Priya Diana Crasta

Long-term anti-HBs antibody persistence following infant vaccination against hepatitis B and evaluation of anamnestic response A 20-year follow-up study in Thailand

Hepatitis B vaccine has been available worldwide since the mid-1980s. This vaccine was evaluated in a clinical trial in Thailand, conducted on subjects born to hepatitis B surface antigen positive and hepatitis B e-antigen positive mothers and vaccinated according to a 4-dose schedule at 0, 1, 2 and 12 mo of age and a single dose of hepatitis B immunoglobulin concomitantly at birth. All enrolled subjects seroconverted and were followed for 20 y to assess the persistence of antibody to the hepatitis B surface antigen (anti-HBs) (NCT00240539). At year 20, 64% of subjects had anti-HBs antibody concentrations ≥ 10 milli-international units per milli liter (mIU/ml) and 92% of subjects had detectable levels (≥ 3.3 mIU/ml) of anti-HBs antibodies. At year 20, subjects with anti-HBs antibody titer < 100 mIU/ml were offered an additional dose of hepatitis B virus (HBV) vaccine to assess immune memory (NCT00657657). Anamnestic response to the challenge dose was observed in 96.6% of subjects with an 82-fold (13.2 to 1082.4 mIU/ml) increase in anti-HBs antibody geometric mean concentrations. This study confirms the long-term immunogenicity of the 4-dose regimen of the HBV vaccine eliciting long-term persistence of antibodies and immune memory against hepatitis B for up to at least 20 y after vaccination.

Seventeen-year antibody persistence in adults primed with two doses of an inactivated hepatitis A vaccine

Background and objectives Antibody persistence and immune memory against hepatitis A (HAV) in adults in a low endemicity country, 15 y after immunisation with two doses of HAV vaccine has been demonstrated. This communication provides additional information on antibody persistence up to Year 17 from two of the longest follow-up studies [NCT00289757/NCT00291876]. Methods In two double-blind primary studies, healthy adults aged 17−40 y and 21−40 y, respectively received two doses of the HAV vaccine following a 0,6 mo or 0,12 mo schedule. Anti-HAV antibody concentrations were measured using an enzyme-linked immunoassay (cut-off: 15mIU/ml) at Year 16 and Year 17. Subjects who became seronegative (anti-HAV < 15mIU/ml) since previous reporting were offered a challenge dose, with anti-HAV antibody concentration measurements at Day 14 and Day 30 thereafter. Results At Year 17, 100% and 96.7% of subjects remained seropositive for anti-HAV antibodies following the 0, 6 mo and 0, 12 mo regimens, respectively (GMCs: 278mIU/ml and 369mIU/ml). One subject who became seronegative at Year 16 received a HAV challenge dose within the next 12 mo and mounted an anamnestic response. The challenge dose was well-tolerated. Conclusions Both HAV immunisation regimens (0,6 mo and 0,12 mo) induced persistence of vaccine-induced antibodies against HAV for at least 17 y after primary vaccination.

Persistence and immune memory to hepatitis B vaccine 20 years after primary vaccination of Thai infants, born to HBsAg and HBeAg positive mothers

This study assessed antibody persistence and immune memory to hepatitis B vaccine 20 y after priming with a recombinant hepatitis B virus (HBV) vaccine during infancy. Infants were vaccinated according to a 0, 1, 6 mo schedule with or without simultaneous administration of hepatitis B immunoglobulin (HBIg). Half of the subjects enrolled received an interim booster dose at year 5 (boosted) group, whereas the other half of the subjects enrolled did not (unboosted group). Antibody persistence was assessed until year 20. Immune memory was assessed by administration of a final HBV vaccine challenge dose at year 20 in a second study. At year 20, anti-HBs antibody concentration ≥ 10 mIU/ml rates and GMCs were higher among subjects in the boosted group (84.2% [16/19]; 95%CI: 60.4–96.6) when compared with those in the unboosted group [44.0% (11/25)]; 95% CI: 24.4–65.1). After the HBV vaccine challenge dose at year 20, anti-HBs anamnestic response for subjects in the unboosted and boosted groups was observed in 93.1% (95% CI: 77.2–99.2) and 100% (95% CI: 76.8–100) of subjects, respectively. The mean anti-HBs antibody concentration (GMC) was 562.0 mIU/ml (292.5–1079.7 mIU/ml) post administration of the challenge dose; this is a 28.5 fold increase from the pre- to post-challenge dose administration at year 20. This study demonstrates persistence of anti-HBs antibodies and presence of immune memory following hepatitis B vaccination for up to at least 20 y in Thailand. Immune memory was demonstrated for virtually all subjects, regardless whether they received they had received the additional HBV dose or not. The challenge dose at year 20 was well tolerated and a robust response was demonstrated. ClinicalTrials.gov Identifier: NCT00240526, NCT00774995.

Lasting immune memory against hepatitis B following challenge 10-11 years after primary vaccination with either three doses of hexavalent DTPa-HBV-IPV/Hib or monovalent hepatitis B vaccine at 3, 5 and 11-12 months of age.

BACKGROUND The combined hexavalent diphtheria-tetanus-pertussis-hepatitis B-inactivated poliomyelitis - Haemophilus influenzae type b conjugate vaccine (Infanrix hexa™; DTPa-HBV-IPV/Hib: GlaxoSmithKline Vaccines) induces robust responses to the HBV component when administered at 3, 5 and 11-12 months of age. We assessed long term HBV antibody persistence 10-11 years after primary vaccination in infancy. METHODS Antibody persistence and immune memory were assessed post-primary vaccination at 3, 5, 11-12 months with DTPa-HBV-IPV/Hib, or monovalent HBV vaccine (Engerix™ B, GlaxoSmithKline Vaccines) co-administered with DTPa-IPV/Hib (Infanrix™-IPV/Hib, GlaxoSmithKline Vaccines) in 185 children aged 11-12 years. Blood samples were collected before and 1 month after a challenge dose of Engerix™ B (10μg dose). RESULTS 10-11 years after primary vaccination the percentage of subjects with persisting anti-HBs antibody concentrations ≥10mIU/ml was 48.4% in the DTPa-HBV-IPV/Hib group and 58.4% in the DTPa-IPV/Hib+HBV group. After the HBV challenge dose, the percentage with anti-HBs ≥100mIU/ml increased from 14.7% to 93.6% in the DTPa-HBV-IPV/Hib group and 19.1% to 94.4% in the DTPa-IPV/Hib+HBV group. Anti-HBs GMCs increased by at least 187-fold in each group. An anamnestic response (≥4-fold increase in initially seropositive or anti-HBs concentration ≥10mIU/ml in initially seronegative subjects) was observed in 96.8% and 96.6% of subjects in the DTPa-HBV-IPV/Hib and DTPa-IPV/Hib+HBV groups, respectively. No serious adverse events occurred that were considered related to challenge vaccination. CONCLUSION Administration of HBV as part of a combination vaccine or as a monovalent vaccine induced long lasting immune memory against HBV in children primed at 3, 5 and 11 months of age. Antibody persistence and immune memory were similar, suggesting that protection afforded by DTPa-HBV-IPV/Hib and monovalent HBV vaccines, is likely to be of similar duration. The administration of HBV challenge dose 10-11 years after the 3, 5, 11-12 months primary schedule induced strong anamnestic responses and was well tolerated. This study is registered at www.clinicaltrials.govNCT01138098.

Long-term antibody persistence after vaccination with a 2-dose Havrix (inactivated hepatitis A vaccine): 20 years of observed data, and long-term model-based predictions.

Antibody persistence in two cohorts of adults, who received inactivated hepatitis A (HAV) vaccine (1440El.U; Havrix; GSK Vaccines) according to a 0-6 or 0-12 month schedule in 1992-1993, has been measured annually. After 20 years, >97% of the subjects in both studies were seropositive for anti-HAV antibodies. Geometric mean concentrations in the according-to-protocol cohorts were 312 mIU/ml in 34/36 subjects vaccinated initially at 0-6 months (NCT00289757) and 317 mIU/ml in 85/86 subjects vaccinated at 0-12 months (NCT00291876). Over the whole follow-up period, seven subjects (2+5, respectively) lost circulating anti-HAV antibodies but mounted a strong response after HAV booster administration (1440El.U). Mathematical modelling, which was applied to assess true persistence at Year 20 (accounting for drop-outs and missing data), and to predict longer-term persistence confirmed previous estimates that seropositive anti-HAV levels would persist in ≥95% vaccinees at Year 30 and ≥90% at Year 40. ClinicalTrials.Gov number: NCT00289757/NCT00291876.

Clarification to Long-term anti-HBs antibody persistence and immune memory in children and adolescents who received routine childhood hepatitis B vaccination. Hum Vaccin Immunother 2012; 8:813-8

Purpose: This paper presents data from two studies that evaluated 5-year and 10-year persistence of antibodies against hepatitis B (HBV) surface antigen (anti-HBs) and immune response to an HBV vaccine challenge in children and adolescents who had received three doses of a HBV vaccine in infancy as part of routine clinical practice [NCT00519649/ NCT00984139]. Results: Anti-HBs antibody concentrations ³ 10mIU/ml persisted in 83.3% (95% confidence interval [CI]: 78.5−87.5) and 78.3% (95% CI: 73.1−83.0) of subjects aged 7−8 years and 12−13 years, respectively 5−10 years after infant vaccination. One month post-challenge dose, 98.2% (95% CI: 95.9−99.4) and 93.7% (95% CI: 90.2−96.2) of subjects in the two age groups, respectively had anti-HBs antibody concentrations ³ 100mIU/ml. Overall, 99.6% (95% CI: 98−100) and 97.2% (95% CI: 94.5−98.8) of subjects aged 7−8 years and 12−13 years mounted an anamnestic response to the HBV challenge dose, which was well-tolerated. Methods: Healthy children aged 7−8 years and adolescents aged 12−13 years received three doses of a monovalent pediatric HBV vaccine (10µg of HBsAg) before 18 months of age. Serum samples collected before and one month post-HBV vaccine challenge dose were tested for anti-HBs antibody concentrations. Safety assessments were made for the HBV vaccine challenge dose. Conclusions: A three-dose childhood HBV immunization regimen induced persistence of antibodies against HBV infection for 10 years, up to adolescence. This vaccination regimen also conferred long-term immune memory against HBV as evidenced by the strong anamnestic response to the HBV vaccine challenge, despite waning anti-HBs antibody levels.

Immunity to hepatitis B persists in adolescents 15–16 years of age vaccinated in infancy with three doses of hepatitis B vaccine

OBJECTIVE Vaccination of infants against hepatitis B virus (HBV) using hepatitis B vaccine is effective in preventing the infection during early childhood and there is a growing evidence of long-term protection. So far, no need for a booster dose has been identified in healthy subjects; however further follow-up continues to determine the exact duration of protection. We evaluated antibody persistence and immune response to a hepatitis B vaccine challenge dose in children aged 15-16 years, previously vaccinated with 3-doses of the same vaccine in infancy (third dose received before 18 months of age). METHODS A single hepatitis B vaccine challenge dose containing 10μg hepatitis B surface (HBs) antigen was administered to adolescents aged 15-16 years. Blood samples were taken before and one month after the challenge dose to measure anti-HBs antibodies using a chemiluminescence immunoassay. Solicited local and general symptoms, as well as unsolicited and serious adverse events were recorded after the challenge dose. RESULTS 303 subjects were enrolled, of whom 302 and 293 subjects formed the total vaccinated and according-to-protocol cohorts, respectively. Pre-challenge, 65.4% (95% CI: 59.6-70.9) subjects were seroprotected (anti-HBs antibody concentration ≥10mIU/mL). One month post-challenge, 97.9% (95% CI: 95.6-99.2) were seroprotected, while 90.8% (95% CI: 86.8-93.8) had anti-HBs antibody concentrations ≥100mIU/mL. The post-challenge geometric mean concentration (GMC; 4134.9 [95% CI: 3114.2-5490.1]) was 150-fold higher than the pre-challenge GMC. Overall, 96.9% (95% CI: 94.2-98.6) subjects mounted an anamnestic response. The safety and reactogenicity profile of the hepatitis B vaccine challenge dose was consistent with previous experience. CONCLUSIONS Immunity to hepatitis B persists in 15-16 year old adolescents following primary vaccination in infancy. TRIAL REGISTRATION http://www.clinicaltrials.govNCT01847430.

Anti-HBs antibody persistence following primary vaccination with an investigational AS02(v)-adjuvanted hepatitis B vaccine in patients with renal insufficiency.

Background: Three doses of the investigational AS02v-adjuvanted hepatitis B virus (HBV) vaccine HB-AS02 have been shown to induce more rapid seroprotection and higher anti-HBs antibody concentrations in patients with renal insufficiency than four doses of FENDrix™ (HB-AS04), an adjuvanted HBV vaccine licensed in Europe for use in this population. This study evaluated persistence of immune response up to 36 months after primary vaccination. Methods: In this open, international, Phase III follow-up study, 151 pre-dialysis, peritoneal dialysis and hemodialysis patients ³15 years of age received HB-AS02 at 0, 1, 6 months and 149 received HB-AS04 at 0, 1, 2, 6 months. Of these, 99 and 80 returned at Month 36, 76 and 62 of whom were eligible for inclusion in the Long-Term According-To-Protocol (LT-ATP) cohort for descriptive analysis of antibody persistence (mean age: 65.6 years). Results: At Month 36, 89.5% of subjects in the HB-AS02 group and 72.6% of those in the HB-AS04 group had anti-HBs antibody concentrations ³10 mIU/ml. Anti-HBs antibody concentrations were ³100 mIU/ml in 82.9% and 35.5% of subjects, respectively. Anti-HBs geometric mean antibody concentrations were higher in the HB-AS02 group over the 36 months of follow-up. An exploratory “time to boost” analysis confirmed that subjects who received HB-AS02 were 2.54 times more likely than those who received HB-AS04 to have anti-HBs antibody concentrations ³10 mIU/ml at Month 36 (p=0.013 [95% CI: 1.22, 5.31]). Conclusion: HB-AS02 candidate vaccine induces high and persistent anti-HBs antibody levels in pre-dialysis, peritoneal dialysis and hemodialysis patients, potentially reducing the need for booster doses in this population.

Immune memory to hepatitis B persists in children aged 7–8 years, who were vaccinated in infancy with 4 doses of hexavalent DTPa-HBV-IPV/Hib (Infanrix™ hexa) vaccine

Protection against hepatitis B disease relies on either protective serum antibodies or on the ability of the immune system to mount an anamnestic response when confronted with the hepatitis B virus (HBV). This open multicenter study (EUDRACT: 2010-022538-10) measured antibodies to HBV surface antigen (anti-HBs) in 7–8-year-old children who had received 4 doses of hexavalent diphtheria-tetanus-acellular pertussis-HBV-inactivated poliovirus-Hemophilus influenzae type b conjugate vaccine (DTPa-HBV-IPV/Hib: Infanrix™ hexa; GlaxoSmithKline Vaccines) in the first 2 years of life through routine vaccine services in Germany. The ability of these children to mount an anamnestic response to a challenge dose of monovalent HBV vaccine (Engerix™ B Kinder; GlaxoSmithKline Vaccines) was also assessed. Before the challenge dose, 78.5% of children had anti-HBs levels ≥6.2 mIU/mL (seropositive) and 72.2% had anti-HBs levels ≥10 mIU/mL (seroprotected). Post-challenge, 98.9% had anti-HBs levels ≥10 mIU/mL and 95.8% had anti-HBs ≥100 mIU/mL. An anamnestic response to the challenge was observed in 96.6% of all subjects. The challenge dose was well tolerated, with a reactogenicity and safety profile consistent with published data. DTPa-HBV-IPV/Hib induces long-lasting immune memory to HBV that appears very similar to that induced by monovalent HBV vaccines. Protection against hepatitis B may be conferred through immune memory in subjects who responded to primary vaccination, even when they subsequently lose detectable levels of circulating anti-HBs antibodies.

Characterization of an age-response relationship to GSK's recombinant hepatitis B vaccine in healthy adults: An integrated analysis.

The immune system becomes less effective with age, and older age is associated with an increased susceptibility to diseases and reduced responses to vaccination. Furthermore, some adult populations, such as those with diabetes mellitus, are at increased risk of acute hepatitis B virus (HBV) infection. Decreasing responses to vaccination with advanced age have been described, but it is not known at what age immunogenicity starts to reduce, or until what age immunogenicity remains acceptable (for example ≥80 % seroprotection post-vaccination). We characterized the relationship between age and seroprotection rate induced by recombinant HBV vaccination by conducting a pooled analysis of clinical trial data. Healthy adults aged ≥20 y who had been vaccinated with 20μg HBV vaccine (Engerix™ B, GSK Vaccines, Belgium) in a 0, 1, 6 months schedule in 11 studies since 1996 were included. The observed seroprotection rate, defined as an anti-HBV surface antigen antibody concentration ≥10 mIU/ml was 94.5% in the whole population (N = 2,620, Total vaccinated cohort), ranging from 98.6% in adults vaccinated at age 20–24 years, to 64.8% in those vaccinated at age ≥65 y A model on seroprotection rates showed a statistically significant decrease with age, and predicted that the anti-HBs seroprotection rate remains ≥90% up to 49 y of age and ≥80% up to 60 y of age. Individuals at risk of HBV infection should be vaccinated as early in life as possible to improve the likelihood of achieving seroprotection. Additional studies are needed to identify whether unvaccinated individuals older than 60 y would benefit from regimens that include additional or higher vaccine doses.