HBV-2 Group: neonates born to HBsAg+ and HBeAg+ mothers who received a 4-dose vaccination regimen (Part of

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: (Ext HBV-064 Y17-Y20) Title: Immunogenicity and protective efficacy of GlaxoSmithKline Biologicals r DNA hepatitis B vaccine (10 g) in newborns of HBeAg+ and HBsAg+ mothers in comparison with a historical control group. Engerix -B (HBV): GlaxoSmithKline (GSK) Biologicals commercially available hepatitis B vaccine. HBeAg: hepatitis B envelope antigen, HBsAg: hepatitis B surface antigen Rationale: The aim of this study was to evaluate the persistence of anti-hbs antibodies, the prevalence and incidence of hepatitis B markers (HBsAg, anti-hbc, HBeAg, anti-hbe) and the clinical significance of the HBsAg positive and anti-hbc positive cases observed during the long-term follow-up of this study, i.e. 20 years after administration of the first dose of the study vaccine. HBsAg: hepatitis B surface antigen, Anti-HBc: hepatitis B core antigen, HBeAg: hepatitis B envelope antigen, Anti-HBe: antibody against hepatitis B envelope antigen Phase: II Study Period: 07 October 2003 (Year 17) to 09 November 2007 (Year 20) Study Design: Open, self-contained long-term follow-up study with 6 groups. Centres: 1 study centre in Thailand. Indication: Primary immunisation of healthy neonates against hepatitis B virus. Treatment: Subjects participating in this study had received either a 4-dose or a 5-dose vaccination regimen in the primary study (103860/064) which was initiated 20 years earlier. Subjects in both the 4-dose and 5-dose vaccination regimen received HBV (10 g) according to a 0, 1 and 2 month schedule with a booster dose at Month 12. Subjects in the 5-dose vaccination regimen received an additional booster dose of HBV (10 g) at Month 60. The study groups were as follows: HBV-1 : neonates born to HBsAg+ and HBeAg+ mothers who received a 5-dose vaccination regimen (Part of 1 in the primary study). HBV-2 : neonates born to HBsAg+ and HBeAg+ mothers who received a 4-dose vaccination regimen (Part of 1 in the primary study). HBV-3 : neonates born to HBsAg+ and HBeAg- mothers who received a 5-dose vaccination regimen (Part of 2 in the primary study). HBV-4 : neonates born to HBsAg+ and HBeAg- mothers who received a 4-dose vaccination regimen (Part of 2 in the primary study). HBV-5 : neonates born to HBsAg- and HBeAg- mothers who received a 5-dose vaccination regimen (Part of 3 in the primary study). HBV-6 : neonates born to HBsAg- and HBeAg- mothers who received a 4-dose vaccination regimen (Part of 3 in the primary study). Objectives: To evaluate the anti-hbs antibody persistence at Year 20 after the first vaccine dose of the primary vaccination. To evaluate the prevalence and incidence of other hepatitis B markers (HBsAg, anti-hbc, HBeAg, anti-hbe) at Year 20 after the first vaccine dose of the primary vaccination. Clinical review for hepatitis B infection status. Primary Outcome/Efficacy Variable: At each follow-up time point: Hepatitis B surface antigen (anti-hbs) seropositivity* rate, seroprotection rate** (SPR) and Geometric Mean concentration (GMC). The prevalence and incidence of other hepatitis B markers (HBsAg, anti-hbc, HBeAg and anti-hbe). Clinical review for hepatitis B infection status over the entire follow-up period. * Seropositivity was defined as a subject with an anti-hbs antibody titre 3.3 miu/ml. ** Seroprotection rate was defined as a subject with an anti-hbs antibody titre 10 miu/ml. Secondary Outcome/Efficacy Variable(s): Outcome variables were not differentiated into primary and secondary in study protocol. Hence, all were considered as primary outcome variables.

2 Statistical Methods: The analyses were performed on the LT Total vaccinated cohort and the LT According-To-Protocol (ATP) cohort for immunogenicity. The LT Total vaccinated cohort included all subjects (i.e. subjects who had received at least one dose of the study vaccine in the primary study) who returned for blood sampling at the particular LT blood sampling time point and for whom serology results of at least one hepatitis B marker were available The LT ATP cohort for immunogenicity included those subjects who returned for the follow-up study and who were included in the ATP immunogenicity cohort of the primary study, who had not been eliminated in the previous Long- Term Follow-Up (LTFU) studies, who had not received an extra study vaccine injection, who had not shown abnormal increase in antibody concentrations since the previous LTFU visits, who had not reported incidence of hepatitis B disease and who came back for the current LTFU visit within an acceptable time-interval. Analysis of immunogenicity The analysis of immunogenicity was performed on the LT ATP cohort for immunogenicity. SPR, seropositivity rates GMCs with 95% confidence intervals (CI) for anti-hbs antibodies at each time point was tabulated. The GMCs were calculated on seropositive subjects. The prevalence and incidence of other hepatitis B markers (HBsAg, anti-hbc, HBeAg, anti-hbe) was tabulated at each time point for each group. Analysis of safety No analysis of safety was performed during this long-term follow-up study. Study Population: Healthy neonates with a birth weight 2000 g born to HBeAg-/+ and/or HBsAg-/+ mothers were recruited in the primary study.. In this follow up study, subjects were enrolled between 17 and 20 years after primary vaccination. Written informed consent was obtained from each subject before the blood sampling at each visit. Number of subjects HBV-1 HBV-2 HBV-3 HBV-4 HBV-5 Planned, N* Randomised, N (LT Total vaccinated NA NA NA NA NA NA cohort) Completed, n (%) Total Number Subjects Withdrawn, n (%) NA NA NA NA NA NA Withdrawn due to Adverse Events n (%) NA NA NA NA NA NA Withdrawn due to Lack of Efficacy n (%) NA NA NA NA NA NA Withdrawn for other reasons n (%) NA NA NA NA NA NA HBV-6 Demographics HBV-1 HBV-2 HBV-3 HBV-4 HBV-5 HBV-6 N (LT Total Cohort) Females:Males 11:6 9:11 18:11 7:16 7:10 1:2 Mean Age, years (SD) 16.5 (0.51) 16.6 (0.50) 16.8 (0.44) 16.4 (0.51) 16.5 (0.51) 16.7 (0.58) East/south east Asia, n (%) 17 (100) 20 (100) 29 (100) 23 (100) 17 (100) 3 (100) *Data on subjects who came back for the Year 17 time point Primary Efficacy Results: Seropositivity rate, seroprotection rate and GMCs (calculated on seropositive subjects) of anti- HBs antibodies (LT ATP cohort for immunogenicity) S+ ( 3.3 miu/ml) SPR ( 10 miu/ml) GMC (miu/ml) Timing N 95% CI 95% CI 95% CI n % n % Value LL UL LL UL LL UL HBV-1 PV(M204) PV(M216) PV(M228) PV(M240) HBV-2 PIV(M204) PIV(M216) 13* PIV(M228) PIV(M240) HBV-3 PV(M204) PV(M216) 26* PV(M228) PV(M240)

3 HBV-4 PIV(M204) PIV(M216) 19* PIV(M228) PIV(M240) HBV-5 PV(M204) PV(M216) PV(M228) PV(M240) HBV-6 PIV(M204) PIV(M216) E9 PIV(M228) PV(M240) N: number of subjects with available results S+: Seropositivity was defined as anti-hbs antibody concentration 1.0 miu/ml up to Month 156 and 3.3 miu/ml from Months 168 onwards SPR: seroprotection rates n (%): number (percentage) of subjects with antibody concentrations specified cut-off value Pre: prevaccination time point Px(My): blood sampling time point y months after dose x of the primary vaccination course. 95% CI: 95% confidence interval; LL = Lower Limit, UL = Upper Limit Note: Blood samples up to Month 156 were tested with the RIA assay kits (with an assay cut-off of 1.0 miu/ml). Blood samples at Month 168, 180 and 204 were tested with the AUSAB EIA test-kit (with an assay cut-off of 3.3 miu/ml); anti- HBs antibody concentrations from years 19 and 20 were measured with an in house, validated ELISA assay. * subjects were not included in the analysis for HBV-2: three subject due to a not sufficient quantity (QNS) for HBV-3: 1 subject because blood sampling was not done (BS ND) and 2 subjects due to QNS for group HBV-4: 1 subject due to QNS Primary Efficacy Results: Prevalence of other hepatitis B markers (HBsAg and anti-hbc) at Year 17 (LT ATP Marker N Result n % HBV-1 HBsAg 14 Negative Anti-HBc 14 Negative Positive HBV-2 HBsAg 16 Negative Positive Anti-HBc 16 Negative Positive HBV-3 HBsAg 27 Negative Positive Anti-HBc 27 Negative HBV-4 HBsAg 19 Negative Anti-HBc 19 Negative HBV-5 HBsAg 15 Negative Anti-HBc 15 Negative HBV-6 HBsAg 3 Negative Anti-HBc 3 Negative Total HBsAg 94 Negative Positive Anti-HBc 94 Negative Positive N = number of subjects with available results Primary Efficacy Results: Prevalence of other hepatitis B markers (HBeAg and anti-hbe) at Year 17 (LT ATP Markers N Result n % HBV-1 HBeAg 3 Negative 3 100

4 Anti-HBe 3 Negative HBV-2 HBe Ag 5 Negative Anti-HBe 5 Negative Positive HBV-3 HBeAg 1 Negative Total HBeAg 9 Negative Anti-HBe 9 Negative Positive N = Number of subjects tested and with available results (only the subjects who were positive for HBsAg or anti-hbc have been tested for HBeAg and anti-hbe) Primary Efficacy Results: Prevalence of other hepatitis B markers (HBsAg and anti-hbc) at Year 18 (LT ATP Markers N Result n % HBV-1 HBs Ag 14 Negative Anti-HBc 14 Negative Positive HBV-2 HBs Ag 16 Negative Anti-HBc 16 Negative Positive HBV-3 HBs Ag 28* Negative Positive Anti-HBc 28* Negative HBV-4 HBs Ag 20 Negative Anti-HBc 20 Negative HBV-5 HBs Ag 17 Negative Anti-HBc 17 Negative Positive HBV-6 HBs Ag 2 Negative Anti-HBc 2 Negative Total HBs Ag 97* Negative Positive Anti-HBc 97* Negative Positive N = number of subjects with available results * 1 subject not inserted in analysis because of blood sampling not done Primary Efficacy Results: Prevalence of other hepatitis B markers (HBeAg and anti-hbe) at Year 18 (LT ATP Markers N Result n % HBV-1 HBe Ag 4 Negative HBV-2 HBe Ag 4 Negative HBV-3 HBe Ag 1 Negative HBV-5 HBe Ag 1 Negative Total HBe Ag 10 Negative Anti-HBe 10 Negative N = Number of subjects tested and with available results (only the subjects who were positive for HBsAg or anti-hbc were tested for HBeAg and anti-hbe) Primary Efficacy Results: Prevalence of other hepatitis B markers (HBsAg and anti-hbc) at Year 19 (LT ATP

5 s Markers N Result n % HBV-1 HBs Ag 14 Negative Anti-HBc 14 Negative Positive HBV-2 HBs Ag 17 Negative Positive Anti-HBc 17 Negative Positive HBV-3 HBs Ag 28 Negative Positive Anti-HBc 28 Negative HBV-4 HBs Ag 20 Negative Positive Anti-HBc 20 Negative Positive HBV-5 HBs Ag 14 Negative Positive Anti-HBc 14 Negative HBV-6 HBs Ag 4 Negative Positive Anti-HBc 4 Negative Total HBs Ag 97 Negative Positive Anti-HBc 97 Negative Positive N: Number of subjects tested and with available results Primary Efficacy Results: Prevalence of other hepatitis B markers (HBeAg and anti-hbe) at Year 19 (LT ATP s Markers N Result n % HBV-1 HBe Ag 3 Negative Anti-HBe 3 Negative HBV-2 HBe Ag 5 Negative Anti-HBe 5 Negative HBV-3 HBe Ag 5 Negative Positive Anti-HBe 5 Negative HBV-4 HBe Ag 4 Negative HBV-5 HBe Ag 1 Negative HBV-6 HBe Ag 1 Negative Total HBe Ag 19 Negative Positive Anti-HBe 19 Negative N: Number of subjects tested and with available results (only the subjects who were positive for HBsAg or anti-hbc have been tested for HBeAg and anti-hbe) Primary Efficacy Results: Prevalence of other hepatitis B markers (HBsAg and anti-hbc) at Year 20 (LT ATP Marker N Result n % HBV-1 HBsAg 14 Negative

6 Positive Anti-HBc 14 Negative Positive HBV-2 HBsAg 17 Negative Positive Anti-HBc 17 Negative Positive HBV-3 HBsAg 26 Negative Positive Anti-HBc 26 Negative HBV-4 HBsAg 19 Negative Positive Anti-HBc 19 Negative HBV-5 HBsAg 16 Negative Anti-HBc 16 Negative Positive HBV-6 HBsAg 2 Negative Anti-HBc 2 Negative Total HBsAg 94 Negative Positive Anti-HBc 94 Negative Positive N = number of subjects tested with available results Primary Efficacy Results: Prevalence of other hepatitis B markers (HBeAg and anti-hbe) at Year 20 (LT ATP Markers N Result n % HBV-1 HBe Ag 4 Negative HBV-2 HBe Ag 7 Negative Anti-HBe 7 Negative HBV-3 HBe Ag 4 Negative HBV-4 HBe Ag 4 Negative HBV-5 HBe Ag 1 Negative Total HBe Ag 20 Negative Anti-HBe 20 Negative N = Number of subjects tested and with available results (only the subjects who were positive for HBsAg or anti-hbc have been tested for HBeAg and anti-hbe) Primary Efficacy Results: Chronic hepatitis B carriers (anti-hbc and HBsAg at more than 2 consecutive follow-up time points) HBV-1 HBV-2 HBV-3 HBV-4 HBV-5 HBV-6 Chronic hepatitis B carriers* Number of subjects who responded to primary vaccination and became chronic Hep B carriers

7 *Chronic hepatitis B carrier is defined as + for anti-hbc AND HBsAg at two or more consecutive time points Safety Results: Number (%) of subjects with unsolicited adverse events (SAEs) Not Applicable Safety Results: Number (%) of subjects with serious adverse events (SAEs) SAEs were not collected during the long-term follow-up study. Conclusion: Please refer to the publication section. Date updated: 08-September-2014