;④PELA·HBsAg免疫小鼠后对SRBC所诱导的DTH反应程度有显著的增强作用 (P <0 .0 5 )。⑤PELA·HBsAg与HBsAg混合后免疫小鼠的脾细胞对P815 HBs细胞的特异杀伤率显著高于其它组别 (P <0 .0 5 )。结论　以PELA为佐剂的HBsAg所     

Predicted 30‐year protection after vaccination with an aluminum‐free virosomal hepatitis A vaccine

Few studies have examined the duration of protection following vaccination against hepatitis A virus (HAV) with currently licensed HAV vaccines. This study explored the long‐term immunogenicity in individuals vaccinated with the virosomal hepatitis A virus, Epaxal®. Adult volunteers (N = 130) previously enrolled into four different studies between 1992 and 1994 and who had completed a 0/12‐month immunization regimen (primary and booster dose) were asked to participate in this follow‐up study. Yearly anti‐HAV titers up to 6 years following booster vaccination, and then once 9–11 years after booster were measured using two assays, Enzygnost® and AxSYM® HAVAB 2.0. Based on the Enzygnost® assay, the seroprotection rate 9–11 years after booster was 100%, with a geometric mean concentration (GMC) of anti‐HAV antibodies of 526 mIU/ml. Females had markedly higher GMCs than males (741 mIU/ml vs. 332 mIU/ml). Using an anti‐HAV cut‐off titer of ≥10 mIU/ml, a linear mixed mathematical model predicted a median duration of protection of 52.1 years. A duration of protection ≥35.7 years was predicted for 95% of subjects. A more stringent cut‐off of ≥20 mIU/ml shortened the median predicted duration of protection to 45.0 years. In conclusion, a two‐dose Epaxal® vaccination regimen confers in healthy adults a real‐time protection of at least 9–11 years; this protection is predicted to last at least 30 years in over 95% of individuals. Further studies are necessary to assess the real duration of seroprotection and whether an additional booster is necessary later. J. Med. Virol. 82:1629–1634, 2010. 2010 Wiley‐Liss, Inc.     

A vaccine prepared from the 22 nm particles of surface hepatitis B antigen (HBsAg)

A method for obtaining a subunit inactivated vaccine preparation from the 22-nm particles of HBsAg is proposed. For inactivation of the residual infectious hepatitis B virus (HBV) the preparations were successively treated with 1% sodium dodecyl sulfate (SDS) and nucleases. In addition, thermal denaturation and ultraviolet irradiation of HBV DNA were used. As a control the biologic activity of a reference virus (SV40) was tested after the same treatment. The effectiveness of DNA inactivation was monitored by adding ³ H-thymidine labeled reference virus to the vaccine preparations. The purified and inactivated HBsAg was adsorbed on Al₂O₃. Antigenicity was calculated on the basis of the determination of antibody in guinea pigs immunized with various doses of the vaccine, and the release of ¹²⁵ I- HBsAg from blood and kidneys in immunized and control mice was analyzed. Possible methods of inactivation and control of HBV vaccine is discussed.     

Immunogenicity and protective efficacy of low dose recombinant DNA hepatitis B vaccine in normal and high-risk neonates.

A low dose of recombinant DNA hepatitis B vaccine (HB-VAX II, MSD) was tested for efficacy in the prevention of perinatal hepatitis B virus (HBV) transmission in normal and high-risk neonates born from HBsAg carrier mothers. A dose of 2.5 micrograms recombinant vaccine was injected intramuscularly at 0, 1, 2 and 12 months of age to 30 newborns from HBsAg negative mother (group I), 30 from HBeAg negative/HBsAg carrier mother (group II) and 30 from HBeAg positive/HBsAg carrier mother (group III). The incidence of persistent HBsAg carrier infants at 13 months of age was 0, 0, and 30.4 percent in groups I, II and III, respectively. The protective efficacy in high risk infants in group III was 65.7 percent. The seroconversion at month 4, after the third dose of vaccination was 96.3, 95.7 and 100 percent in group I, group II and group III, respectively. After a booster dose of vaccination at 12 months of age, the seroconversion rose to 100 percent at month 13 in all three groups. The geometric mean titer (GMT) of anti-HBs antibody at 13 months of age were 2,092, 1,657 and 1,938 mIU/ml in group I, group II and group III, respectively. It is concluded that the low dose (2.5 micrograms) recombinant hepatitis B vaccine using alone is effective in prevention of perinatal HBV transmission in low risk infants (groups I and II), but it is less effective in high risk infants (group III).(ABSTRACT TRUNCATED AT 250 WORDS)     

湖北汉族人群对乙肝疫苗免疫应答能力与HLA-DRB1等位基因相关性的研究

目的分析HLA-DRB1等位基因型别与个体乙肝疫苗免疫应答水平的相关性。方法对37名湖北汉族健康自愿者进行HBV血源型疫苗标准全程接种,共3次(0,1,6月),末次接种后8周用酶免疫法(EIA)检测血清抗-HBs抗体水平(S/N≥2.1为应答者,S/N<2.1为无应答者);同时,对全部受试者进行HLA-DRB1基因分型。结果37名个体中无应答者7名(19%),应答者30名(81%),无应答与HLA-DRB*1001等位基因具有显著相关性,RR=21.75,X2=5.55,P<0.05。结论在湖北汉族人群中,携带HLA-DRB*1001等位基因个体对乙肝疫苗的免疫应答水平明显低于其他个体     

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.