Challenge studies in Rhesus monkeys immunized with candidate hepatitis E vaccines: DNA,DNA-prime-protein-boost and DNA-protein encapsulated in liposomes

Complete ORF2 gene (1983 bp) of hepatitis E virus (HEV) and the 450 bp region within ORF2 containing neutralizing epitope (NE) cloned in pVAX1 and corresponding proteins expressed in baculovirus and prokaryotic systems respectively were evaluated as vaccine candidates. Two doses of liposome encapsulated DNA plus corresponding protein with both ORF2 and NE regions (Lipo-ORF2-DP and Lipo-NE-DP) showed 100% seroconversion and comparable anti-HEV titres in Swiss albino mice. These vaccine candidates were further evaluated as DNA, DNA-prime-protein-boost (DPPB) and liposome formulations in Rhesus monkeys. Monkeys receiving ORF2/NE DNA seroconverted after fourth dose while those immunized employing ORF2-DPPB format seroconverted at 7 weeks post third dose. In view of the delayed weak antibody response, these monkeys were not challenged. Though Lipo-ORF2-DP was immunogenic, 2 of the 4 monkeys developed HEV infection following homologous virus challenge of 100 Monkey Infectious Dose₅₀. Both monkeys immunized with Lipo-NE-DP and 1 of the 2 monkeys immunized with NE-DPPB showed complete protection, the second monkey being protected from hepatitis with limited viral replication. Irrespective of the type of immunogen, all challenged monkeys were protected from hepatitis. The results document Lipo-NE-DP to be a promising vaccine candidate needing further evaluation.     

Safety and immunogenicity of a recombinant hepatitis B vaccine manufactured by a modified process in renal pre-dialysis and dialysis patients

Background

Patients with renal insufficiency are hyporesponsive to vaccination, including to hepatitis B vaccines. A manufacturing process modification for a hepatitis B vaccine (mpHBV) was studied in renal pre-dialysis and dialysis patients.

Methods

This randomized, open-label, multicenter, estimation study enrolled previously unvaccinated, HBV-seronegative adult dialysis and pre-dialysis patients (N = 276, median age 72.0 years). At 0, 1, 6, and 8 months, group 1 received a 1 mL intramuscular dose of mpHBV (containing 40 μg HBsAg) as a single injection, while group 2 received a 1 mL intramuscular dose of a licensed hepatitis B vaccine as two injections (each containing 20 μg HBsAg; 40 μg HBsAg total). Serum antibody to HBsAg (anti-HBs) was measured predose 1, and 1 month postdose 3 and 4. Anti-HBs geometric mean concentration (GMC) and seroprotection rate (SPR, % of subjects with anti-HBs titer ≥10 mIU/mL) were estimated at months 7 and 9.

Results

For group 1, month 7 SPR was 48.5% (49/101, 95% CI: 38.4%, 58.7%); with an additional dose, month 9 SPR increased to 66.7% (66/99, 95% CI: 56.5%, 75.8%). For group 2, month 7 SPR was 57.7% (64/111, 95% CI: 47.9%, 67.0%); with an additional dose, month 9 SPR increased to 69.2% (72/104, 95% CI: 59.4%, 77.9%). group 1 GMCs at months 7 and 9 were 27.5 mIU/mL (95% CI: 15.7, 48.0) and 61.7 mIU/mL (95% CI: 34.2, 111.5), respectively. group 2 GMCs at months 7 and 9 were 48.7 mIU/mL (95% CI: 28.7, 82.7) and 115.8 mIU/mL (95% CI: 65.2, 205.5), respectively. There were 22 serious adverse events; none were considered related to study vaccine.

Conclusions

Both formulations were immunogenic in this population but required more vaccinations to reach seroprotective levels than comparable regimens in healthy individuals, as expected. The relatively reduced SPRs seen in this population support the need for routine screening and re-dosing in this population.     

Long-term antibody persistence and immune memory to hepatitis B virus in adult celiac patients vaccinated as adolescents

Aim of this study was to investigate the anti-HBs antibody persistence and immune memory to hepatitis B virus in adult celiacs vaccinated as adolescents and the effect of a booster administration in non-protected individuals. Eleven years after primary vaccination, the proportion of vaccinees with titres ≥10 mIU/ml and antibody geometric mean concentrations (GMCs) were lower among celiac patients than among controls (68.6% vs 91.7%, p < 0.01; GMCs 29.38 mIU/ml vs 250.6 mIU/ml, p < 0.001). Participants with anti-HBs below 10 mIU/ml received a booster dose and were retested 2 weeks later to assess the anamnestic response. Post-booster anti-HBs levels were still <10 mIU/ml in 71.4% celiacs and 25% controls (p < 0.01).Our findings indicate that the prevalence of seroprotective levels of anti-HBs detected eleven years after primary immunization as well as the frequency of response to a booster dose of vaccine are lower in celiac patients compared to healthy controls.     

Platycodin D is a potent adjuvant of specific cellular and humoral immune responses against recombinant hepatitis B antigen

The ideal adjuvants for hepatitis B vaccines should be capable of eliciting both strong humoral and cellular immune responses, especially Th1 cell and cytotoxic T lymphocyte (CTL) responses. However, Alum used as adjuvants in the hepatitis B vaccines currently commercialized offers limitation in inducing cell-mediated response. Therefore, a less hemolytic saponin platycodin D (PD) from the root of Platycodon grandiflorum has been explored for its potential as an alternative adjuvant. In order to compare the adjuvant activity with Alum, antigen-specific cellular and humoral immune responses were evaluated following immunization with a formulation containing hepatitis B surface antigen (HBsAg) adjuvanted with PD and Alum in mice. The Con A-, LPS-, and HBsAg-induced splenocyte proliferation and the serum HBsAg-specific IgG, IgG1, IgG2a, and IgG2b antibody titers in the HBsAg-immunized mice were significantly enhanced by PD (P < 0.05, P < 0.01 or P < 0.001). PD also significantly promoted the production of Th1 (IL-2 and IFN-γ) and Th2 (IL-10) cytokines and up-regulated the mRNA expression of Th1 cytokines (IL-2 and IFN-γ) in splenocytes from the mice immunized with HBsAg (P < 0.001). Besides, PD remarkably increased the killing activities of natural killer (NK) cells and CTLs from splenocytes in the HBsAg-immunized mice (P < 0.001), which may have important implications for vaccination against hepatitis B virus. The results indicated that PD has strong potential to increase both cellular and humoral immune responses and elicit a balanced Th1/Th2 response against HBsAg, and that PD may be the candidates as adjuvants for use in prophylactic and therapeutic hepatitis B vaccine.     

Presence of immune memory and immunity to hepatitis B virus in adults after neonatal hepatitis B vaccination

Neonatal vaccination against hepatitis B virus (HBV) infection was launched in the 1980s in Qidong, China, where HBV and hepatocellular carcinoma were highly prevalent. Presence of immune memory and immunity against HBV in adults needs to be clarified. From a cohort of 806 who received plasma-derived Hep-B-Vax as neonates and were consecutively followed at ages 5, 10, and 20 years, 402 twenty-four-year-old adults were recruited for booster test. Among them 4 (1%) were found to be HBsAg(+), 27 (6.7%) were HBsAg(−)anti-HBc(+), 121 (30.2%) were HBsAg(−)anti-HBc(−)anti-HBs(+), and 252 (62.4%) were HBsAg(−)anti-HBc(−)anti-HBs(−). Of them, 141 subjects with HBsAg(−)anti-HBc(−) were boosted with 10-μg recombinant HBV vaccine on day-0 and 1-month. The conversion rates of anti-HBs ≥10 mIU/ml on D10-12 and 1-month post-booster were 71.4% and 87.3% respectively in the vaccinees who were anti-HBs(+) at age 5, higher than in those who were anti-HBs(−) at age 5, 57.5% and 80.0% respectively, but no statistically significant. After the second dose of booster, all subjects with anti-HBs(+) at age 5 had anti-HBs >500 mIU/ml. However, 6/40 subjects, with anti-HBs(−) at age 5, had anti-HBs <10 mIU/ml, geometric mean concentration was 3.6 (95% CI 2.0-7.7). Of the subjects received booster, 44 subjects were determined the presence of T cell immunity on D10-12, 41 had HBsAg-specific T cells detectable, including 7/10 subjects whose anti-HBs were <10 mIU/ml 10-12 days post-booster. Among 27 HBsAg(−)anti-HBc(+) subjects, 19 had detectable serum HBV-DNA, and an “a” epitope mutation was found in 1/5 HBV isolates. One subject who was anti-HBc(+) at age 20 converted into HBsAg(+) 4 years later. The adults received neonatal HBV vaccination had immune memory and immunity against HBV infection. However, 31.9% of neonatal HBV vaccinees who responded weakly at an early age might be susceptible to HBV infection after childhood.     

Whole recombinant Hansenula polymorpha expressing hepatitis B virus surface antigen (yeast-HBsAg) induces potent HBsAg-specific Th1 and Th2 immune responses

Recent studies have suggested that yeast cell wall components possess adjuvant activities. In the present study, heat-killed whole recombinant Hansenula polymorpha yeast expressing hepatitis B surface antigen (yeast-HBsAg) was generated, and the immune responses elicited by yeast-HBsAg were investigated in mice. The studies showed that yeast-HBsAg as well as yeast greatly promotes the accumulation of immune cells in mouse spleen and contributes to the maturation of dendritic cells (DCs). Yeast-HBsAg not only induces significantly higher antibody responses (including IgG, IgG1 and IgG2a), but also increases the IgG2a/IgG1 ratio, while alum combined with HBsAg (HBsAg + alum) only enhances antibody responses, but not the IgG2a/IgG1 ratio compared to HBsAg alone. Analysis of HBsAg-specific cytokines revealed that yeast-HBsAg is associated with production of both IFN-γ and IL-4, but neither IFN-γ nor IL-4 was detected in the HBsAg + alum-immunized group. Moreover, yeast-HBsAg induces potent HBsAg-specific lymphocyte proliferation and Cytotoxic T lymphocyte (CTL) responses. In conclusion, yeast-HBsAg enhances both HBsAg-specific Th1 and Th2 immune responses, while alum only enhances Th2 immune responses, suggesting that yeast-HBsAg may be an ideal candidate for an effective vaccine for the control of chronic hepatitis B virus (HBV) infection.     

Immunogenicity of a recombinant hepatitis B vaccine (Euvax-B) in haemodialysis patients and staff

Hepatitis B vaccine is the most effective strategy for preventing the transmission of hepatitis B virus (HBV) in haemodialysis centers. Nevertheless, lower vaccine responses have been reported in haemodialysis patients as compared with healthy subjects. This study examines the response to Euvax-B in Brazilian haemodialysis patients and staff. A total of 102 eligible patients (n = 42) and staff members (n = 60) consented to be studied. Patients were immunized intramuscularly with four doses of 40 g of Euvax-B vaccine at 0, 1, 2 and 6 months. In staff members, the vaccine was administered in three doses of 20 g at 0, 1, and 6 months. Post-vaccine samples were taken from all subjects 1 month after each dose. The vaccine response was determined by measuring antibody to the hepatitis B surface antigen (anti-HBs) levels using ELISA. Subjects with anti-HBs titres equal to or higher than 10 UI/L were considered immune protected. Of the haemodialysis patients who received four doses of hepatitis B vaccine, 89.5% responded to Euvax-B vaccine. The geometric mean of anti-HBs titres was 322.8 IU/L (95% CI: 317.7–328). Among staff members, 93.3% reached anti-HBs protective titres after the third vaccine dose. The geometric mean of anti-HBs titres was 2209 IU/L (CI: 2198–2219). Age, male gender and body mass index were not associated with vaccine response in either group. This study showed a good immunogenicity response to Euvax-B in haemodialysis patients and staff.     

Hepatitis B vaccine response among infants born to hepatitis B surface antigen-positive women

Purpose

Annually, an estimated 25,000 infants are born to hepatitis B surface antigen (HBsAg)-positive women in the United States. Hepatitis B (HepB) vaccine and hepatitis B immune globulin (HBIG) are recommended at birth, followed by completion of vaccine series and post-vaccination serologic testing (PVST). In a large cohort of infants born to HBsAg-positive women, factors influencing vaccine response were evaluated.

Methods

Data were from HBsAg-negative infants born to HBsAg-positive women in the Enhanced Perinatal Hepatitis B Prevention Program (EPHBPP) from 2008 to 2013. Vaccine non-responders were defined as infants with antibody to hepatitis B surface antigen (anti-HBs) <10 mIU/mL at PVST after receiving ≥3 vaccine doses. Multivariable analyses modeled statistically significant predictor variables associated with non-response.

Results

A total of 17,951 maternal-infant pairs were enrolled; 8654 HBsAg-negative infants born to HBsAg-positive mothers received ≥3 doses of vaccine with anti-HBs results. 8199 (94.7%) infants responded to a primary HepB series; 199 (94.8%) to a second series. Factors associated with anti-HBs <10 mIU/mL included gestational age <37 weeks, vaccine birth dose >12 h after birth, timing of final vaccine dose <6 months after birth, receipt of 3 vs. 4 vaccine doses, and PVST interval >6 months from final vaccine dose in bivariate analysis. PVST interval >6 months from final vaccine dose (OR = 2.7, CI = 2.0, 3.6) was significantly associated with anti-HBs <10 mIU/mL; the proportion increased from 2% at 1–2 months to 21.6% at 15–16 months after the final dose. Receipt of a 4th dose improved the response rate (OR = 0.5, CI = 0.3, 0.8).

Conclusions

Ninety-five percent of a large cohort of uninfected infants born to HBsAg-positive mothers in the United States responded to primary HepB vaccine series. The proportion of infants with anti-HBs <10 mIU/mL increased with longer interval between the final vaccine dose and PVST. Optimal timing of PVST is within 1–2 months of final vaccine dose to avoid unnecessary revaccination.     

Characteristics of immune memory 10–15 years after primary hepatitis B vaccination

Background and aimsThe definition of immune memory after hepatitis B vaccination is still under debate. Therefore, we analysed hepatitis B surface antigen (HBsAg)-specific memory in more detail by investigating the kinetics of humoral and cellular responses after hepatitis B booster vaccination.MethodsThe anti-HBs kinetics of 23 individuals with anti-HBs titres below 10 IU/l, who had been vaccinated 10–15 years ago, was monitored at day 0, 3, 7, 14 and 28 after booster vaccination. HBsAg-specific IFNγ- and IL5-secreting cells in enriched CD4⁺ fraction were measured at day 0, 7 and 28 post-booster by enzyme-linked immunospot assay (ELISpot).Results22 of 23 subjects showed similar anti-HBs kinetic curves, including 3 of 4 subjects who did not reach anti-HBs titres of 10 IU/l. The steep anti-HBs increase started between day 3 and 7 and peaked around day 14. A plateau or only minimal changes were visible between day 14 and 28. 17.4% of subjects showed pre-booster cellular responses, and this rate had increased to 47.8% and 56.5% after 7 and 28 days, respectively. The kinetic patterns of T cell responses differed considerably among subjects. A dominance of Th2 responses (IL5 secretion) over Th1 responses (IFNγ secretion) could be observed.ConclusionsThe presence of B cell memory could be shown by a typical anamnestic anti-HBs response curve after a booster dose in all but one individual. In contrast, T cell responses to booster vaccination, which occurred in approximately 50% of participants, were rather heterogeneous.     

Long-term efficacy of plasma-derived and recombinant hepatitis B vaccines in a rural township of Central Taiwan

Aims

To assess the differences of long-term efficacy between plasma-derived and recombinant hepatitis B virus (HBV) vaccines and the effectiveness of catch-up vaccination in adolescents with undetectable anti-HBs.

Methods

Before 1992, infants born in Taiwan were immunized using plasma-derived HB vaccine, and thereafter, by using recombinant HB vaccine. From the only junior middle school of a rural township in central–southern Taiwan, 1788 (93.7%) students from five cross-sectional screenings, grouping into three birth cohorts (Group I: born during 1984–1986, II: 1986–1992 and III: 1992–1995), were enrolled for checking HBsAg, anti-HBs and anti-HBc. Students with undetectable HBsAg and anti-HBs underwent a booster dose (2.5 ug) of recombinant HB vaccine (Engerix-B; GlaxoSmithKline, Rixensart, Belgium) and had anti-HBs re-checked 3 weeks later. Individuals who had remained undetectable for anti-HBs completed the other two doses of HB vaccines at 1 and 6 months later.

Results

The prevalence of HBsAg (11.4, 5.4 and 1.2%), anti-HBs (64.5, 44.1 and 36.0%) and anti-HBc (29.5, 12.5 and 4.4%) decreased from Group I to III (P < 0.001 for trends). After a booster dose, the positive rates of anti-HBs increased up to 80.5% (16% increase) in Group I, 81.0% (36.9% increase) in Group II, and 94.4% (58.4% increase) in Group III. The percentages of anamnestic response increased with a trend (P < 0.001). A total of 110 non-responders completed 3 doses of catch-up HB vaccination, but 3 cases (2.7%) of Group II, evoked primary vaccination response.

Conclusion

Recombinant vaccine showed predominant disappearance rate (62.7%) of anti-HBs 12–15 years after vaccination, but provided better anamnestic response after a booster dose. It also showed high success rate (97.3%) in catch-up vaccination in adolescents.     

Efficacy of yeast-derived recombinant hepatitis B vaccine after being used for 12 years in highly endemic areas in China

Objective

To evaluate the long-term efficacy and duration of yeast-derived recombinant hepatitis B vaccine in hepatitis B virus (HBV)-endemic areas.

Method

A cross-sectional investigation was carried out in five HBV-endemic areas. Children who were born between 1997 and 2008 and vaccinated with yeast-derived recombinant hepatitis B vaccine were selected. Serum samples were taken to test HBV infection markers by microparticle enzyme immunoassay, and the results were compared to those before vaccination.

Results

7066 subjects were enrolled. The average adjusted hepatitis B surface antigen (HBsAg) prevalence was 1.02%. HBV core antibody (anti-HBc) prevalence was 3.54%. The overall percentage of HBsAg(−)&Anti-HBc(−)&Anti-HBs(+) was 61.34%. With time after immunization, the percentage annually decreases from 86.11% in 2008 to 49.80% in 1997. Geometric mean concentration (GMC) of anti-HBs decreased significantly annually. The portion of GMC = 100–999.9 mIU/ml was 48.0% in 2008, and decreased to 16.7% in 1997.

Conclusion

HBsAg prevalence decreased dramatically. This shows that the yeast-derived recombinant hepatitis B vaccine is effective and stable after being used for 12 years in HBV-endemic areas. It is not suggested to carry out booster immunization.     

1 500名儿童重组乙型肝炎疫苗免疫效果观察

目的 评价临沂市儿童重组酵母乙型肝炎疫苗接种8年后的免疫效果。方法 采取随机整群抽样法，采用固相放射免疫法（SPRIA）检测血清HBsAg、抗-HBs和抗-HBc水平，并对免疫后HBsAg阳性原因进行分析。结果 1500名3～8岁儿童中HBsAg阳性率为0.47%，疫苗免疫保护率为89.00%，抗-HBc阳性率为2.07%，各年龄组比较差异无统计学意义。抗-HBs阳性率为44.47%，但随年龄增大抗体阳性率下降。几何平均滴度为58.03mIU/mL，各年龄组比较差异无统计学意义。在7例HBsAg阳性儿童中，57.14%儿童的母亲HBsAg阳性。结论 重组酵母乙型肝炎疫苗接种3～8年后，免疫人群保护效果理想，HBsAg阳性率未随免疫时间延长而明显增加。重组酵母乙型肝炎疫苗接种后抗-HBs阳性率随年龄增大而下降，应加强血清学监测。     

Seroprotection after recombinant hepatitis B vaccination among newborn infants: A review

Introduction

Hepatitis B vaccination starting at birth provides a safety net for infants exposed to hepatitis B virus (HBV) during delivery or in early life. Hepatitis B vaccine is recommended in the United States for infants prior to birthing facility discharge, and within the first 12 h of life for infants born to hepatitis B surface antigen (HBsAg)-positive mothers. We performed a literature review and summarized the response to recombinant hepatitis B vaccine among infants.

Methods

Studies published between 1987 and 2011 assessing seroprotection from recombinant hepatitis B vaccine starting within the first 30 days of life were eligible. Seroprotection was defined using an antibody to hepatitis B surface antigen (anti-HBs) threshold of 10 mIU/mL at series completion. Infant seroprotection was compared in trial arms varying by maternal hepatitis B antigen status (e antigen [HBeAg], HBsAg), hepatitis B immune globulin (HBIG) administration, birth weight, vaccine dosage, schedule, and age at first dose.

Results

Forty-three studies were included. The median seroprotection proportion overall was 98% (range 52%, 100%). The final median seroprotection proportions did not vary appreciably by maternal HBsAg status, HBIG administration, or schedule. Higher compared to lower dosage resulted in earlier increases in anti-HBs but not in final seroprotection proportions. Infants with birth weights <2000 g compared to ≥2000 g had lower median seroprotection proportions (93% and 98%, respectively). Median seroprotection proportions were also lower when infants with birth weights <2000 g were vaccinated at 0–3 days of age compared to 1 month of age or older (68% versus 95%, respectively).

Conclusion

High levels of protection from recombinant hepatitis B vaccine are achieved in term infants vaccinated at birth, effectively preventing transmission of HBV and resultant morbidity and mortality. Implications, if any, for long-term protection are unknown for differences in responses among infants vaccinated at birth compared to ages older than 1 month.     

Small is beautiful: N-trimethyl chitosan-ovalbumin conjugates for microneedle-based transcutaneous immunisation

To provoke an immune response, a transcutaneously administered vaccine has to diffuse into the skin, reach the lymph nodes and be taken up by dendritic cells (DCs). To study these three steps we immunised mice transcutaneously (with microneedles), intradermally and intranodally. The effect of the formulation was investigated by formulating ovalbumin (OVA) in three ways with N-trimethyl chitosan (TMC): TMC + OVA mixtures, TMC-OVA conjugates and TMC/OVA nanoparticles. Both the percentage OVA⁺ DCs in the lymph node and the resultant immunogenicity (serum IgG titres) were studied.Transcutaneously, the TMC-OVA conjugates induced the highest IgG levels and resulted in more OVA⁺ DCs in the lymph nodes after 24 h than the other TMC formulations. Intradermally, all TMC-adjuvanted OVA formulations increased IgG titres compared to plain OVA. These formulations formed a depot in the skin, prolonging OVA delivery to the lymph nodes. The prolonged delivery of TMC-adjuvanted OVA to lymph node resident DCs was also observed after intranodal immunisation, but in this case the higher uptake did not correspond with elevated antibody titres compared to plain OVA.In conclusion, after transcutaneous administration, TMC-OVA conjugates are most immunogenic among the tested formulations, likely because they penetrate the skin more easily than nanoparticles and consequently are better delivered to DCs, while they show higher uptake by DCs than TMC + OVA mixtures.     

Post-vaccination serologic testing of infants born to hepatitis B surface antigen positive mothers in 4 provinces of China

ObjectiveTo evaluate prenatal maternal hepatitis B virus (HBV) screening and post-vaccination hepatitis B surface antigen (HBsAg) and antibody to hepatitis B surface antigen (anti-HBs) status and titers of babies born to HBsAg positive mothers, and to provide evidence for development of standard postvaccination serologic testing (PVST) strategies for babies born to HBsAg positive mothers in China.MethodsIn 2014, we conducted a baseline survey of HBV mother to child transmission (MTCT) interruption strategy implementation and PVST for babies born to HBsAg positive mothers after received 3 doses of hepatitis B vaccine (HepB) in 8 counties in 4 Provinces. Bivariate analysis and multivariable analyses modeled statistically significant predictor variables associated with infant HBsAg, anti-HBs positive, anti-HBs titer.ResultsAmong the 1563 infants born to HBsAg positive mothers, 1025 (65.6%) maternal-infant pairs were enrolled in PVST after receiving 3 doses of HepB. 38 infants tested HBsAg positive for an HBsAg positive rate of 3.7%. Maternal hepatitis B e antigen (HBeAg) status and age of infant were significantly associated with infant HBsAg positivity. A total of 932 infants were anti-HBs positive when tested at 7–24 months of age, yielding an anti-HBs positivity rate of 90.9%. Maternal HBeAg status was the factor associated with infant anti-HBs status. Amount of antigen of HepB and infant’s age were most associated with anti-HBs titers. PVST performed 1–2 months after the 3rd dose of HepB was associated with the highest anti-HBs level and the anti-HBs Geometric Mean Concentration (GMC) decreased as the PVST intervals prolonged.ConclusionsIn China, perinatal HBV transmission is approaching the theoretical minimum possible with the current strategy of HepB coupled with HBIG administration for HBV-exposed newborns. PVST of infants born to an HBsAg positive mother is an essential strategy to ensure full protection for vaccine non-responders and appropriate medical care for those infected.     

Seroepidemiology of hepatitis B virus infection among adults in Singapore: A 12-year review

We undertook a national hepatitis B seroprevalence study to assess the seroprevalence of hepatitis B virus (HBV) markers in the adult population in Singapore in 2010 and make comparisons with the seroprevalence in 1998 and 2004. The study involved residual sera from national health surveys conducted every six years since 1998. The tests for HBV markers were carried out using commercial chemiluminescent microparticle immunoassay. In 2010, the prevalence of hepatitis B surface antigen (HBsAg) among 3293 Singapore residents aged 18–79 years was 3.6% (95% confidence interval [CI] 2.9–4.2%). Hepatitis B e antigen (HBeAg) was detected in 4.2% of those who were HBsAg positive. About 22.5% (95% CI 21.1–23.9%) were positive for antibody to hepatitis B core antigen (anti-HBc). The overall population immunity to HBV, as determined by antibody to hepatitis B surface antigen (anti-HBs) ≥ 10 mIU/mL, was 43.9% (95% CI 42.2–45.6%). Among young adults below 30 years of age, HBsAg prevalence (1.1%) was half that in 1998 and 2004, and in those positive for HBsAg, none was positive for HBeAg in 2010, compared to 20.8% in 1998 and 15.8% in 2004. In this age group, anti-HBc prevalence also decreased significantly from 22.1% in 2004 to 4.4% in 2010, while anti-HBs (≥10 mIU/mL) prevalence increased significantly from 27.9% in 1998 to 43.3% in 2010 (p < 0.001). The national childhood HBV immunisation and catch-up programmes implemented in 1987 and 2001–2004, respectively, had a significant impact in reducing HBV infection and in raising the immunity of the adult population 18–29 years of age.     

深圳地区人群接种乙肝疫苗后抗体水平监测研究

目的了解深圳地区人群乙肝疫苗接种后对抗-HBs的影响.方法采用单纯随机抽样的方法对1996～2003年来某院健康体检的资料完整的35 000人进行HBsAg和抗-HBs调查.结果35 000人中HBsAg平均阳性率为4.82%,抗-HBs平均阳性率为61.47%.抗-HBs阴性和抗-HBs阳性人群乙肝疫苗的平均接种率分别是99.92%和94.92%;乙肝疫苗接种后第1年和第3年检测抗-HBs阳性水平;全阴者平均抗-HBs阳性率分别为95.61%和37.46%;加强接种者平均抗-HBs阳性率分别为86.83%和57.62%.结论接种乙肝疫苗是预防乙型肝炎的最有效措施,乙肝疫苗接种3 a后抗-HBs下降明显,需加强免疫.     

Immune response to hepatitis B vaccination in drug using populations: A systematic review and meta-regression analysis

Injecting and non-injecting drug users are at increased risk of contracting HBV infection, and show lower antibody response to hepatitis B vaccination compared to the general population. This systematic review and meta-regression analysis aimed to estimate seroprotection rates and identify host or vaccine factors associated with varying immune response following hepatitis B vaccination in drug using populations. Original research articles were searched using online databases (Medline, PubMed, and Embase) and from reference lists of eligible articles. HBV vaccine intervention studies reporting seroprotection rates in drug users, published in English during or after 1989 were eligible. Of 978 citations reviewed, 11 studies were eligible and included for final analysis. The reported seroprotection rates ranged from 54.5% to 97.1%. The studies were significantly heterogeneous (Q = 180.850, p = 0.000). Measurement of anti-HBs antibody at 2 months after the third vaccine dose (RR = 2.62, 95%CI = 1.16–5.94, p = 0.026) was significantly associated with higher seroprotection rates compared to measurement at 1 month and 6 month following third vaccine dose. Age, gender, current drug use, vaccine dose and schedule, anti-HBc, anti-HCV and anti-HIV antibody seropositivity, and proportion of IDU study population did not show a significant association with seroprotection rates. Recommendations for future research include the definition of a standardized time point for the measurement of anti-HBs antibody levels, to enhance comparability of the immune response between different studies. Studies should strive to accurately report all potentially relevant factors affecting immune response to vaccine. Long-term follow up studies are needed to assess the seroprotection status in drug using populations receiving hepatitis B vaccine by standard or accelerated schedules.     

乙型肝炎疫苗长期免疫对人群乙型肝炎病毒流行状况的影响

目的探讨乙型肝炎（乙肝）疫苗长期免疫接种后整体人群乙肝病毒（HBV）感染状况及其变化趋势。方法采用整群抽样结合横断面调查方法，共收集资料完整的调查对象4686名，采集静脉血并分离血清，用固相放射免疫法检测HBV感染标志。结果整体人群平均HBsAg阳性率为7．5％，抗-HBs为44．5％，抗-HBc为47．8％；0～19岁人群HBsAg和抗-HBc阳性率较≥20岁人群显著下降。乙肝疫苗免疫组的HBsAg阳性率为2．8％，抗-HBc阳性率为12．0％，HBV感染率为12．5％，未免疫组分别为10．2％、69．8％和71．2％。男性平均HBsAg阳性率比女性高，抗-HBc和抗-HBs阳性率男女性别间无差异。0～19岁人群的HBsAg阳性率为2．4％，而20～30岁人群阳性率达到13．6％～17．7％，到60岁开始下降；0～19岁人群的抗-HBs阳性率随年龄增长而明显下降，≥20岁人群的抗-HBs、抗-HBc阳性率均随着年龄增长而呈升高趋势。结论长期开展新生儿乙肝疫苗免疫使人群HBV流行状况发生变化，感染高峰年龄段后移。     

Immunogenicity and safety of an investigational hepatitis B vaccine with a toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared with a licensed hepatitis B vaccine in patients with chronic kidney disease

Background

Hemodialysis patients are at increased risk of hepatitis B virus (HBV) infection and patients with chronic kidney disease (CKD) are commonly hyporesponsive to HBV vaccines. Current recommendations for CKD patients are to utilize 4 double-doses (2 × 20 mcg HBsAg) of a licensed hepatitis B vaccine (HBsAg-Eng).

Methods

An observer-blind, randomized, active-controlled, parallel group, multicenter trial was conducted among 521 patients 18–75 years of age with CKD, comparing 3 single doses of an investigational hepatitis B vaccine (20 mcg rHBsAg + 3000 mcg 1018, a toll-like receptor 9 agonist) given at 0, 4, and 24 weeks to 4 double-doses of HBsAg-Eng (2 × 20 mcg rHBsAg + 500 mcg alum) given at 0, 4, 8, and 24 weeks (total of 8 injections). Participants were followed for 1 year.

Results

Among 467 participants in the modified intent-to-treat population, at the primary endpoint at week 28, the seroprotection rate (SPR: % with anti-HBs ≥ 10 mIU/mL) in the HBsAg-1018 group (89.9%) met criteria for noninferiority and superiority to the SPR in the HBsAg-Eng group (81.8%). At week 28, the percentage of participants with anti-HBs ≥ 100 mIU/mL in theHBsAg-1018 group (73.6%) was significantly higher than in the HBsAg-Eng group (63.2%). In addition, the geometric mean concentration of anti-HBs in the HBsAg-1018 group (587.1 mIU/mL) was significantly higher than in the HBsAg-Eng group (156.5 mIU/mL). At weeks 8 and 12 after the first study injection, SPRs in the HBsAg-1018 group were significantly higher than in the HBsAg-Eng group. At 52 weeks, the immune response toHBsAg-1018 remained higher than to HBsAg-Eng. HBsAg-1018 was generally well tolerated and had a similar safety profile to HBsAg-Eng.

Conclusion

In CKD patients, 3 doses of HBsAg-1018 induced significantly higher seroprotection, earlier seroprotection, and more durable seroprotection than 4 double doses of HBsAg-Eng.