Plasma-derived Vaccine Research Articles

Review article: Hepatitis B and dialysis

The incidence of hepatitis B virus (HBV) infection in dialysis populations has declined over recent decades, largely because of improvements in infection control and widespread implementation of HBV vaccination. Regardless, outbreaks of infection continue to occur in dialysis units, and prevalence rates remain unacceptably high. For a variety of reasons, dialysis patients are at increased risk of acquiring HBV. They also demonstrate different disease manifestations compared with healthy individuals and are more likely to progress to chronic carriage. This paper will review the epidemiology, modes of transmission and diagnosis of HBV in this population. Prevention and treatment will be discussed, with a specific focus on strategies to improve vaccination response, new therapeutic options and selection of patients for therapy.

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.

Twenty-two years follow-up of a prospective randomized trial of hepatitis B vaccines without booster dose in children: Final report

Long-term immunogenicity and efficacy of HBV vaccination with different regimens of HBV vaccines (A: 2-dose recombinant vs. B: 3-dose recombinant vs. C: 3-dose plasma-derived vaccines) without booster dose were examined in 318 Chinese children. Geometric mean titer (GMTs) of anti-HBs of group A subjects was significantly lower than that of groups B and C subjects at years 1, 5, 10 and 15. At year 22, the proportion of subjects with anti-HBs ≥10 mIU/mL for groups A, B and C were 35.3%, 76.5% and 52.4%, respectively ( p < 0.05 between groups A and B) in 55 subjects. In the 22 years study period, none was found to be HBsAg positive, and 72 subjects had ≥1 episodes of anamnestic response. In conclusion, the 3-dose regimens have a better long-term immunogenicity. In terms of protection against HBV infection, the 2-dose and 3-dose vaccines had equal efficacies.

Hepatitis B vaccination of haemodialysis patients: randomized controlled trial comparing plasma-derived vaccine with and without pre-S2 antigen

The pre-S2 protein of the hepatitis B virus envelope evokes anti-pre-S2 antibodies and enhances the anti-HBs response after vaccination in mice. In order to evaluate the immunogenicity of the pre-S2 Ag in man, 102 HBsAg, anti-HBs, anti-HBc-negative haemodialysis patients were vaccinated at random according to one of four vaccination schedules: 5 micrograms plasma vaccine Pasteur (containing 1% pre-S2) or 20 micrograms plasma vaccine MSD (no pre-S2) at 0, 1, 2, 4, 6 and 12 months; or 10 micrograms Pasteur or 40 micrograms MSD at 0, 1, 2 and 6 months. Anti-HBs levels were measured by RIA and expressed in IU l-1; anti-pre-S2 response was evaluated by both EIA and Western blot analysis. Eighty-four per cent (95% confidence interval: 75-93) of the patients exhibited an anti-HBs response of 2 IU l-1 or more and 71% (95% confidence interval: 61-81) reached an anti-HBs level of at least 10 IU l-1 within 13 months of the start of vaccination. Anti-HBs response correlated with age (the response rate decreased with increasing age) but not with either the type of vaccine or dosage. An anti-pre-S2 response was observed in 16% (EIA) and 46% (Western blot) of the patients immunized with the Pasteur vaccine and none (EIA, Western blot) of the MSD group. The level of anti-pre-S2 antibodies correlated with high anti-HBs titres; an anti-pre-S2 response occurred in only one anti-HBs-negative patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Humoral and Cellular Immune Responses to a Hepatitis B Vaccine Booster 15–18 Years after Neonatal Immunization

Whether hepatitis B (HB) vaccine-conferred immunity persists into adulthood is unknown. We aimed to investigate long-term HB immunity in adolescents. In 2004-2005, 6156 high school students (15-21 years old) who had been vaccinated with plasma-derived HB vaccine as infants were recruited for HB seromarker screening. The immune response to an HB vaccine booster was evaluated in 872 subjects who were seronegative. HB surface antibody (anti-HBs) titers and levels of HB surface antigen (HBsAg)-specific interferon (IFN)-gamma- or interleukin (IL)-5-secreting peripheral blood mononuclear cells (PBMCs; measured by enzyme-linked immunospot assay) were determined 4 weeks later. Although the vaccine remained highly efficacious in reducing the HBsAg positivity rate, 63.0% of the vaccinees had no protective anti-HBs. After the booster, anti-HBs remained undetectable in 28.7% (158/551) of the subjects who had received complete HB vaccination (4 doses) during infancy. We estimated that 10.1% of the total population had lost their HB vaccine-conferred booster response. HBsAg-specific IFN-gamma- or IL-5-secreting PBMCs remained negative in 27.2% (25/92) of subjects after the booster. A notable proportion of fully vaccinated adolescents had lost immune memory conferred by a plasma-derived HB vaccine 15-18 years later. This decay of immune memory may raise concerns about the need for a booster vaccine for high-risk groups in the long run.

Differences in Response to a Hepatitis B Vaccine Booster Dose Among Alaskan Children and Adolescents Vaccinated During Infancy

The duration of protection provided by hepatitis B vaccination is unknown, but the presence of immune memory can be evaluated indirectly by measuring the immune response to a booster dose of vaccine. Participants included 74 adolescents (aged 11.7-14.9 years) who had received a plasma-derived 3-dose primary vaccine series and 138 adolescents (aged 10.0-14.7 years) and 166 children (aged 5.0-7.0 years) who received a recombinant 3-dose primary vaccine series. All were born to hepatitis B surface antigen-negative mothers and had received the first dose of hepatitis B vaccine within 7 days of birth. The proportion of participants with serologic evidence of protective immunity (antibody to hepatitis B surface antigen > or = 10 mIU/mL) at baseline (prebooster), the proportion who developed an anamnestic response (increase to > or = 10 mIU/mL or at or more than fourfold increase in antibody to hepatitis B surface antigen to > 10 mIU/mL), and the geometric mean concentration by 1, 2, and 4 weeks after a 5-microg recombinant vaccine booster dose were determined. No participant had evidence of chronic hepatitis B virus infection. Overall, 99% of the group of children who received recombinant hepatitis B vaccine, 83% of the group of adolescents who received recombinant hepatitis B vaccine, and 69% of the group of adolescents who received the plasma-derived vaccine had an anamnestic response to a booster dose; among responders, the geometric mean concentration at 2 weeks postbooster was 3360 and 128 mIU/mL among adolescents who received plasma-derived vaccine with antibodies to hepatitis B surface antigen > or = 10 and < 10 mIU/mL at baseline, respectively, compared with 1283 and 369 mIU/mL among adolescents who received recombinant hepatitis B vaccine and 5091 and 696 mIU/mL for children who received recombinant hepatitis B vaccine. The anamnestic response rate at 2 weeks postbooster among participants with antibodies to hepatitis B surface antigen < 10 mIU/mL at baseline was inversely associated with age; 97% of 5-year-olds responded compared with 60% of 14-year-olds. Although most participants responded to a booster dose of hepatitis B vaccine, the significance of the increased proportion of nonresponses among older adolescents might indicate waning immune memory.

HBV serological markers of vaccinated children in remote areas of Taiwan: Emphasis on factors contributing to vaccine failure

A serosurvey targeting Hepatitis B virus (HBV)-vaccinated children born between 1986 and 1998 was conducted in 2001 in remote Taiwanese villages where a 1993 serosurvey indicated high vaccine failure. The HBV S antigen (HBsAg) seropositive rate among vaccinees of 3-6-year-old children in 2001 was significantly lower than that of 1993 and was higher among children who had a delayed vaccination schedule and received the plasma-derived vaccine. Vaccine escape variants were more prevalent among recipients of recombinant HBV vaccine residing in Hualien. Our study highlights the importance of continued monitoring of vaccinees for incidence of HBV infection in order to refine future vaccination policy.

Cochrane review: Hepatitis B immunisation for newborn infants of hepatitis B surface antigen‐positive mothers

AbstractBackgroundHepatitis B vaccine and hepatitis B immunoglobulin are considered for newborn infants of HBsAg‐positive mothers to prevent hepatitis B infection.ObjectivesTo assess the beneficial and harmful effects of hepatitis B vaccines and hepatitis B immunoglobulin in newborn infants of HBsAg‐positive mothers.Search strategyTrials were identified through The Cochrane Neonatal Group Controlled Trials Register, The Cochrane Hepato‐Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, and EMBASE (until February 2004), authors of trials, and pharmaceutical companies.Selection criteriaRandomised clinical trials comparing: plasma‐derived vaccine (PDV) or recombinant vaccine (RV) versus no intervention, placebo, or other active vaccines; hepatitis B immunoglobulin versus no intervention, placebo, or other control immunoglobulin; as well as PDV or RV plus hepatitis B immunoglobulin versus no intervention, placebo, or other control vaccines or immunoglobulin.Data collection and analysisOutcomes are assessed at maximal follow‐up. The primary outcome measure was hepatitis B occurrence, based on a blood specimen positive for HBsAg, HBeAg, or antibody to hepatitis B core antigen (anti‐HBc). Binary outcomes are reported as relative risks (RR) with 95% confidence interval (CI). Subgroup analyses were performed with regard to methodological quality of the trial, mother's HBe‐Ag status, and time of immunisation after birth.Main resultsWe identified 29 randomised clinical trials, five of which were considered high quality. Only three trials reported inclusion of hepatitis B e‐antigen negative mothers. Compared with placebo/no intervention, vaccine reduced hepatitis B occurrence (RR 0.28, 95% confidence interval (CI) 0.20 to 0.40, 4 trials). No significant differences of hepatitis B occurrence were found comparing recombinant vaccine (RV) versus plasma‐derived vaccine (PDV) (RR 1.00, 95% CI 0.71 to 1.42, 4 trials) and high‐dose versus low‐dose vaccine (PDV: RR 0.97, 95% CI 0.55 to 1.68, 3 trials; RV: RR 0.78, 95% CI 0.31 to 1.94, 1 trial). Compared with placebo/no intervention, hepatitis B immunoglobulin or the combination of vaccine plus hepatitis B immunoglobulin reduced hepatitis B occurrence (hepatitis B immunoglobulin: RR 0.50, 95% CI 0.41 to 0.60, 1 trial; PDV plus hepatitis B immunoglobulin: RR 0.08, 95% CI 0.03 to 0.17, 3 trials). Compared with vaccine, vaccine plus hepatitis B immunoglobulin reduced hepatitis B occurrence (RR 0.54, 95% CI 0.41 to 0.73, 10 trials). Hepatitis B vaccine and hepatitis B immunoglobulin seem safe, but few trials reported on adverse events.Authors' conclusionsVaccine, hepatitis B immunoglobulin, and vaccine plus hepatitis B immunoglobulin prevent hepatitis B occurrence in newborn infants of HBsAg positive mothers.Plain language summaryHepatitis B vaccine, hepatitis B immunoglobulin, and hepatitis B vaccine plus immunoglobulin prevent perinatal transmission of hepatitis BHepatitis B vaccination and hepatitis B immunoglobulin are considered as preventive measures for newborn infants of HBsAg positive mothers. When all the identified trials were combined, hepatitis B vaccine alone, hepatitis B immunoglobulin alone, and hepatitis B vaccine plus hepatitis B immunoglobulin reduced perinatal transmission of hepatitis B compared with placebo or no intervention. Hepatitis B vaccine plus hepatitis B immunoglobulin were superior to hepatitis B vaccination alone. Adverse events were rare and mostly non‐serious.

Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers

Hepatitis B vaccine and hepatitis B immunoglobulin are considered for newborn infants of HBsAg-positive mothers to prevent hepatitis B infection. To assess the beneficial and harmful effects of hepatitis B vaccines and hepatitis B immunoglobulin in newborn infants of HBsAg-positive mothers. Trials were identified through The Cochrane Neonatal Group Controlled Trials Register, The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, and EMBASE (until February 2004), authors of trials, and pharmaceutical companies. Randomised clinical trials comparing: plasma-derived vaccine (PDV) or recombinant vaccine (RV) versus no intervention, placebo, or other active vaccines; hepatitis B immunoglobulin versus no intervention, placebo, or other control immunoglobulin; as well as PDV or RV plus hepatitis B immunoglobulin versus no intervention, placebo, or other control vaccines or immunoglobulin. Outcomes are assessed at maximal follow-up. The primary outcome measure was hepatitis B occurrence, based on a blood specimen positive for HBsAg, HBeAg, or antibody to hepatitis B core antigen (anti-HBc). Binary outcomes are reported as relative risks (RR) with 95% confidence interval (CI). Subgroup analyses were performed with regard to methodological quality of the trial, mother's HBe-Ag status, and time of immunisation after birth. We identified 29 randomised clinical trials, five of which were considered high quality. Only three trials reported inclusion of hepatitis B e-antigen negative mothers. Compared with placebo/no intervention, vaccine reduced hepatitis B occurrence (RR 0.28, 95% confidence interval (CI) 0.20 to 0.40, 4 trials). No significant differences of hepatitis B occurrence were found comparing recombinant vaccine (RV) versus plasma-derived vaccine (PDV) (RR 1.00, 95% CI 0.71 to 1.42, 4 trials) and high-dose versus low-dose vaccine (PDV: RR 0.97, 95% CI 0.55 to 1.68, 3 trials; RV: RR 0.78, 95% CI 0.31 to 1.94, 1 trial). Compared with placebo/no intervention, hepatitis B immunoglobulin or the combination of vaccine plus hepatitis B immunoglobulin reduced hepatitis B occurrence (hepatitis B immunoglobulin: RR 0.50, 95% CI 0.41 to 0.60, 1 trial; PDV plus hepatitis B immunoglobulin: RR 0.08, 95% CI 0.03 to 0.17, 3 trials). Compared with vaccine, vaccine plus hepatitis B immunoglobulin reduced hepatitis B occurrence (RR 0.54, 95% CI 0.41 to 0.73, 10 trials). Hepatitis B vaccine and hepatitis B immunoglobulin seem safe, but few trials reported on adverse events. Vaccine, hepatitis B immunoglobulin, and vaccine plus hepatitis B immunoglobulin prevent hepatitis B occurrence in newborn infants of HBsAg positive mothers.

P.032 Evolution of hepatitis B virus diversity in French blood donors through a seven-year survey

The G145R mutant of the small S-protein is a major escape mutant of hepatitis B virus observed in natural infection, after immunization and HBIG therapy. In a previous study we found that plasma-derived and recombinant DNA-derived vaccine HBsAg reacted differently with monoclonal antibodies sensitive for the G145R change. In the present study we investigated the binding of polyclonal anti-HBs obtained after immunization with plasma vaccine and recombinant DNA vaccine to synthetic peptides (adw2, adr) and rHBsAg (HepG2) (ayw3; wild type and a 145R mutant). Anti-HBs binding to synthetic peptids (25-mers, 7aa overlap) from the “a”-loop was significantly reduced by the G145R substitution and by changing the amino acid sequence from adw2 into adr. With mutant G145R rHBsAg the inhibitory activity of vaccine anti-HBs was decreased compared to rHBsAg wild type. In general only minor differences were observed between plasma vaccine and recombinant DNA vaccine related antibody responses. However, the individual heterogeneity in epitope specific reactivity with its possible consequences for protection (against escape mutants) is not reflected in an anti-HBs titer by standard anti-HBs assays. The presented differentiation in anti-HBs response after immunization may deliver new tools for evaluation of future vaccines.

Vaccines for preventing hepatitis B in health-care workers

Hepatitis B virus (HBV) causes acute and chronic liver diseases. Hepatitis B vaccination is recommended for health-care workers. To assess the beneficial and harmful effects of hepatitis B vaccination in health-care workers. We searched the trial registers of The Cochrane Hepato-Biliary Group, The Cochrane Library, MEDLINE, and EMBASE to February 2003. Randomised trials comparing any dose, injection route, injection site, or schedule of hepatitis B plasma-derived vaccines (PDV) or recombinant vaccines (RV) versus placebo, no intervention, or another hepatitis B vaccine in health-care workers. Two reviewers extracted the data independently. The reviewers assessed the methodological quality of the trials regarding generation of the allocation sequence, allocation concealment, double blinding, and follow-up. The results were presented as relative risk (RR) with 95% confidence intervals (CI). We identified 21 randomised trials, all with one or more methodological weaknesses. Four trials demonstrated that PDV versus placebo significantly decreased hepatitis B events at maximum follow-up (RR 0.51, 95% CI 0.35 to 0.73). RV did not differ significantly from PDV in eliciting a protective hepatitis B surface antibody (anti-HBs) level in two trials. Both vaccines were well tolerated. Low-dose vaccine (1 or 2 microg) by the intradermal route resulted in significantly more participants without protective anti-HBs level compared with high-dose (10 or 20 microg) by the intramuscular route (RR 1.41, 95% CI 1.13 to 1.76). The intradermal route caused significantly more local adverse events, while the intramuscular route caused significantly more systemic adverse events. The gluteal injection produced significantly more participants without protective anti-HBs level than the deltoid injection. The prevalence of anti-HBs seroconversion by rapid vaccination (0, 1, and 2 months) was significantly lower than that by standard vaccination (0, 1, and 6 months). Booster vaccinations with different RV doses (2.5, 5, 10, 20, or 40 microg) produced similar prevalence of anti-HBs seroconversion in three trials assessing participants who did not respond to previous HBV vaccination. PDV significantly prevents hepatitis B events. RV seems to be able to elicit similar protective anti-HBs levels. The intramuscular route with 20 microg RV was significantly more effective compared with the intradermal route with 2 microg RV as was the standard schedule compared with a rapid schedule and deltoid intramuscular injection compared with the gluteal intramuscular injection. It is unclear if booster vaccination of non-responders offers higher anti-HBs seroconversion and hepatitis B vaccine prevents the infection of hepatitis B mutants in health-care workers.

Multiple sclerosis and hepatitis B vaccination: Could minute contamination of the vaccine by partial Hepatitis B virus polymerase play a role through molecular mimicry?

Reports of multiple sclerosis developing after hepatitis B vaccination have led to the concern that this vaccine might be a cause of multiple sclerosis in previously healthy subjects. Some articles evidenced that minor Hepatitis B virus (HBV) polymerase proteins could be produced by alternative transcriptional or translational strategies. Their detection is very difficult because they are in minute concentration and probably enzymatically inactive, however, it was shown that they could be exposed on the outside of the virus particles and also be immunogenic. In addition, HBV polymerase shares significant amino acid similarities with the human myelin basic protein. We hypothesise that some of the apparent adverse reactions to the vaccine could be due to a process called of molecular mimicry, the HBV polymerase, which could be a contaminant in the recombinant or plasma-derived vaccines, could act as autoantigens and induce autoimmune demyelinating diseases such as multiple sclerosis.

Reply

We agree with Dr. Tabor that our findings1 cannot be extrapolated to recipients of other hepatitis B (HB) vaccines, and hence more data are needed to issue a recommendation of routine booster vaccination for recombinant HB vaccine recipients. Although a qualitative difference does exist between plasma-derived and genetically engineered HB vaccine, the durability of antibodies produced by them may not differ from each other. Studies to understand long-term outcome of recipients of recombinant HB vaccine are the priority data that we need. We also appreciate the comments by Dr. Chan and colleagues on our report. HB vaccine is indeed a reliable vaccine that has prevented chronic infections in most of vaccinees. Many previous reports, including one by ourselves2 showed a routine booster vaccination may not be required to provide protection against chronic HB virus infection before age 15 years. However, most of the studies were confined to subjects in early ages of life. The real threat may emerge when the vaccinated subjects become older and begin to both engage in sexual activity and get along with older generations who still have a high HB surface antigen (HBSAg) carrier rate. Encouragement of safe sex, of course, is certainly an option in preventing not only HB infection but also other sexually transmitted diseases. However, if safe sex practice could be easily executed, diseases such as AIDS would not spread so rampantly. Maintaining and prolonging the protection by vaccination may be a more reliable choice. Nevertheless, we agree that cost-effectiveness analyses are needed. Our data1 showed that 2.7% of children whose postvaccination anti-HBs had been documented did not respond to one dose of HB vaccine booster at the age of 15 years. Besides, a blunted serological response was noted in approximately 20% of the patients. Furthermore, a breakthrough infection was found in a child whose anti-HBs had been documented after primary immunization and persisted to age 7 years. All the findings imply the immune memory, either humoral or cellular immunity, has waned significantly. A booster dose given prior to age 15 years or a two-dose HB vaccine regimen would have been needed for the children to maintain a protective level of antibody. Although Dr. Chan stated the percentage of patients that became HBsAg-positive was low (1/26, 4%), we are concerned with the possibility that this number will increase as the immune memory continues to decay and due to any possible increased risk of exposure in life after the teenage years. Generally speaking, a booster dose is needed to maintain the protection conferred by a killed vaccine. From the perspective of public health, if a booster vaccination program is to be implemented, it is imperative to set booster vaccination at an age when all the children are still easily accessible and one-dose regimen is universally effective in inducing a protective antibody. Although we are not yet ready to recommend routine booster vaccination for all HB vaccines, our study on plasma-derived vaccine provided an important observation that for sure will invite more elegant studies to elucidate this issue. Chun-Yi Lu*, Yen-Hsuan Ni*, Mei-Hwei Chang*, Chin-Yun Lee*, Li-Min Huang*, * Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.

Persistence of antibody after hepatitis B vaccine and the question of boosters†

Lu et al.1 document the waning of protective immunity to hepatitis B virus (HBV) in adolescents 15 years after receiving a plasma-derived hepatitis B vaccine manufactured in France, and they conclude that booster doses of the vaccine should be given. Levels of antibody to the hepatitis B surface antigen (anti-HBs) had fallen below the levels generally accepted as providing protection (≥10 mIU/mL) in 29.9% of subjects in a group of 78 children whose postvaccination anti-HBs had been documented. In a similar study,2 we documented the loss of protective anti-HBs in 33% of 101 children and adults 9 years after receiving a plasma-derived hepatitis B vaccine manufactured in the United States. Although the concordance of these results with two different plasma-derived hepatitis B vaccines (given in different concentrations on different dose schedules) might appear to justify extrapolation to recipients of other hepatitis B vaccines, this is not necessarily the case. Plasma-derived hepatitis B vaccines were entirely displaced by recombinant hepatitis B vaccines in the 1990s. Some differences exist in the chemical structure of the hepatitis B surface antigen used to manufacture recombinant vaccines compared with that used to manufacture plasma-derived vaccines. In addition, the characteristics and durability of antibodies made in response to different vaccines can differ. Only follow-up studies of antibody persistence in recipients of recombinant hepatitis B vaccines can demonstrate whether booster doses should be recommended for those who were vaccinated with recombinant vaccines. Edward Tabor*, * Office of Blood Research and Review, Food and Drug Administration, Rockville, MD.

Meta‐analysis: the effect of age on immunological response to hepatitis B vaccine in end‐stage renal disease

Patients on maintenance dialysis typically show a suboptimal immune response to hepatitis B virus vaccine compared with the non-uraemic population. A variety of inherited or acquired factors have been implicated in this diminished response. Age-associated changes in immune status may contribute to decreased vaccine efficacy in older individuals although contradictory results have been reported in individuals with normal kidney function. To evaluate the relationship between age and immune response to hepatitis B vaccine in patients with end-stage renal disease by performing a systematic review of the literature with a meta-analysis of clinical trials. We used the random effects model of DerSimonian and Laird; sources of heterogeneity in effect estimates were explored by performing sensitivity analyses. We identified 17 clinical trials (1800 unique patients); six (35%) were controlled studies. Pooling of study results demonstrated a significantly decreased risk of response to hepatitis B vaccine among older dialysis patients (overall risk ratio: 0.74; 95% confidence intervals: 0.70-0.79). The P-value was 0.0139 for our test of study heterogeneity. A lowered risk of response to hepatitis B vaccine persisted after exclusion of trials based on plasma-derived vaccines; it was present even when 'older' individuals were defined as being as 50 years (RR: 0.85, 95% CI: 0.75-0.96) or more (cut-off 60 years RR: 0.75; 95% CI: 0.66-0.85). An effect of age on seroprotection rate was present in all clinical reports, irrespective of the geographic origin of the study group: Europe (RR: 0.76; 95% CI: 0.70-0.83) North America (RR: 0.67; 95% CI: 0.60-0.74) or other countries (RR: 0.83; 95% CI: 0.71-0.97). Additional doses of vaccine did not appear to have an impact on RR of response by age. Our meta-analysis showed a clear association between older age and impaired response to hepatitis B virus vaccine in end-stage renal disease patients. Such a relationship is biologically plausible. Vaccination schedules with adapted vaccine doses and frequent serum testing for loss of immunity against hepatitis B virus are recommended in elderly patients on maintenance dialysis.

18-year follow-up study of a prospective randomized trial of hepatitis B vaccinations without booster doses in children

The long-term immunogenicity and efficacy of hepatitis B virus (HBV) vaccination remain to be defined. We aimed to examine the long-term immunogenicity and efficacy of HBV vaccination with 3 different regimens over 18 years of follow-up. A total of 318 Chinese subjects receiving 3 different regimens of HBV vaccination (2-dose recombinant vs. 3-dose recombinant vs. 3-dose plasma-derived vaccines) without receiving a booster dose were recruited. The HBV serologic markers, including hepatitis B surface antigen (HBsAg), antibody to hepatitis B surface antigen (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc), were determined at yearly follow-up. After 18 years, 88 subjects were still being followed up. Compared with subjects receiving the 2-dose regimen, subjects receiving the 3 dose regimens had a significantly higher geometric mean titer of anti-HBs and a higher proportion had anti-HBs titers > or =10 mIU/mL during the 18 years of follow-up. There were no differences in these 2 parameters between subjects receiving the 3-dose recombinant and subjects receiving the 3-dose plasma-derived vaccines. A total of 88 anamnestic responses were documented in 70 subjects (8 with initial anti-HBs titers <100 mIU/mL at 12 months and 7 with anti-HBs titers <10 mIU/mL before the anamnestic responses). No subject became positive for HBsAg. Three subjects had benign breakthrough HBV infection without leading to chronicity indicated by isolated anti-HBc positivity. There was less long-term immunogenicity associated with the 2-dose regimen when compared with the 3-dose regimens of HBV vaccination. Because of the highly effective anamnestic responses, a booster dose was not necessary at least up to 18 years after the primary vaccination.

Duration of hepatitis B immunity in low risk children receiving hepatitis B vaccinations from birth.

The duration of protection after hepatitis B vaccination of infants is unknown. We determined antibody to hepatitis B surface antigen (anti-HBs) at 4-13 years of age in 363 low risk children who had been vaccinated starting at birth with hepatitis B vaccine. Those with nonprotective titers (<10 mIU/mL) received a booster dose. We similarly followed 16 children of hepatitis B surface antigen (HBsAg)-positive mothers. Of low risk infants receiving a plasma-derived vaccine, 41% (42 of 102) of those whose primary response was unknown and 24% (4 of 17) who had initially responded retained protective titers (> or = 10 mIU/mL) of anti-HBs at 9 and 13 years, respectively. Of those who did not have protective antibody titers, 61% (33 of 54) and 67% (8 of 12), respectively, responded to a booster dose. In children of HBsAg-positive mothers, 31% retained protective anti-HBs at 12 years, and 90% (9 of 10) with nonprotective titers responded to a booster. In low risk children initially receiving a recombinant vaccine, 12.5% (26 of 208) and none (0 of 36) retained protective anti-HBs titers at 5 and 7 years of age, respectively. Of those who did not have protective titers, 90% (120 of 134) and 91% (32 of 35), respectively, responded to a booster. Anti-HBs disappeared by 5 years of age in most children who were vaccinated with hepatitis B vaccine from birth. Although most children showed immunologic memory, one-third failed to demonstrate an anamnestic response to a booster dose. Additional long term studies of low risk infants are needed to determine duration of protection and the necessity for or timing of booster doses.

Waning Immunity To Plasma–Derived Hepatitis B Vaccine and the Need for Boosters 15 Years After Neonatal Vaccination

Neonatal immunization with hepatitis B (HB) vaccine is highly effective; however, more needs to be learned about the duration of protection and indications for boosters. We measured antibody to HB core antigen (anti-HBc), HB surface antigen (HBsAg), and pre- and postbooster titers of HBsAg antibody (anti-HBs) 15 years after primary neonatal immunization with plasma-derived HB vaccines in 2 cohorts of 15-year-old children. Group A consisted of 78 children who were born to HB e antigen-positive HBsAg carrier mothers and had developed protective levels of anti-HBs antibodies (> or =10 mIU/mL) following HB immunization. Group B consisted of 113 apparently healthy children whose anti-HBs titers after vaccination were unknown. Anti-HBs was undetectable (antibody titer <10 mIU/mL) in 29.9% in group A and 62.4% in group B (P < .001). Anti-HBc was detected in 33.3 % in group A and 4.4 % in group B (P < .001). After a single booster dose of HB vaccine, 2.7% in group A and 3.3% in group B remained anti-HBs-negative. A blunted serological response was noted in approximately 20% in both groups. One HBsAg carrier was detected in group A (1.3%) and 4 in group B (3.5%). Fifteen years after neonatal immunization with plasma-derived HB vaccine, a large proportion of children exhibited waning immunity. This poses the risk of breakthrough infection. A single booster augmented the serological response to the vaccine in most but not all subjects. In conclusion, our findings suggest that one or more booster immunizations are needed in seronegative subjects by at least 15 years following neonatal immunization with plasma-derived HB vaccine.

Hepatology highlights

Hepatology highlights

Long-term persistence of anti-HBs after vaccination against HBV: an 18 year experience in health care workers

The aim of the present study was to evaluate the long-term persistence of seroprotection after hepatitis B virus (HBV) vaccination. A total of 422 health care workers (HCWs) were evaluated 4.8–18.8 years after primary immunization (mean follow-up 11.8 years); 241 of them had received plasma-derived vaccines and 181 had been given yeast-derived vaccines; 107 subjects received a booster dose of yeast-derived vaccine 6 years after primary immunization with either plasma-derived or yeast-derived vaccines. Seroprotection was assumed when the anti-HBs titers were >10mIU/ml. The overall response after primary immunization was 98.8%. Among subjects who reached a 10 year follow-up, those treated with plasma-derived vaccine had a seroprotection rate of 87.8 compared to 81.6% of those vaccinated with yeast-derived vaccines (P<0.001). Anti-HBs geometric mean titers (GMTs) after primary immunization were similar in the two groups, but were significantly lower at 10 years follow-up in the group that had received a yeast-derived vaccine (104mIU/ml versus 244mIU/ml in those who used a plasma-derived vaccine, P<0.05). Anti-HBs GMTs in the 107 subjects given the booster dose were 242mIU/ml pre-booster titer, and rose to 35,171mIU/ml after the booster dose. A mean 10.1 years after the booster dose, GMTs were 952mIU/ml. Overall, the anti-HBs seroprotection rate was 95.4% (102 subjects). Based on GMT results, no booster dose is necessary in healthy adults for at least 10 years after primary immunization.