Immunogenicity of a recombinant hepatitis B vaccine in hemophiliacs

Yeast-recombinant vaccines against hepatitis B virus (HBV) are now available, but there is no information about whether or not they are immunogenic in patients with hemophilia and other congenital bleeding disorders. Twenty micrograms of a recombinant vaccine expressing the adw serotype of the hepatitis B surface antigen (HBsAg) were given to 41 patients negative for HBV markers and again after 1 and 6 months. Ten percent of the vaccinees had anti-hepatitis B surface antibody (anti-HBs) responses, with titers of 10 mIU/ml or more, 1 month after the first dose of vaccine. The percentage of anti-HBs-positive patients increased to 54% after the second dose and to 98% after the third dose, with only one non-responder. Hence, the recombinant vaccine was immunogenic, with percentages of seroconversion and anti-HBs titers similar to those achieved with plasma-derived vaccines.     

Immunogenicity and reactogenicity of a combined hepatitis A/B candidate vaccine: first results

Abstract: We evaluated immunogenicity and reactogenicity of an inactivated, combined hepatitis A/B candidate vaccine in 50 seronegative volunteers. Each volunteer received a total of three doses of vaccine (720 EIU HAV and 20 μg HBs antigen) according to a 0, 1 and 6 month vaccination schedule. One month after the first injection, the seroconversion rate was 90% (45/50) for anti-HAV and 28% (14/50) for anti-HBs, respectively. After the booster dose, at month 7, the seroconversion rate was as high as 100% (49/49) for anti-HAV and 94% (46/49) for anti-HBs. The geometric mean titres increased with each dose of vaccine administered. Mild, and mostly local side effects were reported in 54% of the volunteers after the first injection and in less than 10% after the third injection. Our results show that this inactivated, candidate hepatitis A/B vaccine is highly immunogenic and well-tolerated.     

Long-term effectiveness of infancy low-dose hepatitis B vaccine immunization in Zhuang minority area in China

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Immunogenicity of a 'pre-S2 plus S' hepatitis B vaccine in healthy adults

SUMMARY. The product of the pre-S plus S gene of hepatitis B virus appears to be more immunogenic in mice than the S-gene product (HBsAg) alone. Therefore, we tested the immunogenicity in healthy adults of a hepatitis B vaccine containing the 'middle protein' gene product of pre-S2 plus S (pre-S vaccine). We compared the immunogenicity of three doses of the pre-S vaccine with that of a commercially available recombinant hepatitis B vaccine (Recombivax-HB®): 87 seronegative adults were randomized to receive 12 μg (group 1), 24 μg (group 2), or 48 μg (group 3) of the pre-S vaccine or 10μg of Recombivax-HB (group 4) by deltoid injection at 0, 1 and 6 months. Antibody to HBsAg (anti-HBs) appeared after booster vaccination in 94% of vaccinees. Immunogenicity was best in recipients of 48 μg of the pre-S vaccine and Recombivax-HB, and geometric mean titres (GMT) for the pre-S vaccine were higher than those for Recombivax-HB only at the pre-S vaccine dose of 48 μg (group 3). Antibody to pre-S2 developed in 75% of the pre-S2 vaccine recipients (not in Recombivax-HB recipients) within 7 months. These findings indicate that the pre-S vaccine is immunogenic in healthy adults but that a dose of 48 μg of the current formulation is required to equal or exceed the immunogenicity of currently available, recombinant S-only vaccine. Studies in non-responders to S-only vaccines will be necessary to define an immunological advantage of the pre-S vaccines, and additional assessments will be necessary to determine whether anti-pre-S2 enhances protective efficacy.     

Poor efficacy of intradermal administration of recombinant hepatitis B virus immunization in HIV-infected individuals who fail to respond to intramuscular administration of hepatitis B virus vaccine

OBJECTIVE: It is recommended that hepatitis B virus (HBV)-susceptible, HIV-infected persons be immunized for HBV. However, 44-76% of HIV-infected persons fail to respond to a standard series of recombinant HBV vaccine. Intradermal (i.d.) administration of HBV vaccine has been effective in nonresponders to intramuscularly administered vaccine among healthcare workers, haemodialysis patients and renal transplant recipients. We evaluated the immunogenicity of HBV vaccine given by the intradermal route in HIV-infected individuals who failed to respond to two series of HBV vaccine given intramuscularly. METHODS: Recombinant HBV vaccine [10 microg HBV surface antigen (HBsAg)/mL] was administered as 0.25 mL i.d. every 2 weeks for four doses in 12 HIV-infected adults who failed to respond to six doses of HBV vaccine administered by the intramuscular route. Anti-HBs was tested at least 2 weeks following the fourth dose of i.d. administered vaccine, and if the anti-HBs titre was negative or <30 IU/L, a second series of four i.d. doses were administered every 2 weeks. Anti-HBs was measured at least 2 weeks following the second series of i.d. administered HBV vaccine and 6 and 12 months after the last dose. RESULTS: Protective levels of anti-HBs (>10 IU/L) were achieved in six subjects (50%) after four doses. Administration of four additional i.d. doses to the six nonresponders did not result in any additional seroconverters. Five of the six responders had no detectable anti-HBs at 12 months after the last dose of i.d. administered vaccine. CONCLUSIONS: The i.d. route of administration of recombinant HBV vaccine does not appear to be immunogenic in HIV-infected adults who fail to respond to six doses of intramuscularly administered vaccine.     

Immunogenicity, reactogenicity and adherence to a combined hepatitis A and B vaccine in illicit drug users

AIMS: The use of illegal drugs is associated with an increase in infective risk for the hepatitis viruses, against which the vaccination of drug users (DUs) is recommended unanimously. The aim of the study was to determine tolerability, adherence and immune response of a combined vaccine providing dual protection against hepatitis A virus (HAV) and hepatitis B virus (HBV). METHODS: The vaccine was administered to 38 DU, attending three public health centres for drug users in northern Italy, with a three-dose schedule (at 0, 1 and 6 months). The vaccine was well tolerated: only one adverse reaction (fever) was recorded after the 110 doses administered (0.9%). The vaccine schedule was completed successfully in 35 cases (92.1%). At month 8, in 34 subjects (89.5%) antibody response was evaluated: all showed seroprotection for HAV and in 33 subjects (97.1%) for HBV. CONCLUSIONS: The vaccine, studied for the first time in DUs, proved to be safe, well accepted and immunogenic; anti-HAV response was 1272 mIU/ml and 1726 mIU/ml for anti-HBV, titres lower than reported in literature for the general population. This study suggests that DUs who are HAV/HBV-negative could be vaccinated with combined vaccine.     

新型乙型肝炎病毒核心区核酸疫苗的免疫原性研究

目的观察新型乙型肝炎病毒(HBV)核心抗原(HBcAg)核酸疫苗的免疫原性。方法应用新型人体应用载体质粒pSW389l构建HBcAg核酸疫苗(pSW3891／HBc)，对照组和实验组Balb／c小鼠分别以基因枪法免疫对照载体质粒(PSW3891)和HBcAg核酸疫苗，采用酶联免疫吸附试验检测抗HBc，乳酸脱氢酶(LDH)释放测定法检测小鼠HBcAg特异性cTL杀伤活性。结果HBcAg核酸疫苗可在体外293T细胞中高效表达，免疫小鼠后可产生高滴度抗HBc(1：97200)，免疫鼠脾细胞HBc特异性CTL杀伤活性达73．25％。结论新型HBcAg核酸疫苗在Balb／c小鼠实验中表现出良好的体液和细胞免疫原性。     

The long-term efficacy of plasma-derived hepatitis B vaccine in babies born to carrier mothers

summary.  The long-term efficacy of a childhood hepatitis B vaccination programme was evaluated. A total of 112 newborn babies of hepatitis B carrier mothers were given hepatitis B immune globulin (HBIG) and a 10-μg three-dose regimen of plasma-derived vaccine administered at a conventional (0, 1, 6 months), delayed (2, 3, 8 months) or accelerated (0, 1, 2 months) schedule. The vaccinees were followed up to determine their anti-HBs status over a 16-year period. Upon completion of the vaccination schedules, 92.6% developed antibody against surface antigen (anti-HBs) seroconverion, the rate of which fell to 33.3% at year 16. The three schedules were equally effective in preventing chronic infection, with a protective efficacy of 88.9% from hepatitis B surface antigen (HBsAg) carriage, compared with historical control. Vaccinees on the delayed schedule had a slightly higher seroconversion rate over years, and were better able to maintain an anti-HBs level of ≥ 100 iu/L. Overall, a quarter demonstrated evidence of exposure to the virus, being positive for antibody against core antigen or HBsAg, or mounting a rise in anti-HBs during the follow-up period. We conclude that a three-dose hepatitis B vaccination regimen is generally effective in protecting newborns of hepatitis B carrier mothers from infection and chronic carriage. Booster is not needed even after 16 years of monitoring.     

Immune response to hepatitis B vaccine in patients with chronic hepatitis C infection: A systematic review and meta‐analysis

Hepatitis B virus and hepatitis C virus (HCV) co‐infection can add to the severity of hepatitis and the risks of liver cirrhosis and hepatocellular carcinoma. Whether chronic HCV infection decreases antibody response to hepatitis B vaccination is still controversial. We evaluate the influence of HCV infection on antibody response to hepatitis B vaccination by a systematic review of published works with a meta‐analysis of clinical trials. The random‐effects model of DerSimonian and Laird with heterogeneity and sensitivity analyses were used in this study. The end‐point of interest was the rate of patients showing seroconversion of antibody responses at completion of hepatitis B vaccination schedule among patients with chronic HCV infection versus healthy controls. We identified 11 studies involving 704 patients with HCV and 812 controls. Our results show a significant decrease in antibody seroconversion rates among patients with HCV versus healthy controls (pooled odds ratio = 0.17 [95% confidence interval, 0.11–0.28]). The P‐value was 0.21 for our test of study heterogeneity. Stratified analysis in subgroups of interest and sensitivity analysis did not meaningfully change our results. Our meta‐analysis showed patients with hepatitis C infection have a statistically significant lower rate of seroconversion in comparison to healthy controls, both in cirrhotic and non‐cirrhotic patients. Chronic HCV infection can decrease the immune response to a standard schedule of hepatitis B vaccination. Further studies are needed to investigate the optimum vaccination schedule for patients with chronic HCV infection.     

从人源免疫抗体库筛选抗乙型肝炎病毒PreS1单链抗体

目的 获得高亲和力的全人源化抗乙型肝炎病毒PreS1的单链抗体。 方法 以健康供血者的外周血淋巴细胞为来源,以PreS1肽体外致敏后,借助噬菌体展示技术构建人源免疫单链抗体库,库容量7×10 8。 结果 以PreS1肽进行3轮固相筛选。获得了亲和力10 7～10 8mol/L的抗PreS1单链抗体。结论 通过体外致敏的方法构建人源免疫抗体库,可以快速获得高亲和力基因工程抗体。     

Intradermal vs intramuscular vaccine against hepatitis B infection in dialysis patients: a meta‐analysis of randomized trials

Summary. Chronic dialysis patients are at risk of contracting hepatitis B virus infection and have a diminished immune response to hepatitis B virus vaccine. Recent reports support intradermal administration of hepatitis B virus vaccine in patients on regular dialysis but the efficacy and safety of this approach remain unclear. We conducted a meta‐analysis of randomized, controlled clinical trials to compare seroprotection achieved by intradermal vs intramuscular hepatitis B vaccine, in patients on maintenance dialysis. Meta‐analysis of data from 718 adults (14 trials) on long‐term dialysis demonstrated that intramuscular hepatitis B vaccination was less likely to achieve seroprotection than intradermal vaccination, the pooled odds ratio was 0.454 (95% CI, 0.3; 0.67), P = 0.001. The test of study heterogeneity was not significant. This difference did not persist during follow‐up (6–60 months after completing vaccine schedule), the pooled odds ratio being 0.718 (95% CI, 0.36; 1.47), NS. Some evidence of significant heterogeneity including publication bias was present but stratified analysis in various subgroups showed that this issue did not meaningfully change our results. Intradermal hepatitis B vaccine was safe and well tolerated. We conclude that intradermal hepatitis B vaccine induces a superior response rate compared to intramuscular route at completion of vaccine cycle, despite a lower vaccine dose. No significant advantage was found over longer follow‐up. It remains unclear whether the higher seroprotection rate achieved with intradermal route translates into a lower frequency of de novo hepatitis B among patients on maintenance dialysis.     

儿童接种乙肝疫苗后乙肝表面抗体滴度的影响因素分析

目的　分析乙型肝炎（乙肝）表面抗体阴性的儿童加强免疫后抗体滴度的影响因素。方法　选取2017年1—12月期间海南省妇幼保健院乙肝疫苗免疫后乙肝表面抗体阴性的84名儿童作为研究对象,比较1～3岁及4～7岁儿童的抗体滴度,并分析低免疫或无免疫反应的相关因素。结果　1～3岁儿童抗体滴度显著高于4～7岁儿童（P＜0.05）。30例（35.71%）儿童接种乙肝疫苗后呈低免疫反应,无患儿出现无免疫反应。Logistic多因素分析显示：年龄≥4岁是接种疫苗后低免疫反应的危险因素,母乳喂养时间越长、体质量百分位数越大、血清总蛋白越高,低免疫反应发生率越低。结论　年龄是儿童乙肝疫苗接种后抗体滴度的主要影响因素,母乳喂养及营养状态亦对免疫反应产生影响。     

Hepatitis C virus and the immunological response to hepatitis B virus vaccine in dialysis patients: meta-analysis of clinical studies

It is well known that the seroconversion rate of patients following hepatitis B virus (HBV) vaccination is lower in uraemic than healthy subjects. A variety of inherited or acquired factors have been implicated in this diminished response, and the high prevalence of hepatitis C virus (HCV) infection among patients on maintenance dialysis has been suggested to play a role. However, the impact of HCV on the immune response to HB vaccine in patients receiving long-term dialysis is not entirely understood. Here, we evaluate the influence of HCV infection on the immunological response to HBV vaccine in dialysis population by performing a systematic review of the literature with a meta-analysis of clinical studies.We used the random-effects model of DerSimonian and Laird with heterogeneity and sensitivity analyses. The end-point of interest was the rate of patients showing seroprotective anti-hepatitis B titres at completion of HBV vaccine schedule among HCV-positive versus HCV-negative patients on chronic dialysis. We identified eight studies involving 520 unique patients on long-term dialysis. Aggregation of study results did not show a significant decrease in response rates among HCV-infected versus noninfected patients [pooled odds ratio = 0.621 (95% CI, 0.285; 1.353)]. The P-value was 0.007 for our test of study heterogeneity. Stratified analysis in various subgroups of interest did not meaningfully change our results. Our meta-analysis showed no association between immunological response to hepatitis B vaccine and HCV infection in individuals on long-term dialysis. These results support the use of recombinant vaccine against hepatitis B in patients on regular dialysis with HCV infection.     

Identification of a hepatitis B virus S gene mutant in lamivudine-treated patients experiencing HBsAg seroclearance

BACKGROUND & AIMS: Seroclearance of hepatitis B virus (HBV) surface antigen (HBsAg) is a rare event in chronic hepatitis B patients receiving lamivudine therapy. It is generally believed to be a benevolent sign, implicating clearance of viremia. The aim of this study is to examine the authenticity of this dogma. METHODS: In a 5-year period, 11 patients treated with lamivudine experienced seroclearance of HBsAg. The clinical data were examined. The HBV S gene sequences derived from the patient's serum samples before and after seroclearance of HBsAg were analyzed. RESULTS: Serum HBV-DNA could be detected by nested polymerase chain reaction (PCR) in all 11 patients, by 1-step PCR in 8, and by Cobas Amplicor HBV-DNA test (>200 copies/mL) in 5. A mutation hot spot, P120A in the S gene, was identified in 6 of the 11 patients. Site-directed mutagenesis experiments indicated that the Ausria-II RIA test failed to detect this mutant. Decreased sensitivity of detection was also observed when other monoclonal antibodies were applied. CONCLUSIONS: Seroclearance of HBsAg during lamivudine therapy may not indicate viral clearance. Specifically, it may be caused by a point mutation in the S gene, which results in detection failure. In such patients, further verification and follow-up using a sensitive HBV-DNA test are advised.     

Anti-pre-S antibodies in different groups of patients with hepatitis B virus infection

The anti-pre-S antibody in the samples of sera from normal healthy persons and patients with different clinical types of liver diseases due to hepatitis B virus (HBV) infection was detected by a newly established enzyme-linked immunosorbent assay technique. This test is a blocking assay where anti-pre-S antibody in the patient's serum blocks subsequent addition of horse radish peroxidase-labelled polymerized human serum albumin (pHSA) to the pHSA-receptor site of HBsAg molecules fixed on a solid surface. Anti-pre-S activity was not detected in any from 95 healthy persons who were negative for all HBV-markers or from 105 healthy HBV carriers. In 12 sera from HBV vaccine recipients, anti-pre-S activity was noted in higher proportions compared with anti-HBs, after both the second and third doses of vaccine. Anti-pre-S activity was detected in small proportions of HBsAg positive sera from acute viral hepatitis (4.2%) and chronic active hepatitis (10%). In subacute viral hepatitis patients, the anti-pre-S antibody was totally absent. However, anti-pre-S activity was recorded in high proportions of HBsAg-positive sera from patients with cirrhosis of liver (57.2%) and fulminant hepatitis (41.6%). The anti-pre-S antibodies were assumed to be implicated in the clearance of HBV particles from circulation without causing tissue damage.     

A 12-year cohort study on the efficacy of plasma-derived hepatitis B vaccine in rural newborns

AIM:To understand the anti HBs persistence and the long-term preventive efficacy in rural newborns after vaccination with plasma-derived hepatitis B vaccine.METHODS:In the time of expanded program on immunization (EPI), the newborns were vaccinated with 10&mgr;gcenter dot3 doses of hepatitis B vaccine and 762 newborns who were HBsAg negative after primary immunization were selected for cohort observation from 1986 to 1998. Their serum samples were detected qualitatively and quantitatively for hepatitis B infecting markers, including HBsAg, anti-HBs and anti-HBc by SPRIA Kits. The annual HBsAg positive conversion rate was counted by life-table method.RESULTS:(1)The anti-HBs positive rate was 94.44% for the babies born to HBsAg negative mothers and 84.21% for those born to HBsAg positive mothers in the 1st year after immunization, and dropped to 51.31% and 52.50% in the 12th year respectively.GMT value was dropped from 31.62 to 3.13 and 23.99 to 3.65 in the 2nd to the 12th year respectively. There was a marked drop in GMT at the 3rd to the 5th year, and in anti HBs positive rate at the 9th to the 10th year. (2) In the period of 12 years observation, the person-year HBsAg positive conversion rates were 0.12% (5/4150.0) in newborns born to HBsAg negative mothers and 0.20% (1/508.0) in those born to HBsAg positive mothers, and none of the HBsAg positive converted children became HBsAg chronic carriers. Compared with the baseline before immunization, the protective rates were 97.19% and 95.32% respectively.CONCLUSION:The protective efficacy of plasma-derived hepatitis B vaccine persisted at least 12 years, and a booster dose seems not necessary within at least 12 years after the primary three-doses immunization to newborns born to HBsAg negative mothers.     

HLA-DPB1 alleles in hepatitis B vaccine response: A meta-analysis

Background:The role of the HLA-DRB1 and HLA-DQB1 genes in the antibody response to hepatitis B (HB) vaccine has been well established; however, the involvement of the HLA-DPB1 allele in the HB vaccine immune response remained to be clarified by a systematic review.Methods:A meta-analysis was performed in which databases were searched for relevant studies published in English or Chinese up until June 1, 2020. Six studies were identified and a total of 10 alleles were processed into statistical processing in this meta-analysis.Results:Three thousand one hundred forty four subjects (including 2477 responders and 667 non-responders) were included in this research. Alleles HLA-DPB1^∗02:02, DPB1^∗03:01, DPB1^∗04:01, DPB1^∗04:02, and DPB1^∗14:01 were found to be associated with a significant increase in the antibody response to HB vaccine, and their pooled odds ratios (ORs) were 4.53, 1.57, 3.33, 4.20, and 1.79, respectively; whereas DPB1^∗05:01 (OR = 0.73) showed the opposite correlation.Conclusions:These findings suggested that specific HLA-DPB1 alleles are associated with the antibody response to HB vaccine.     

Combined passive and active immunoprophylaxis for preventing perinatal transmission of the hepatitis B virus in infants born to HBsAg positive mothers in comparison with vaccine alone

BACKGROUND: In order for liver cirrhosis and hepatocellular carcinoma not to be inflicted upon in infants' lifetime, it is essential to prevent hepatitis B virus (HBV) infection in them. OBJECTIVES: The aim of this study is to reveal the efficacy of passive and active immunoprophylaxis in preventing perinatal transmission of HBV in Iran. STUDY DESIGN: In this cohort study with historical controls, 823 children born to the HBsAg positive mothers were evaluated. Out of this number, 638 had received neither hepatitis B (HB) vaccine nor hepatitis B immune globulin (HBIG) and aged more than 16 years (n=481, group 1) or 16 years or less (n=157, group 2). The other 125 persons had received only HB vaccine (group 3), and 60 neonates received both HB vaccine and HBIG (group 4). RESULTS: The prevalence of HBsAg in groups 1, 2, 3 and 4 was 56.1%, 40.3%, 12.6%, and 3.6%, respectively. The prevalence of anti-HBsAb had a significantly descending rate in groups 4 (85.7%), 3 (68.8%), 2 (33.3%), and 1 (21.8%), respectively. CONCLUSIONS: The addition of HBIG to recombinant vaccine will significantly increase the protection against HBV infection in comparison with HB vaccine alone.