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, 020 10 Púchov 2. Pediatric ambulatory surgery, Rozkvet 2010, 01701 Povazska Bystrica, Povazska Bystrica 3. Paediatric Outpatient Dept, Centrum 3, 018 41, Dubnica nad Vahom 4. Outpatient Paediatric Office, Municipal health center-nova Dubnica, Gagarinova 773/5, 018-51, 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;25:1953-1961. 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 10-15 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 10-15 to assess antibody persistence and immune memory. 104083/037 Synopsis page 1 of 12
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. 1.06 mg Phenol as preservative. Sodium Chloride 0.9% Liquid in prefilled syringes, clear, colorless solution Y0387 Intramuscular injection Right deltoid Duration of treatment: 10-15 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 10-15 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 104083/037 Synopsis page 2 of 12
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. 104083/037 Synopsis page 3 of 12
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 47 1 2.1 0.1 11.3 0.03 0.03 0.04 PIII(m3) 50 50 100 92.9 100 1.53 1.22 1.91 PIII(m9) 49 34 69.4 54.6 81.7 0.37 0.28 0.49 PIV(m10) 50 50 100 92.9 100 2.53 2.16 2.96 PRE-23PS 47 18 38.3 24.5 53.6 0.12 0.09 0.15 PI(D15) 50 50 100 92.9 100 21.62 18.18 25.70 Unprimed PRE 47 0 0.0 0.0 7.5 0.03 0.02 0.03 PIII(m3) 49 0 0.0 0.0 7.3 0.03 0.02 0.03 PIII(m9) 43 2 4.7 0.6 15.8 0.03 0.03 0.04 PIV(m10) 44 3 6.8 1.4 18.7 0.03 0.03 0.04 PRE-23PS 48 5 10.4 3.5 22.7 0.04 0.03 0.06 PI(D15) 49 49 100 92.7 100 7.16 5.40 9.48 Anti-3 Primed PRE 41 4 9.8 2.7 23.1 0.05 0.04 0.06 PIII(m3) 51 51 100 93.0 100 3.83 3.08 4.76 PIII(m9) 51 45 88.2 76.1 95.6 0.75 0.51 1.10 PIV(m10) 51 51 100 93.0 100 2.82 2.17 3.67 PRE-23PS 50 22 44.0 30.0 58.7 0.34 0.19 0.60 PI(D15) 50 50 100 92.9 100 7.88 6.14 10.13 Unprimed PRE 46 5 10.9 3.6 23.6 0.06 0.04 0.08 PIII(m3) 49 3 6.1 1.3 16.9 0.04 0.03 0.05 PIII(m9) 38 4 10.5 2.9 24.8 0.04 0.03 0.07 PIV(m10) 49 4 8.2 2.3 19.6 0.05 0.03 0.06 PRE-23PS 49 19 38.8 25.2 53.8 0.20 0.10 0.38 PI(D15) 49 49 100 92.7 100 5.01 4.01 6.26 Anti-4 Primed PRE 43 1 2.3 0.1 12.3 0.03 0.03 0.04 PIII(m3) 51 51 100 93.0 100 2.13 1.73 2.61 PIII(m9) 50 40 80.0 66.3 90.0 0.44 0.35 0.56 PIV(m10) 51 51 100 93.0 100 2.24 1.90 2.63 PRE-23PS 49 10 20.4 10.2 34.3 0.13 0.09 0.18 PI(D15) 50 50 100 92.9 100 18.51 15.00 22.84 Unprimed PRE 47 1 2.1 0.1 11.3 0.03 0.03 0.04 PIII(m3) 49 2 4.1 0.5 14.0 0.03 0.02 0.03 PIII(m9) 43 1 2.3 0.1 12.3 0.03 0.02 0.03 PIV(m10) 43 1 2.3 0.1 12.3 0.03 0.02 0.03 PRE-23PS 48 7 14.6 6.1 27.8 0.05 0.03 0.06 PI(D15) 49 49 100 92.7 100 7.31 5.56 9.60 104083/037 Synopsis page 4 of 12
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 46 0 0.0 0.0 7.7 0.03 0.03 0.03 PIII(m3) 50 50 100 92.9 100 1.89 1.52 2.36 PIII(m9) 49 45 91.8 80.4 97.7 0.51 0.41 0.64 PIV(m10) 50 50 100 92.9 100 2.87 2.33 3.53 PRE-23PS 50 25 50.0 35.5 64.5 0.20 0.15 0.26 PI(D15) 50 50 100 92.9 100 18.48 14.32 23.86 Unprimed PRE 48 2 4.2 0.5 14.3 0.03 0.03 0.04 PIII(m3) 49 1 2.0 0.1 10.9 0.03 0.03 0.04 PIII(m9) 39 0 0.0 0.0 9.0 0.03 0.03 0.04 PIV(m10) 43 1 2.3 0.1 12.3 0.03 0.03 0.04 PRE-23PS 48 7 14.6 6.1 27.8 0.07 0.05 0.09 PI(D15) 48 47 97.9 88.9 99.9 2.45 1.66 3.63 Anti-6B Primed PRE 42 5 11.9 4.0 25.6 0.05 0.03 0.06 PIII(m3) 49 39 79.6 65.7 89.8 0.61 0.43 0.86 PIII(m9) 51 41 80.4 66.9 90.2 0.54 0.40 0.74 PIV(m10) 51 50 98.0 89.6 100 2.20 1.73 2.80 PRE-23PS 50 42 84.0 70.9 92.8 1.59 0.89 2.84 PI(D15) 50 50 100 92.9 100 10.23 7.57 13.83 Unprimed PRE 44 7 15.9 6.6 30.1 0.05 0.04 0.07 PIII(m3) 49 0 0.0 0.0 7.3 0.03 0.03 0.03 PIII(m9) 48 0 0.0 0.0 7.4 0.03 0.03 0.03 PIV(m10) 46 0 0.0 0.0 7.7 0.03 0.03 0.03 PRE-23PS 49 16 32.7 19.9 47.5 0.13 0.09 0.20 PI(D15) 49 35 71.4 56.7 83.4 0.52 0.36 0.75 Anti-7F Primed PRE 45 4 8.9 2.5 21.2 0.06 0.04 0.07 PIII(m3) 51 51 100 93.0 100 2.16 1.78 2.62 PIII(m9) 51 50 98.0 89.6 100 0.92 0.76 1.11 PIV(m10) 50 50 100 92.9 100 4.64 3.94 5.48 PRE-23PS 47 36 76.6 62.0 87.7 0.31 0.24 0.39 PI(D15) 50 50 100 92.9 100 21.19 17.19 26.12 Unprimed PRE 45 5 11.1 3.7 24.1 0.06 0.04 0.08 PIII(m3) 48 2 4.2 0.5 14.3 0.03 0.03 0.04 PIII(m9) 44 1 2.3 0.1 12.0 0.03 0.03 0.04 PIV(m10) 48 1 2.1 0.1 11.1 0.03 0.03 0.04 PRE-23PS 49 3 6.1 1.3 16.9 0.04 0.04 0.06 PI(D15) 49 49 100 92.7 100 4.60 3.74 5.65 104083/037 Synopsis page 5 of 12
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 43 5 11.6 3.9 25.1 0.06 0.04 0.08 PIII(m3) 50 48 96.0 86.3 99.5 1.47 1.10 1.98 PIII(m9) 51 47 92.2 81.1 97.8 0.65 0.51 0.83 PIV(m10) 51 51 100 93.0 100 3.06 2.50 3.74 PRE-23PS 48 20 41.7 27.6 56.8 0.23 0.15 0.36 PI(D15) 50 50 100 92.9 100 25.13 19.07 33.11 Unprimed PRE 47 1 2.1 0.1 11.3 0.04 0.03 0.04 PIII(m3) 45 0 0.0 0.0 7.9 0.03 0.02 0.03 PIII(m9) 46 1 2.2 0.1 11.5 0.03 0.02 0.03 PIV(m10) 44 2 4.5 0.6 15.5 0.03 0.03 0.04 PRE-23PS 49 8 16.3 7.3 29.7 0.06 0.04 0.08 PI(D15) 49 48 98.0 89.1 99.9 2.20 1.57 3.09 Anti-14 Primed PRE 44 27 61.4 45.5 75.6 0.30 0.19 0.46 PIII(m3) 51 51 100 93.0 100 2.89 2.24 3.73 PIII(m9) 51 50 98.0 89.6 100 1.35 1.02 1.78 PIV(m10) 51 51 100 93.0 100 5.31 4.33 6.51 PRE-23PS 44 41 93.2 81.3 98.6 2.05 1.14 3.71 PI(D15) 50 50 100 92.9 100 38.15 29.92 48.63 Unprimed PRE 46 31 67.4 52.0 80.5 0.31 0.21 0.48 PIII(m3) 48 11 22.9 12.0 37.3 0.08 0.06 0.12 PIII(m9) 41 6 14.6 5.6 29.2 0.05 0.03 0.07 PIV(m10) 45 5 11.1 3.7 24.1 0.05 0.03 0.07 PRE-23PS 46 14 30.4 17.7 45.8 0.17 0.10 0.27 PI(D15) 48 40 83.3 69.8 92.5 1.14 0.67 1.95 Anti-18C Primed PRE 44 4 9.1 2.5 21.7 0.05 0.04 0.07 PIII(m3) 50 50 100 92.9 100 1.52 1.19 1.94 PIII(m9) 48 43 89.6 77.3 96.5 0.49 0.39 0.61 PIV(m10) 51 51 100 93.0 100 2.56 2.17 3.02 PRE-23PS 50 16 32.0 19.5 46.7 0.16 0.10 0.26 PI(D15) 50 50 100 92.9 100 18.33 14.77 22.74 Unprimed PRE 46 8 17.4 7.8 31.4 0.05 0.04 0.07 PIII(m3) 47 0 0.0 0.0 7.5 0.03 0.03 0.03 PIII(m9) 39 0 0.0 0.0 9.0 0.03 0.02 0.03 PIV(m10) 42 0 0.0 0.0 8.4 0.03 0.02 0.03 PRE-23PS 47 6 12.8 4.8 25.7 0.04 0.03 0.06 PI(D15) 49 48 98.0 89.1 99.9 1.53 1.08 2.17 104083/037 Synopsis page 6 of 12
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 42 11 26.2 13.9 42.0 0.09 0.06 0.13 PIII(m3) 51 49 96.1 86.5 99.5 2.16 1.54 3.02 PIII(m9) 48 42 87.5 74.8 95.3 0.63 0.47 0.85 PIV(m10) 51 51 100 93.0 100 4.07 3.34 4.96 PRE-23PS 50 41 82.0 68.6 91.4 3.59 1.72 7.49 PI(D15) 50 50 100 92.9 100 39.13 27.93 54.81 Unprimed PRE 45 13 28.9 16.4 44.3 0.09 0.06 0.13 PIII(m3) 46 7 15.2 6.3 28.9 0.05 0.03 0.06 PIII(m9) 39 2 5.1 0.6 17.3 0.03 0.03 0.05 PIV(m10) 41 4 9.8 2.7 23.1 0.04 0.03 0.06 PRE-23PS 49 30 61.2 46.2 74.8 0.33 0.18 0.60 PI(D15) 49 49 100 92.7 100 4.80 3.41 6.75 Anti-23F Primed PRE 43 4 9.3 2.6 22.1 0.04 0.03 0.06 PIII(m3) 49 46 93.9 83.1 98.7 0.83 0.61 1.13 PIII(m9) 49 45 91.8 80.4 97.7 0.58 0.44 0.77 PIV(m10) 51 50 98.0 89.6 100 2.99 2.29 3.90 PRE-23PS 48 33 68.8 53.7 81.3 0.92 0.50 1.69 PI(D15) 50 50 100 92.9 100 14.43 10.86 19.19 Unprimed PRE 47 5 10.6 3.5 23.1 0.05 0.03 0.06 PIII(m3) 47 0 0.0 0.0 7.5 0.03 0.03 0.03 PIII(m9) 39 0 0.0 0.0 9.0 0.03 0.02 0.03 PIV(m10) 47 0 0.0 0.0 7.5 0.03 0.03 0.03 PRE-23PS 49 12 24.5 13.3 38.9 0.08 0.05 0.12 PI(D15) 48 38 79.2 65.0 89.5 0.60 0.39 0.92 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 347414/010 Unprimed group = subjects received a dose of Pneumo 23 (received control Havrix in study 347414/010) 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 347414/010 trial PIII(m3) = 1 month after dose 3 of 11Pn-PD/HAV in 347414/010 trial PIII(m9) = before booster dose of 11Pn-PD/HAV in 347414/010 trial PIV(m10) =1 month after booster dose of 11Pn-PD/HAV in 347414/010 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 104083/037 Synopsis page 7 of 12
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 14 1 7.1 0.2 33.9 4.9 3.2 7.5 PIII(m3) 32 24 75.0 56.6 88.5 35.4 20.7 60.3 PIII(m9) 50 17 34.0 21.2 48.8 9.7 6.6 14.3 PIV(m10) 51 49 96.1 86.5 99.5 343.0 237.5 495.2 PRE-23PS 48 6 12.5 4.7 25.2 5.0 4.2 6.0 PI(D15) 41 41 100 91.4 100 7357.8 5316.9 10182.0 PIII(m3) 6 0 0.0 0.0 45.9 4.0 4.0 4.0 PIII(m9) 49 2 4.1 0.5 14.0 4.5 3.8 5.2 PIV(m10) 49 2 4.1 0.5 14.0 4.6 3.8 5.5 PRE-23PS 48 0 0.0 0.0 7.4 4.0 4.0 4.0 PI(D15) 44 44 100 92.0 100 1000.2 675.4 1481.1 Opsono-3 Primed PRE 13 2 15.4 1.9 45.4 5.6 3.1 10.0 PIII(m3) 31 29 93.5 78.6 99.2 65.4 42.6 100.3 PIII(m9) 50 35 70.0 55.4 82.1 18.9 12.3 29.1 PIV(m10) 51 51 100 93.0 100 182.3 143.9 230.9 PRE-23PS 48 20 41.7 27.6 56.8 14.7 8.5 25.3 PI(D15) 49 49 100 92.7 100 865.4 677.8 1105.1 PIII(m3) 6 0 0.0 0.0 45.9 4.0 4.0 4.0 PIII(m9) 49 2 4.1 0.5 14.0 4.5 3.8 5.3 PIV(m10) 49 5 10.2 3.4 22.2 5.1 4.0 6.4 PRE-23PS 47 13 27.7 15.6 42.6 9.5 6.0 14.9 PI(D15) 47 47 100 92.5 100 518.3 407.6 659.2 Opsono-4 Primed PRE 14 0 0.0 0.0 23.2 4.0 4.0 4.0 PIII(m3) 30 30 100 88.4 100 390.6 281.7 541.8 PIII(m9) 50 43 86.0 73.3 94.2 82.7 49.1 139.4 PIV(m10) 51 51 100 93.0 100 1154.0 925.2 1439.2 PRE-23PS 35 10 28.6 14.6 46.3 17.0 7.4 39.1 PI(D15) 49 49 100 92.7 100 18268.3 14472.9 23058.9 PIII(m3) 6 0 0.0 0.0 45.9 4.0 4.0 4.0 PIII(m9) 48 0 0.0 0.0 7.4 4.0 4.0 4.0 PIV(m10) 46 2 4.3 0.5 14.8 4.8 3.7 6.3 PRE-23PS 38 2 5.3 0.6 17.7 5.3 3.5 7.8 PI(D15) 43 43 100 91.8 100 13246.1 10682.8 16424.3 104083/037 Synopsis page 8 of 12
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 14 1 7.1 0.2 33.9 5.6 2.7 11.5 PIII(m3) 32 31 96.9 83.8 99.9 91.3 62.4 133.6 PIII(m9) 50 39 78.0 64.0 88.5 24.1 16.4 35.3 PIV(m10) 51 51 100 93.0 100 409.5 324.0 517.4 PRE-23PS 47 20 42.6 28.3 57.8 10.2 7.1 14.5 PI(D15) 43 43 100 91.8 100 3288.7 2415.6 4477.4 PIII(m3) 6 0 0.0 0.0 45.9 4.0 4.0 4.0 PIII(m9) 49 0 0.0 0.0 7.3 4.0 4.0 4.0 PIV(m10) 49 1 2.0 0.1 10.9 4.3 3.8 4.8 PRE-23PS 48 1 2.1 0.1 11.1 4.2 3.8 4.5 PI(D15) 45 44 97.8 88.2 99.9 164.3 109.2 247.3 Opsono-6B Primed PRE 14 3 21.4 4.7 50.8 8.3 3.4 20.5 PIII(m3) 32 31 96.9 83.8 99.9 555.8 344.6 896.4 PIII(m9) 50 44 88.0 75.7 95.5 197.8 112.2 348.7 PIV(m10) 51 50 98.0 89.6 100 1203.5 866.3 1672.0 PRE-23PS 25 23 92.0 74.0 99.0 829.8 363.2 1896.0 PI(D15) 44 44 100 92.0 100 3763.5 2593.4 5461.5 Unprimed PRE 6 1 16.7 0.4 64.1 5.2 2.7 10.1 PIII(m3) 6 0 0.0 0.0 45.9 4.0 4.0 4.0 PIII(m9) 46 6 13.0 4.9 26.3 7.4 4.6 11.9 PIV(m10) 49 8 16.3 7.3 29.7 8.3 5.1 13.5 PRE-23PS 27 21 77.8 57.7 91.4 382.7 135.8 1078.2 PI(D15) 46 44 95.7 85.2 99.5 1744.5 1037.2 2934.2 Opsono-7F Primed PRE 14 8 57.1 28.9 82.3 38.0 10.9 132.6 PIII(m3) 32 32 100 89.1 100 2780.2 1906.6 4053.9 PIII(m9) 50 50 100 92.9 100 1570.9 1185.4 2081.8 PIV(m10) 51 51 100 93.0 100 5134.2 3987.6 6610.4 PRE-23PS 20 14 70.0 45.7 88.1 243.5 63.8 929.7 PI(D15) 44 44 100 92.0 100 36063.3 26969.6 48223.4 Unprimed PRE 5 3 60.0 14.7 94.7 17.6 3.0 104.2 PIII(m3) 6 3 50.0 11.8 88.2 29.5 2.9 300.2 PIII(m9) 48 34 70.8 55.9 83.0 157.3 75.4 328.2 PIV(m10) 47 35 74.5 59.7 86.1 176.5 86.8 358.8 PRE-23PS 14 3 21.4 4.7 50.8 16.4 3.2 83.8 PI(D15) 41 41 100 91.4 100 23762.4 16961.0 33291.2 104083/037 Synopsis page 9 of 12
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 13 0 0.0 0.0 24.7 4.0 4.0 4.0 PIII(m3) 31 31 100 88.8 100 1838.2 1309.7 2580.0 PIII(m9) 50 49 98.0 89.4 99.9 673.1 459.1 986.8 PIV(m10) 51 51 100 93.0 100 4885.8 3741.2 6380.6 PRE-23PS 14 13 92.9 66.1 99.8 391.4 129.4 1183.4 PI(D15) 33 33 100 89.4 100 30558.6 22517.2 41471.7 PIII(m3) 6 1 16.7 0.4 64.1 8.7 1.2 64.4 PIII(m9) 44 21 47.7 32.5 63.3 36.2 17.4 75.6 PIV(m10) 48 27 56.3 41.2 70.5 59.0 28.3 123.0 PRE-23PS 13 11 84.6 54.6 98.1 259.4 80.1 840.7 PI(D15) 39 39 100 91.0 100 18338.9 12438.3 27038.7 Opsono-14 Primed PRE 14 7 50.0 23.0 77.0 12.8 5.4 30.2 PIII(m3) 32 32 100 89.1 100 1297.7 884.9 1903.0 PIII(m9) 49 49 100 92.7 100 247.8 189.7 323.8 PIV(m10) 51 51 100 93.0 100 1697.5 1292.6 2229.2 PRE-23PS 43 43 100 91.8 100 858.6 555.6 1326.8 PI(D15) 49 49 100 92.7 100 9374.0 6959.4 12626.4 Unprimed PRE 6 1 16.7 0.4 64.1 7.7 1.4 40.9 PIII(m3) 6 3 50.0 11.8 88.2 13.6 3.2 58.7 PIII(m9) 43 27 62.8 46.7 77.0 43.1 23.3 79.9 PIV(m10) 47 25 53.2 38.1 67.9 30.1 16.6 54.8 PRE-23PS 40 38 95.0 83.1 99.4 347.2 226.1 533.2 PI(D15) 46 46 100 92.3 100 3468.7 2567.9 4685.4 Opsono-18C Primed PRE 14 1 7.1 0.2 33.9 5.1 3.0 8.5 PIII(m3) 32 30 93.8 79.2 99.2 46.3 30.2 71.0 PIII(m9) 45 19 42.2 27.7 57.8 9.9 6.7 14.7 PIV(m10) 51 51 100 93.0 100 120.8 92.3 158.1 PRE-23PS 43 7 16.3 6.8 30.7 6.9 4.6 10.4 PI(D15) 49 49 100 92.7 100 2227.4 1737.3 2855.8 PIII(m3) 6 0 0.0 0.0 45.9 4.0 4.0 4.0 PIII(m9) 49 0 0.0 0.0 7.3 4.0 4.0 4.0 PIV(m10) 44 1 2.3 0.1 12.0 4.1 3.9 4.2 PRE-23PS 46 5 10.9 3.6 23.6 6.0 4.2 8.5 PI(D15) 47 46 97.9 88.7 99.9 865.2 566.8 1320.8 104083/037 Synopsis page 10 of 12
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 14 1 7.1 0.2 33.9 5.4 2.8 10.1 PIII(m3) 32 30 93.8 79.2 99.2 87.4 53.3 143.4 PIII(m9) 50 27 54.0 39.3 68.2 12.1 8.7 16.9 PIV(m10) 51 51 100 93.0 100 402.6 312.4 519.0 PRE-23PS 46 33 71.7 56.5 84.0 110.9 48.9 251.7 PI(D15) 33 33 100 89.4 100 1889.5 1162.1 3072.2 PIII(m3) 7 0 0.0 0.0 41.0 4.0 4.0 4.0 PIII(m9) 49 1 2.0 0.1 10.9 4.5 3.5 5.9 PIV(m10) 49 2 4.1 0.5 14.0 4.8 3.7 6.2 PRE-23PS 44 8 18.2 8.2 32.7 6.8 4.7 9.8 PI(D15) 37 31 83.8 68.0 93.8 277.1 128.7 596.4 Opsono-23F Primed PRE 11 0 0.0 0.0 28.5 4.0 4.0 4.0 PIII(m3) 31 30 96.8 83.3 99.9 1528.8 899.4 2598.4 PIII(m9) 50 47 94.0 83.5 98.7 546.6 319.2 936.2 PIV(m10) 51 51 100 93.0 100 3301.2 2568.9 4242.3 PRE-23PS 40 31 77.5 61.5 89.2 625.7 236.9 1652.4 PI(D15) 48 48 100 92.6 100 15055.0 10880.7 20830.7 PIII(m3) 6 1 16.7 0.4 64.1 7.0 1.7 29.5 PIII(m9) 46 15 32.6 19.5 48.0 21.5 10.3 44.8 PIV(m10) 47 19 40.4 26.4 55.7 30.5 14.3 64.8 PRE-23PS 38 22 57.9 40.8 73.7 184.8 59.3 575.7 PI(D15) 45 40 88.9 75.9 96.3 2954.2 1305.3 6685.9 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 347414/010 Unprimed group = subjects received a dose of Pneumo 23 (received control Havrix in study 347414/010) 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 347414/010 trial PIII(m3) = 1 month after dose 3 of 11Pn-PD/HAV in 347414/010 trial PIII(m9) = before booster dose of 11Pn-PD/HAV in 347414/010 trial PIV(m10) =1 month after booster dose of 11Pn-PD/HAV in 347414/010 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 104083/037 Synopsis page 11 of 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 2007 104083/037 Synopsis page 12 of 12