New vaccines against hepatitis B

The high cost and limited availability of the plasma-derived hepatitis B vaccines have prevented their widespread use, especially in the less developed areas where they are needed most. Hepatitis B vaccines produced by recombinant technology seem to offer a solution to these difficulties. Studies reported up to now confirmed the safety of this vaccine. Immunogenicity studies in various population groups showed that seroconversion rates and antibody titres are comparable to plasma vaccine. In assessing the efficacy of the vaccine, information concerning the quality of the anti-HBs induced should complement these data. Potential live vaccines using recombinant vaccinia viruses have been constructed for hepatitis .B. Preliminary studies in rabbits and chimpanzees indicated the feasibility of future using a recombinant vaccinia virus.Chemically synthesized polypeptides corresponding to relevant epitopes of HBsAg may be useful as synthetic vaccines offering the advantages of a cheap viral immunogen free from irrelevant antigenic determinants.Finally preliminary studies for an idiotypic vaccine have already been reported.     

The development of novel hepatitis B vaccines

Development of vaccines against viral hepatitis B has proceeded along four main lines. (1) Human plasma-derived vaccines are safe, effective and are now in general use. (2) Subunit polypeptide vaccines formulated in micelles have reached the stage of clinical trials. (3) Recombinant DNA vaccines have been produced in prokaryotic and eukaryotic cells, notably in yeast. The yeast-derived recombinant vaccines have proved safe and effective in extensive clinical trials, eliciting antibodies which in quantity and specificity are equal to those elicited by plasma-derived vaccine. DNA recombinant has also been applied to the development of hybrid and vaccinia virus vaccines which are capable of immunological ”priming”, and other hybrid virus vaccines are under development. (4) Finally, chemical synthesis has succeeded in producing small peptides which include specific epitopes eliciting antibody responses in experimental animals. Such chemically synthesized preparations offer a prospect of ultimately producing multivalent synthetic vaccines against several viruses, bacteria and protozoa.     

Tomorrow's hepatitis B vaccines. Arie Zuckerman discusses hepatitis B vaccines of the future and the impact of AIDS on immunization

Recombinant hepatitis B vaccines produced in yeast and in mammalian cells are the first of future vaccines against this important public health problem. Hybrid virus vaccines and the use of baculoviruses for expression of hepatitis B antigens in insect cell cultures will follow shortly and chemically synthetic vaccines are under development. The impact of AIDS on future immunization programmes should be considered.     

Duration of hepatitis B antibody response in children immunised with hepatitis B and compulsory vaccines

Twenty four subjects were simultaneously administered DT toxoids, OPV and HBV vaccines at the age of 3, 4–5 and 11 months and then followed up for 2 and 4 years in order to evaluate the duration of the immune response and the need and the timing of HBV revaccination. A fall in anti-HBs titre below 10 mIU/ml was observed at the follow up in 4/24 (16.7%) of the subjects. In other 5 children (20.8%) anti-HBs titre was found to be just above 10 mIU/ml. This would suggest that a revaccination is indicated and it could be performed at the age of 5–6 years when children enter school. This schedule is simple, effective and money saving since it reduces the cost/benefit ratio and the number of visits for immunisations, and it is expected to improve the compliance for the vaccination.     

Adjuvant synergy in the response to hepatitis B vaccines

The adjuvant properties of interleukin-12 (IL-12) and a phosphorothioate oligodeoxynucleotide (S-ODN) hexamer consisting of the sequence, 5'-GACGTT-3', were evaluated in mice using hepatitis B (HBs) protein and DNA vaccines. GACGTT was an effective adjuvant when co-injected with HBs protein intramuscularly or when injected at the same anatomic site within 1 day before or 1 day after injection of the protein. Surprisingly, IL-12 had a negligible adjuvant effect when co-injected with HBsAg; however, when bound to "alum", IL-12 stimulated a dramatic increase in anti-HBs titers and a switch from a TH2 to a TH1 response profile as evidenced by an increase in IgG2a subclass anti-HBs antibodies and the ability to secrete interferon-gamma (IFN-gamma) upon in vitro stimulation with an HBs peptide. Interestingly, aluminum phosphate was a far better co-adjuvant (with IL-12) than was aluminum hydroxide even though both "alums" bound >99% of the IL-12. Finally, the combination of IL-12, GACGTT, and aluminum phosphate was found to elicit a markedly polarized TH1 response. The results indicate that aluminum phosphate is highly effective at delivering an antigen (HBsAg) together with TH1 adjuvants such as IL-12 and GACGTT resulting in a shift from a TH2 to a TH1 response.     

Nucleic acid vaccines for hepatitis B and C virus

Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infections accounts for an important global health problem affecting over 250 million people all around the world. They can cause acute, transient and chronic infections in the human liver. Chronic infection of liver can lead to its failure or cancer. To deal with this problem, alternative approaches or strategies to inhibit these infections have already been started. DNA and mRNA-based vaccination will increase the efficacy and reduce toxicity in patients with Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infections. Gene vaccines represent a promising alternative to conventional vaccine approaches because of their high potency, capacity for rapid development, low-cost manufacture and safe administration. MRNA-based vaccination is a method to elicit potent antigen-specific humoral and cell-mediated immune responses with a superior safety profile compared with DNA vaccines. Exploring the intricacies of these pathways can potentially help the researchers to explore newer vaccines. In this study, DNA and mRNA-based vaccination are introduced as an approach to treat Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infections. DNA and mRNA-based vaccines as one of the most successful therapeutics are introduced and the clinical outcomes of their exploitation are explained.     

Combined vaccine against hepatitis A and B

Among the infectious virus hepatitis diseases, types A and B can be successfully prevented with vaccinations. WHO recommend effective control of hepatitis A through immunisation, especially among populations with indirect or high endemicity. Since 1991 WHO has been recommending vaccinations against hepatitis B. It is planned to introduce it in all countries by the year 2007. Vaccinations against hepatitis A & B are recommended for people travelling to the regions endemic for these infections or for those with high professional risk of HAV and HBV. Presented here are the characteristic features of the vaccine, the analysis concerning the evaluation of its effectiveness, comparison of this effectiveness with monovalent vaccine effectiveness, as well as evaluation of the tolerance and safety.     

慢性乙型肝炎的联合抗病毒治疗

慢性乙型肝炎的主要疗法是抗病毒,而联合抗病毒已逐渐发展为一个新的方向.此文旨在对治疗乙型肝炎的不同抗病毒药物联合应用的目的、疗效及其进展进行综述.     

重组乙肝疫苗免疫持久性观察

目的：了解儿童重组乙肝疫苗基础免疫与加强免疫后的免疫持久性。方法选择免疫史信息保存完备、婴儿期完成0-1-6月基础免疫的493名中小学生为对象。对所有对象检测抗-HBs等指标,并对是否作加强免疫、不同年龄时间作加强免疫以及距末次免疫接种不同时间的抗-HBs平均水平和达到乙肝免疫保护水平的阳性率作比较,分析乙肝疫苗不同免疫接种情况下的免疫持久性。结果加强免疫组与基础免疫组抗-HBs阳性率分别为91.40%和57.14%,两组比较差异有统计学意义（ P〈0.01）。10μg加强免疫组0-5年后抗-HBs滴度较高,抗体阳性率94.99%;5μg加强免疫组8-15年后抗-HBs滴度较低,抗体阳性率下降至64.71%,与基础免疫组比较差异无统计学意义（ P=0.49）。结论乙肝疫苗加强免疫后可提高抗-HBs阳性率,远期抗-HBs滴度水平和抗体阳性率降低;婴儿期基础免疫3-11年后免疫记忆缺失率低。     

Immunogenicity of hepatitis B vaccines: implications of immune memory

The subunit recombinant hepatitis B virus (HBV) vaccines available in the US differ in hepatitis B surface antigen content. Clinical studies have linked higher antigen formulations with enhanced peak protective antibody levels. This is important for the elderly, smokers, the obese, and the immunocompromised. Immune memory, which is responsible for prolonged protection when HBV vaccine-induced antibody levels become undetectable, may be related to antigen persistence on immunologically active cells. Antigen persistence may be related to antigen content of the vaccine and thereby influences the duration of immunity. Proof of this concept will require additional studies of immune memory in HBV.     

Comparison of immunogenicity of two yeast-derived recombinant hepatitis B vaccines.

A comparison was conducted of the immunogenicity of two yeast recombinant vaccines with different doses [10 micrograms Recombivax-HB (Merck Sharpe & Dohme Ltd) vs. 20 micrograms Engerix-B (Smith Kline Biologicals)]. This was conducted as a randomized, blinded study in healthy preclinical medical students, negative for hepatitis B markers. The geometric mean titres (GMT) showed a wide individual variability for both vaccines, and approximately a two- to threefold greater GMT of anti-HBs in recipients of the 20 micrograms vaccine. However, the 95% confidence interval showed an overlap of the means of the GMT for both vaccine groups, and in this study there was no significant difference in immunogenicity of these two vaccines. At 6-7 months after completion of immunization, antibody levels fell to one-third of the levels of one month post-immunization. A case report of an allergic urticarial reaction to one of the recombinant vaccines is presented.     

乙肝免疫球蛋白联合乙肝疫苗阻断乙型肝炎母婴传播的系统评价

目的 系统评价联合乙型肝炎(以下简称乙肝)免疫球蛋白和乙型肝炎疫苗阻断乙肝表面抗原(hepatitis B surface antigen,HBsAg)阳性母亲对其新生儿造成母婴传播的阻断效果,为新生儿乙肝预防提供理论证据.方法 检索文献数据库,收集以联合免疫为主要干预措施,对HBsAg阳性和(或)HBsAg、乙肝e抗原(hepatitis B e antigen,HBeAg)双阳性的慢性乙肝孕妇及其所生的新生儿进行免疫治疗的随机对照试验(randomized controlled trials,RCT),运用Revman 5.0进行Meta分析.结果 共纳入6项研究,试验组426人,对照组373人.结果显示,联合乙肝疫苗和免疫球蛋白使用相比单独使用疫苗获得更佳的母婴传播阻断效果,其婴儿HBsAg感染风险低,且差异有统计学j意义(RR =0.23,95％ CI:0.15 ～0.34,P＜0.001);亚组分析显示,无论感染状态,联合疫苗干预均能在单阳性或双阳性HBsAg感染状态的母亲中取得较好的母婴传播阻断效果(RR合并单阳=0.23,95％ CI:0.07 ～0.71,P=0.010,RR合并双阳=0.22,95％ CI:0.13～0.38,P＜0.001).结论 联合使用乙肝免疫球蛋白和乙肝疫苗更能降低新生儿HBsAg感染率.但受研究样本限制,仍需大样本和高质量的RCT试验来证实.     

Most humoral non-responders to hepatitis B vaccines develop HBV-specific cellular immune responses

About 10% of health care professionals vaccinated against hepatitis B virus (HBV) fail to develop protective antibodies. We tested the capacity of peripheral blood lymphocytes from 121 health care professionals, including 76 non-responders, to proliferate to four HBV vaccines, examined the proliferating cells' subset, production of IFN-gamma, IL-4 and IL-10, and for 22 subjects, the cytokine production genotype. Specific proliferative responses to at least one HBV antigen were noted in 75% humoral non-responders. These cells differed from the CD4+ strongly proliferating cells of responders. Non-responders frequently displayed a genotype of high TGF-beta and intermediate IL-10 secretion. Most humoral non-responders to HBV thus develop specific cellular immune responses, eventually liable to protect them against viral infection.     

不同种类乙型肝炎疫苗序贯免疫可行性研究

目的研究不同种类乙型肝炎疫苗序贯免疫的免疫效果。方法随即选取107名新生儿分为3组,按照0、1、6月龄免疫程序分别接种10μg CHO乙肝疫苗、5μg酿酒酵母乙肝疫苗以及两种疫苗替代接种,全程免疫1 a后对抗乙肝病毒表面抗原抗体(Anti-HBs)进行定量检测。结果接种10μg CHO乙肝疫苗、5μg酿酒酵母乙肝疫苗以及两种疫苗序贯免疫,Anti-HBs阳性率分别为94.29%、85.71%、81.08%,平均86.92%;Anti-HBs几何平均浓度分别为117、116、106 mIU/ml。不同种类疫苗接种阳性率差异无统计学意义(P0.05)。结论 10μg CHO乙肝疫苗和5μg酿酒酵母乙肝疫苗可以互相替代接种,Anti-HBs阳性率达到81.08%。     

A comparison of two commercial recombinant vaccines for hepatitis B in adolescents

The immunogenicity and reactogenicity profiles of three doses each of Engerix-B(R) (10 microg hepatitis B surface antigen) and Recombivax(R) (5 microg hepatitis B surface antigen), given on a 0, 1, 6 month schedule to healthy adolescents were compared in a single-blind, randomized clinical trial. One month following the third dose, seroprotection rates after Engerix-B and Recombivax were similar (99 and 98%, respectively). The geometric mean titre (GMT) was statistically significantly higher following vaccination with Engerix-B (3961 vs. 1001 mIU/ml; P=0.0001, Fisher's exact test). Most of the symptoms reported were mild or moderate in intensity and transient. There were no vaccine-related serious adverse events.