Recombinant hepatitis B core antigen carrying preS1 epitopes induce immune response against chronic HBV infection

Many studies have provided evidence that core antigen of hepatitis B virus (HBcAg) is extremely immunogenic, HBcAg can be function as both a T-cell-dependent antigen and a T-cell-independent antigen, and thus may be a promising candidate for therapeutic vaccine for control of chronic HBV infection. HBcAg is also an effective carrier for heterologous peptide epitopes. The preS1 is a surface protein of HBV and is immunogenic at the T and B cell level. The amino acid sequence 21-47 of preS1 is crucial for HBV binding to human hepatocytes as well as to PBMC and haematopoietic cell lines of the B cell lineage. Here we expressed a chimeric protein named HBVCS1, created by fusing the preS1 sequence 3-55 to the carboxyl terminus of the truncated HBcAg sequence 1-155 in E. coli. Analysis of its antigenicity and immunogenicity revealed that both HBc and preS1 epitopes are surface accessible, and that fusion of preS1 did not affect the HBc antigenicity and immunogenicity of the truncated HBc sequence. HBVCS1 induced strong anti-HBc and moderate anti-preS1 immune responses as well specific T-cell response in Balb/c mice. HBVCS1 vaccination reduced of the titer of HBsAg and HBV DNA in sera of HBV-Tg mice. These results indicate that HBVCS1 may have potential as a therapeutic vaccine for treatment of HBV chronic infection.     

在校大学生乙肝疫苗普种效果对比观察

目的 分析北京市农村居民乙肝疫苗接种状况及影响因素,为提高农村居民乙肝疫苗接种率和乙肝防控政策的制定提供参考依据。 方法 本研究数据采集于2011年1月 — 2012年4月,应用随机抽样的方法和结构式访谈问卷调查的方式在北京大兴区3个自然村进行入户调查 ≥ 16岁成年人,并采用方差分析、二元logistic回归模型进行统计分析。 结果 本研究共调查2 006人,总接种率29.86 %。其中男性1 004人（50.05 %）,接种率30.38 %,女性1 002人（49.95 %）,接种率29.34 %;平均年龄39.8岁。多因素分析中,结合回归系数和OR值分析可得,随着年龄的下降、家庭人均年收入的增加、乙肝认知水平的增加,乙肝疫苗的接种概率逐渐上升（P < 0.01）。职业分组中,接种率由高到低依次是学生、固定工作者、个体工商业者、打工者、农民（P < 0.01）。到达最近的医疗机构花费的时间越短,乙肝疫苗接种概率越高（P < 0.01）。 结论 高年龄、低收入、认知水平低都是阻碍乙肝疫苗接种的重要因素,农民和打工者群体接种率最低,医疗服务的可及性也会影响乙肝疫苗接种率。     

Maternal antibody to hepatitis B core antigen detected in dried neonatal blood spot samples.

Despite Department of Health recommendations, universal antenatal testing for hepatitis B virus (HBV) is not performed throughout Scotland. We describe the evaluation of an assay to document past or present infection with HBV, by identifying maternal antibody in routine Guthrie dried neonatal blood spot samples taken when infants are 7 days old. A modified haemagglutination assay to detect antibody to hepatitis B core antigen (CORECELL, Green Cross) was validated and found to be 79% sensitive (44/56) and 100% (105/105) specific when used with dried blood spot samples made from panels of serum of known reactivity. Ninety-three percent (13/14) of HBV carriers were CORECELL positive. Sixty-six (0.5%) of 14044 routine Guthrie samples taken from babies born in Scotland from June August 1992 were CORECELL positive indicating past or present maternal infection with HBV. A cross-sectional survey would document the maternity hospitals where universal antenatal hepatitis B screening should be urgently established.     

Recombinant heat shock protein 65 carrying hepatitis B core antigen induces HBcAg-specific CTL response

Many studies have provided evidence that heat shock protein 65 (Hsp65) can elicit potent specific cellular adaptive immune responses (e.g. CD8(+) cytotoxic T-cell effectors or classic CTLs) based on their ability to chaperone antigenic peptides. Hsp65 is thus an effective carrier for heterologous peptide epitopes for therapeutic vaccines against cancer or chronic infectious diseases. The core antigen of hepatitis B virus (HBcAg) is extremely immunogenic, and functions as both a T-cell-dependent and a T-cell-independent antigen. Therefore, HBcAg may be a promising candidate target for therapeutic vaccine control of chronic HBV infection. Here, a chimeric protein, Hsp65Bc, was created by fusing the HBcAg sequence to the carboxyl terminus of the Hsp65 sequence in E. coli. Analysis of its antigenicity and immunogenicity revealed that HBc epitopes are surface accessible. Hsp65Bc induced moderate anti-HBc immune responses as well as a strong specific T-cell response in BALB/c mice. These results indicate that Hsp65Bc may have potential as a vaccine for treatment of HBV chronic infection.     

Delta virus and hepatitis B surface antigen in chronic liver diseases.

This work was carried out on 45 patients with chronic liver diseases, including 24 cases of liver cirrhosis and 21 cases of chronic hepatitis. Their ages ranged from 2 to 15 years (median 5). All cases were examined clinically and assessed biochemically for liver function tests. Serological studies were performed to detect hepatitis B surface antigen (HBsAg) and delta IgG antibody (IgG anti-HD) using Enzyme Immunoassay (EIA) technique. The study showed that IgG anti-HD was detected in 8.9% of cases with chronic liver diseases (all positive cases were with liver cirrhosis). On the other hand, HBsAg was detected in 53.3% of cases (54.2% of them with cirrhosis and 45.8% with chronic hepatitis) with no significant association between HBsAg positivity and type of hepatic illness. Moreover, IgG anti-HD was positive in only 4.2% of HBsAg positive cases, while 14.3% of HBsAg negative cases were positive for IgG anti-HD. A significant association was also found between delta positivity and serum glutamic oxaloacetic transferase level (SGOT). We concluded that chronic delta hepatitis appeared to be more severe than other types of chronic viral hepatitis, as all delta positive cases were with liver cirrhosis and had elevated SGOT levels. Screening of delta markers in addition to hepatitis B viral markers could improve the understanding of a number of obscure cases of chronic hepatic illnesses and would help in the control of HBV and consequently HDV infection in the general population.     

基因多态性和慢性乙型肝炎干扰素疗效的相关性

影响慢性乙型肝炎(CHB)IFN疗效的因素很多,宿主免疫遗传背景的差异是重要原因之一.最近关于基因多态性和CHB患者IFN疗效的相关性研究越来越多,此文就相关的研究进展进行了简要综述.     

基因多态性和慢性乙型肝炎干扰素疗效的相关性

影响慢性乙型肝炎(CHB)IFN疗效的因素很多,宿主免疫遗传背景的差异是重要原因之一.最近关于基因多态性和CHB患者IFN疗效的相关性研究越来越多,此文就相关的研究进展进行了简要综述.     

基因多态性和慢性乙型肝炎干扰素疗效的相关性

影响慢性乙型肝炎(CHB)IFN疗效的因素很多,宿主免疫遗传背景的差异是重要原因之一.最近关于基因多态性和CHB患者IFN疗效的相关性研究越来越多,此文就相关的研究进展进行了简要综述.     

Persistence of antibody to hepatitis B surface antigen after low-dose, intradermal hepatitis B immunization and response to a booster dose.

To determine the duration of antibody after low-dose, intradermal (i.d.), plasma-derived hepatitis B vaccination and the response to a booster dose, we studied two classes of medical students who were immunized with 2 micrograms doses i.d. In one class, 73/88 (85%) who had been immunized by skilled personnel at 0, 1 and 6 months, had protective concentrations (greater than or equal to 10 mIU ml-1) of anti-HBs at 20 months after the first dose. Twelve (92%) out of 13 students who received only two doses at 0 and 1 months also had protective concentrations at month 20. At month 27, 11/16 (69%) with antibody less than or equal to 10 mIU ml-1 responded to a fourth dose of 2 micrograms i.d. with protective concentrations of anti-HBs. In the second class, after three doses of vaccine at 0, 1, and 6 months, protective concentrations of anti-HBs were present in 90/93 (97%) at 14 months and in 71/80 (89%) at 25 months. In those who received only two doses, protective concentrations were found in 24/31 (74%) at 14 months and 9/16 (56%) at 25 months. After a booster dose of 2 micrograms i.d. at month 25, anti-HBs concentrations rose from a geometric mean of 78 to 1198 mIU ml-1 in 60 subjects previously immunized with three doses and from 18 to 1054 mIU ml-1 in 16 students previously immunized with only two doses. Overall, 73/76 (96%) of students in the second group had protective concentrations of antibody after the booster dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ten-year persistence of antibody to hepatitis B surface antigen in healthcare workers vaccinated against hepatitis B virus, and response to booster vaccination.

This study estimated the number of HCWs with protective antibody levels 5 and 10 years after HBV vaccination. Kaplan-Meier probabilities of protective levels were 0.95 at 60 days after vaccination, 0.87 at 5 years, and 0.79 at 10 years. Those without protective levels displayed good response 7 and 30 days after a booster.     

Efficacy of antigen dosage on the hepatitis B vaccine response in infants born to hepatitis B-uninfected and hepatitis B-infected mothers

ObjectiveTo compare the safety and immunogenicity of two dosages of recombinant hepatitis B (HB) vaccine administered to infants born to HB-uninfected and HB-infected mothers.MethodsA phase III, controlled, single-blinded clinical trial was conducted with 506 healthy newborns. The newborns were assigned to three groups based on maternal levels of HB surface antigen (HBsAg) and HB e antigen (HBeAg): Group A, HBsAg negative; Group B, HBsAg positive and HBeAg negative; and Group C, HBsAg positive and HBeAg positive. Three doses of 10 or 5 μg recombinant HB vaccine were randomly administered by 1:1 within 24 h after birth, at 1 month and at 6 months. Safety data and pre- and postvaccination blood samples were collected.ResultsA total of 326, 93, and 87 subjects were included in Groups A, B, and C, respectively. Both dosages of HB vaccine were well tolerated by all subjects. The most common injection-site adverse reactions (ARs) and systemic ARs were pain and fever. After 1 month of the third dose, the Group A infants who received the 10 μg HB vaccine achieved a higher geometric mean concentration (GMC) of HB surface antibody (anti-HBs) than those who received the 5 μg dosage. Maternal anti-HBs serostatus did not influence HB vaccine immunogenicity at either dosage. In contrast, there was no significant difference in the anti-HBs seroconversion rate, GMCs, or estimated vaccine efficacy (EVE) against perinatal transmission between Groups B and C, regardless of dosage. However, the seroconversion rate and EVE of the 5 μg HB vaccine was lower in Group C than in Group B.ConclusionsBoth dosages of the HB vaccine were well tolerated and elicited a good immune response in infants of Group A, regardless of the maternal anti-HBs serostatus. EVE did not significantly differ between Groups B and C.Clinicaltrails.gov identifier: NCT02152709     

Influence of maternal antibody against hepatitis B surface antigen on active immune response to hepatitis B vaccine in infants

Transplacentally acquired maternal antibodies in infants may inhibit active immune responses to vaccines. In this study, we compared the immunogenicity of the recombinant hepatitis B vaccine, which was intramuscularly injected at 0, 1, and 6 months of age, in 71 infants born to mothers with positive or negative antibody against hepatitis B surface antigen (anti-HBs). Forty-one infants born to anti-HBs positive mothers were all positive at birth. At 2 months after the second injection, anti-HBs in 30 infants with negative maternal antibody was significantly higher than that in 41 infants with positive maternal anti-HBs (191.1mIU/ml vs. 96.2mIU/ml, P=0.018). At one month after the full immunization, the anti-HBs levels had no statistical difference between maternal anti-HBs negative and positive groups, but the antibody response in infants with high maternal anti-HBs (>1000mIU/ml) was significantly inhibited. Nevertheless, all infants had anti-HBs higher than the protective level. In conclusion, passively acquired maternal anti-HBs in infants may to some extent impair the antibody response to hepatitis B vaccine. The long-term efficacy of hepatitis B vaccine in infants with high titers of maternal anti-HBs remains to be further evaluated.     

血清乙型肝炎表面抗原定量在慢性乙型肝炎诊治中的临床应用和价值

HBsAg定量在慢性乙型肝炎诊治中相当重要。已有研究证明,HBsAg和HBV DNA水平的结合检测可鉴别非活动性HBV携带者。抗HBV治疗过程中,检测HBsAg定量可反映抗病毒疗效。HBAg水平快速下降可预测持续应答。此文就HBsAg定量在慢性乙型肝炎诊治中的临床应用和价值进行了综述。     

遗传易感因素与慢性乙型肝炎干扰素治疗反应的相关性

IFN-α以抗病毒及免疫调节双莺作用用于慢性乙型肝炎的治疗,对治疗反应的早期预测有利于治疗的持续.随着人类基因组学和蛋白质组学的研究进展,国内外对HBV感染发病及治疗反应遗传易感因素有较多报道,主要集中于抗病毒蛋白和免疫调节相关细胞因子的基因多态性.此文就遗传易感因素对IFN-α治疗慢性乙型肝炎疗效的影响作了综述.     

抗—HBs不同水平者接种乙型肝炎疫苗的初探

After hepatitis B vaccine immunization, serum antibody response was of primary type in 33 cases with anti-HBs less than 2.1 S/N (S/N Ratio Unit) at T0, the anti-HBs positive rate was 39.4%, 84.8%, 96.7% and 96.7% in T1, T2, T0 and T12 respectively. Anti-HBs S/N rose gradually month by month, the antibody response in younger children was better than that in adult. Anamnestic type in 38 cases with anti-HBs greater than 2.1 S/N at T0, the antibody levels rose rapidly in T1, T2 and began to fall in T8. The children were negative for HBsAg, anti-HBs and anti-HBc in sera by RPHA, PHA and ELISA respectively, most (100% in 1-4 age group and 63.2% in 5-9 age group) of them were also negative for HBV serological markers by SPRIA repeatedly, thus they were susceptible and need for hepatitis B vaccine immunization. Indication of hepatitis B vaccination for adult population was also discussed.     

Hepatitis B surface antigen (HBsAg) and core antigen (HBcAg) combine CpG oligodeoxynucletides as a novel therapeutic vaccine for chronic hepatitis B infection

Hepatitis B virus infection is a non-cytopathic hepatotropic virus which can lead to chronic liver disease and hepatocellular carcinoma. Traditional therapies fail to provide sustained control of viral replication and liver damage in most patients. As an alternative strategy, immunotherapeutic approaches have shown promising efficacy in the treatment of chronic hepatitis B patients. Here, we investigated the efficacy of a novel therapeutic vaccine formulation consisting of two HBV antigens, HBsAg and HBcAg, and CpG adjuvant. This vaccine formulation elicits forceful humoral responses directed against HBsAg/HBcAg, and promotes a Th1/Th2 balance response against HBsAg and a Th1-biased response against HBcAg in both C57BL/6 and HBV transgenic mice. Vigorous cellular immune response was also detected in HBV transgenic mice, for a significantly higher number of HBs/HBc-specific IFN-γ secreting CD4+ and CD8+ T cells was generated. Moreover, vaccinated mice elicited significantly intense in vivo CTL attack, reduced serum HBsAg level without causing liver damage in HBV transgenic mice. In summary, this study demonstrates a novel therapeutic vaccine with the potential to elicit vigorous humoral and cellular response, overcoming tolerance in HBV transgenic mice.