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1 Title of the study : A phase III, multicentric open study to evaluate the immunological memory induced by a 3-dose primary vaccination followed by a booster dose with GSK Biologicals 11-valent conjugate pneumococcal compared to unprimed subjects by giving a single dose of Aventis Pasteur s 23- valent pneumococcal polysaccharide (Pneumo 23 ) Principal/co-ordinating investigator: PPD, MD Study Centers: Four pediatric outpatient offices: 1. Pediatric ambulatory surgery Pod, Lachovcom 1727/55, Púchov 2. Pediatric ambulatory surgery, Rozkvet 2010, Povazska Bystrica, Povazska Bystrica 3. Paediatric Outpatient Dept, Centrum 3, , Dubnica nad Vahom 4. Outpatient Paediatric Office, Municipal health center-nova Dubnica, Gagarinova 773/5, , Nová Dubnica Publication (reference): Schuerman L, Prymula R, Chrobok V, Dieussaert I and Poolman J. Kinetics of the immune reponse following pneumococcal PD conjugate vaccination. Vaccine 2007;25: Study period: Clinical phase: III Study Initiation Date: 03 March 2005 Study Completion Date: 18 April 2005 Objectives: Primary: To assess the immune memory induced by the full four dose vaccination schedule with GSK Biologicals 11-valent pneumococcal compared to unprimed subjects by giving a single dose of Aventis Pasteur s 23-valent pneumococcal polysaccharide (Pneumo 23). Secondary: To assess the antibody persistence of the immune response induced by the full four dose vaccination schedule with GSK Biologicals 11-valent pneumococcal conjugate in healthy children prior to the administration of a single dose of Aventis Pasteur s 23-valent pneumococcal polysaccharide (Pneumo 23). Study design: Extension of protocol Undeca-Pn-010 (347414/010) Experimental design: Phase III, open, multi-centric study with 2 parallel groups. Primed group: 50 subjects, previously primed with 4 doses of GSK Biologicals 11Pn-PD in infancy, received a single dose of Aventis Pasteur s 23-valent pneumococcal polysaccharide (referred to as Pneumo 23) Unprimed group (Control group): 50 subjects primed with GSK Biologicals commercially available Havrix in infancy received a single dose of Pneumo 23. Treatment allocation: 1:1 ratio Vaccination schedule: both groups received a single dose of Pneumo 23 Data collection: Remote data entry (RDE) Duration of the study: for each subject, the study duration was approximately days. Serious adverse events were recorded throughout the study period. Any SAE occurring beyond the 15-day follow-up period was reported and handled through the Post study SAE procedure. Two blood samples (6.5 ml) were taken from each subject one at Day 0 and the other at Day to assess antibody persistence and immune memory /037 Synopsis page 1 of 12

2 As previously planned (in the primary study Undeca-Pn-010 [347414/010]) subjects in the primed group were offered the opportunity to receive immunization with commercially available hepatitis A, Havrix (referred to as Havrix), outside of the study to obtain the same antigen coverage at the end of the study as subjects in the unprimed group. Number of subjects: Planned: 100 (50 per group) Enrolled and Total vaccinated cohort: 100 (group primed with 11Pn-PD = 51, unprimed group = 49) Completed: 100 (group primed with 11Pn-PD = 51, unprimed group = 49) Diagnosis and criteria for inclusion: Male and female subjects who participated in study Undeca-Pn-010 (347414/010) and received the full vaccination course (4 doses) of GSK Biologicals 11Pn-PD or were part of the control group who received Havrix. All subjects must have been included in the blood sampling subset for the Undeca-Pn-010 study. Free of obvious health problems as established by medical history and clinical examination before entering into the study Written informed consent obtained from subjects parents or guardians. Test product, dose, mode of administration, lot no. : One dose of the following was administered to subjects in both groups: Vaccine Formulation Presentation Lot Administration (per dose volume of 0.5 ml) Pneumo 23 Aventis Pasteur 25 µg of purified capsular polysaccharides of pneumococcal serotypes: 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F mg Phenol as preservative. Sodium Chloride 0.9% Liquid in prefilled syringes, clear, colorless solution Y0387 Intramuscular injection Right deltoid Duration of treatment: days Criteria for evaluation: Immunogenicity: Primary Antibody concentrations (22F-ELISA) against pneumococcal serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F, measured days after vaccination with Pneumo 23 Secondary Prior to vaccination: Antibody concentrations (22F-ELISA) against pneumococcal serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F Antibody concentrations against pneumococcal serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F 0.2 µg/ml Opsonophagocytic activity ( Final OPA assay ) against pneumococcal serotypes /037 Synopsis page 2 of 12

3 10-15 days after vaccination: Anti-pneumococcal serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F antibody concentrations 0.2 µg/ml Opsonophagocytic activity against pneumococcal serotypes Safety: Occurrence of any serious adverse event occurring during the entire study period. Statistical methods: The analyses were descriptive (i.e., no statistical comparisons were performed). Demography: Calculation of mean age by gender and race distribution. Immunogenicity: Geometric mean antibody concentrations/titers (GMCs/GMTs) and seropositivity rates were calculated with their 95% confidence interval (CIs) for each group, each antigen/serotype and at each applicable blood-sampling time point; Distributions of post-dose 3 antibody concentrations/titers were displayed using tables and reverse cumulative curves for each group and each antigen/serotype. Safety and reactogenicity: Serious adverse events occurring during the study were described Summary (results): All analyses were descriptive only and were performed as planned in the protocol on the Total vaccinated cohort (no subject received an elimination code). Demography All 100 enrolled subjects completed the study. The mean age at vaccination was 3.6 years and all subjects were white (Caucasian). There were four centers with a maximum of 42 subjects (42.0%) enrolled in a single center. Immunogenicity Ten to 15 days after the single dose of Pneumo 23, all subjects (100%) in the primed group and at least 71.4% in the unprimed group reached antibody levels 0.2 g/ml for each serotype. For all serotypes, post 23 PS vaccination antibody GMCs were at least 2.8 fold (and up to 9.6 fold) higher compared to the blood sampling time point one month after the fourth dose of GSK Biologicals 11Pn-PD. Observed post 23 PS vaccination antibody GMCs were higher in the primed group compared to unprimed group for all serotypes, Post-vaccination seropositivity rates (% 8) for opsonophagocytic activity were 100% for the primed group and at least 83.8% for the unprimed group /037 Synopsis page 3 of 12

4 Table 1: Percentage of subjects with pneumococcal PS antibody concentrations 0.2 µg/ml and geometric mean antibody concentrations (GMCs) using 22F-ELISA (Total vaccinated cohort) Antibody Group Timing N 0.2 g/ml GMC n % 95% CI 95% CI Anti-1 Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Unprimed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Anti-3 Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Unprimed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Anti-4 Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Unprimed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) /037 Synopsis page 4 of 12

5 Table 1 continued: Percentage of subjects with pneumococcal PS antibody concentrations 0.2 µg/ml and geometric mean antibody concentrations (GMCs) using 22F-ELISA (Total vaccinated cohort) Antibody Group Timing N 0.2 g/ml GMC n % 95% CI 95% CI Anti-5 Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Unprimed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Anti-6B Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Unprimed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Anti-7F Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Unprimed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) /037 Synopsis page 5 of 12

6 Table 1 continued: Percentage of subjects with pneumococcal PS antibody concentrations 0.2 µg/ml and geometric mean antibody concentrations (GMCs) using 22F-ELISA (Total vaccinated cohort) Antibody Group Timing N 0.2 g/ml GMC n % 95% CI 95% CI Anti-9V Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Unprimed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Anti-14 Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Unprimed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Anti-18C Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Unprimed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) /037 Synopsis page 6 of 12

7 Table 1 continued: Percentage of subjects with pneumococcal PS antibody concentrations 0.2 µg/ml and geometric mean antibody concentrations (GMCs) using 22F-ELISA (Total vaccinated cohort) Antibody Group Timing N 0.2 g/ml GMC n % 95% CI g/ml 95% CI Anti-19F Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Unprimed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Anti-23F Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Unprimed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Primed group= subjects received a dose of Aventis Pasteur s 23-valent pneumococcal polysaccharide (Pneumo 23) after receiving 4 doses of GSK Biologicals 11Pn-PD in study /010 Unprimed group = subjects received a dose of Pneumo 23 (received control Havrix in study /010) N = number of subjects with available results n/% = number/percentage of subjects with concentration within the specified range PRE= before dose 1 of 11Pn-PD/HAV in /010 trial PIII(m3) = 1 month after dose 3 of 11Pn-PD/HAV in /010 trial PIII(m9) = before booster dose of 11Pn-PD/HAV in /010 trial PIV(m10) =1 month after booster dose of 11Pn-PD/HAV in /010 trial PRE-23PS = before 23PS dose PI(D15) = 10 to 15 days after 23PS dose GMC = geometric mean antibody concentration calculated on all subjects 95% CI, LL UL= 95% confidence interval; lower and upper limits /037 Synopsis page 7 of 12

8 Table 2: Seropositivity rates and GMTs for opsonophacytic activity against the 11 pneumococcal serotypes (Total vaccinated cohort) 8 GMT Antibody Group Timing N n % 95% CI 95% CI Opsono-1 Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Opsono-3 Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Opsono-4 Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) /037 Synopsis page 8 of 12

9 Table 2 continued: Seropositivity rates and GMTs for opsonophacytic activity against the 11 pneumococcal serotypes (Total vaccinated cohort) 8 GMT Antibody Group Timing N n % 95% CI 95% CI Opsono-5 Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Opsono-6B Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Unprimed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Opsono-7F Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Unprimed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) /037 Synopsis page 9 of 12

10 Table 2 continued: Seropositivity rates and GMTs for opsonophacytic activity against the 11 pneumococcal serotypes (Total vaccinated cohort) 8 GMT N n % 95% CI 95% CI Opsono-9V Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Opsono-14 Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Unprimed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Opsono-18C Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) /037 Synopsis page 10 of 12

11 Table 2 continued: Seropositivity rates and GMTs for opsonophacytic activity against the 11 pneumococcal serotypes (Total vaccinated cohort) 8 GMT N n % 95% CI 95% CI Opsono-19F Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Opsono-23F Primed PRE PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) PIII(m3) PIII(m9) PIV(m10) PRE-23PS PI(D15) Primed group= subjects received a dose of Aventis Pasteur s 23-valent pneumococcal polysaccharide (Pneumo 23) after receiving 4 doses of GSK Biologicals 11Pn-PD in study /010 Unprimed group = subjects received a dose of Pneumo 23 (received control Havrix in study /010) N = number of subjects with available results n/% = number/percentage of subjects with concentration within the specified range PRE= before dose 1 of 11Pn-PD/HAV in /010 trial PIII(m3) = 1 month after dose 3 of 11Pn-PD/HAV in /010 trial PIII(m9) = before booster dose of 11Pn-PD/HAV in /010 trial PIV(m10) =1 month after booster dose of 11Pn-PD/HAV in /010 trial PRE-23PS = before 23PS dose PI(D15) = 10 to 15 days after 23PS dose GMT = geometric mean antibody titer calculated on all subjects 95% CI, LL UL = 95% confidence interval, lower and upper limits /037 Synopsis page 11 of 12

12 Safety: There were no serious adverse events reported during this study. Conclusions: This study describes the immune response of a single dose of 23-valent plain polysaccharide in children who were previously primed with four doses of GSK Biologicals pneumococcal conjugate or with 4 doses of the hepatitis A, Havrix as the unprimed group. Primary vaccination with GSK Biologicals 11Pn-PD induced clear ELISA and OPA responses which varied considerably for the different serotypes. Antibody levels declined following primary vaccination but were restored following booster vaccination, to above post primary levels (with the exception of serotype 3). Antibody levels declined again in the approximately two year period between the post booster (fourth dose) and pre 23-valent plain polysaccharide sampling. However, in the primed group, for some of the serotypes (6B, 14 and 19F), the pre-23 valent IgG antibody levels remained similar to what was observed one month after the fourth dose. In the unprimed group, the pre-23 valent sampling even shows an increase in ELISA and OPA for some of the serotypes. These observations could indicate a natural exposure of subjects to either the pneumococcal serotypes or to cross-reacting bacteria in the period following booster vaccination and pre-23 valent vaccination. The administration of the single dose of 23-valent native polysaccharide elicited immune responses in both the primed and the unprimed groups for all serotypes including serotype 3. Although for this serotype, the absolute antibody level was low (the lowest of the 11 serotypes) and the difference between the 11Pn-PD and the control group was small (the smallest of the 11 serotypes) these results indicate that the serotype 3 PD-conjugate would not have induced a hypo-responsiveness and that the capacity of children to respond to a natural infection was not impaired. Although the 23-valent elicited both ELISA and OPA responses to all 11 serotypes in both groups, the post 23 PS vaccination antibody GMCs or OPA GMTs in the unprimed group were lower than those observed in the primed group. No serious adverse events were reported during the study. In summary, primary vaccination with 11Pn-PD conjugate stimulates the production of functional serotype specific antibodies and induces antigen-specific memory B-cells for long lasting immunity. Date of report: 6 March /037 Synopsis page 12 of 12

Study No.: Title: Rationale: Phase: Study Period: Study Design Centers: Indication: Treatment: Objectives: Primary Outcome/Efficacy Variable:

Study No.: Title: Rationale: Phase: Study Period: Study Design Centers: Indication: Treatment: Objectives: Primary Outcome/Efficacy Variable: 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.