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

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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.: (10PN-PD-DIT-007 BST:001) Title: A phase IIIa single-blind, controlled multicentre study to assess the safety, reactogenicity and immunogenicity of GSK Biologicals 10-valent pneumococcal conjugate vaccine or Prevenar when given as a fourth dose between months of age in children previously vaccinated in infancy in the primary study -PD-DIT-001 (105553) with either GSK Biologicals 10-valent pneumococcal conjugate vaccine or Prevenar. -PD-DiT: GlaxoSmithKline (GSK) Biologicals 10-valent pneumococcal conjugate vaccine () Prevenar: Wyeth s 7-valent pneumococcal conjugate vaccine () Rationale: The aim of this study was to assess the safety and immunogenicity of a booster dose of the -PD-DiT vaccine, co-administered with DTPa-HBV-IPV/Hib, at 12 to 18 months of age, in subjects primed in study 10PN-PD-DIT- 001 (105553). The persistence of antibodies prior to the booster vaccination was also evaluated. DTPa-HBV-IPV/Hib: GSK Biologicals combined diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated poliovirus and Haemophilus influenzae type b vaccine (Infanrix TM hexa). For results on the primary study, please refer to -PD-DIT-001 (105553) Phase: III Study Period: 25 September 2006 to 17 November 2007 (including the extended safety follow-up) Study Design: Multi-centre, partially-randomized*, single-blinded and controlled study with 3 parallel groups. * Subjects received the same lot of the vaccine as in the primary study 10PN-PD-DIT-001 (105553). Only subjects having received vaccine in the primary study were randomized with a 3:1 ratio to receive a booster dose of either the vaccine (one of the 3 different lots used in the primary vaccination study) or vaccine. Some of the subjects primed with were diverted to the 022 booster study to evaluate the co-administration with a combined measles mumps-rubella-varicella vaccine. Centres: Study conducted in 35 centres: 16 in Finland, 13 in France and 6 in Poland Indication: Booster vaccination against Streptococcus pneumoniae, diphtheria, tetanus, pertussis, Hib, hepatitis B and polio virus types in children 12 to 18 months old. Treatment: The study groups were as follows: - Group: subjects primed with at least one dose of received a single dose of vaccine. Group: subjects primed with at least one dose of vaccine received a single dose of vaccine. Group: subjects primed with at least one dose of vaccine received a single dose of vaccine. Pneumococcal vaccines were co-administered with DTPa-HBV-IPV/Hib vaccine. All vaccines were injected intramuscularly into the thigh or deltoid region, -PD-DiT and in the right side and DTPa-HBV-IPV/Hib in the left side. Objectives: To demonstrate that a booster dose of -PD-DiT vaccine was non-inferior to vaccine, both coadministered with DTPa-HBV-IPV/Hib vaccine, in terms of post-immunization febrile reactions with rectal temperature > 39.0 C. Demonstration of non-inferiority refers to the statistical method used to rule out an increase in the incidence of postimmunization febrile reactions with rectal temperature > 39.0 C in the candidate vaccine group compared to the control group that would exceed a pre-defined limit of 10%, considered to be clinically acceptable. Primary Outcome/Efficacy Variable: Occurrence of fever with rectal temperature > 39.0 C within 4 days (Day 0-3) after the booster vaccination. Secondary Outcome/Efficacy Variable(s): Safety: Occurrence of solicited local symptoms (any and grade 3) within 4 days (Day 0-3) after the booster vaccination. Occurrence of solicited general symptoms (any and grade 3) within 4 days (Day 0-3) after the booster vaccination. Occurrence of unsolicited adverse events (AEs) within 31 days (Day 0-30) after the booster vaccination. Occurrence of serious adverse events (SAEs) throughout the active phase of the study, within 31 days after the booster vaccination (Day 0-30). Occurrence of serious adverse events during the extended 5-month safety follow-up *. * The SAEs analysis performed at the end of the safety follow-up included all SAEs from Day 0 until study conclusion. Immunogenicity: Prior to and one month after the booster vaccination with -PD-DiT conjugate vaccine or vaccine, co-

2 administered with DTPa-HBV-IPV/Hib vaccine: Anti-pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F antibody concentrations 0.20 μg/ml. Antibody concentrations against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. Opsonophagocytic activity against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. Antibody concentrations against protein D (anti-pd). Seropositivity status, defined as: - Anti-pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F antibody concentrations 0.05 μg/ml. - Opsonophagocytic activity against pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F 8. - Anti-PD antibody concentrations 100 EL.U/mL. Prior to and one month after the administration of the booster dose of DTPa-HBV-IPV/Hib vaccine: Anti-diphtheria and anti-tetanus toxoids, anti-polyribosyl ribitol phosphate (anti-prp), anti-pertussis toxoid (anti-pt), anti-filamentous haemagglutinin (anti-fha) and anti-pertactin (anti-prn), anti-hepatitis B surface antigen (anti-hbs) antibody concentrations, and anti-polio type 1, 2 and 3 titres. Seropositivity status, defined as: - Anti-PT antibody concentrations 5 EL.U/mL. - Anti-FHA antibody concentrations 5 EL.U/mL. - Anti-PRN antibody concentrations 5 EL.U/mL. Seroprotection status, defined as: - Anti-diphtheria toxoid antibody concentrations 0.1 IU/mL. - Anti-tetanus toxoid antibody concentrations 0.1 IU/mL. - Anti-PRP antibody concentrations 0.15 μg/ml and 1.0 μg/ml. - Anti-HBs antibody concentrations 10 miu/ml. - Anti-polio type 1 titres 8. - Anti-polio type 2 titres 8. - Anti-polio type 3 titres 8. Booster vaccine response to PT, FHA and PRN antigens one month after the booster vaccination; defined as appearance of antibodies in subjects who were seronegative prior to the booster vaccination or at least 2-fold increase of pre-booster vaccination antibody concentrations in subjects who were seropositive prior to the booster vaccination. Statistical Methods: Analyses were performed on the Primary total vaccinated cohort, on the Total vaccinated cohort, on the According-To- Protocol (ATP) cohort for persistence and on the ATP cohort for immunogenicity. - The Primary total vaccinated cohort included all vaccinated subjects from the primary study 10PN-PD-DIT-001 (105553), who were planned to be enrolled in the present booster vaccination study. - The Total vaccinated cohort included all vaccinated subjects. Thus, the Total vaccinated cohort for analysis of safety included all subjects with vaccine administration documented. - The ATP cohort for persistence included all subjects who had received the full 3-dose primary course in study 10PN-PD- DIT-001 (105553), who had received their study vaccine according to their planned assignment, for whom administration route of study vaccine was known, who had not received a vaccine not specified or forbidden in the protocol and for whom assay results were available for antibodies against at least one study vaccine antigen component for the blood sampling taken before the administration of the study booster dose. - The ATP cohort for immunogenicity included all evaluable subjects (i.e. those meeting all eligibility criteria, complying with the procedures and intervals defined in the protocol, with no elimination criteria during the study) and with available immunogenicity data This included subjects for whom assay results were available for antibodies against at least one study vaccine antigen component after booster vaccination. Analysis of immunogenicity Descriptive assessments of pneumococcal antibody persistence were performed on the ATP cohort for persistence and descriptive analyses of booster response were performed on the ATP cohort for immunogenicity. Persistence: The tables were generated according to the primary phase treatment groups, for each pneumococcal serotype and for the following available blood sampling time points: post dose III blood sample (primary phase) and pre-booster vaccination blood sample (booster phase). Geometric mean antibody concentrations or geometric mean titres (GMCs or GMTs) with 95% confidence intervals (CIs) and seropositivity/seroprotection rates with exact 95% CIs were tabulated for each pneumococcal serotype and for Protein D. Antibody concentrations/titres below the cut-off of the assay were given an arbitrary value of half the cut-off for the purpose of GMC/GMT calculation. Booster response:

3 The tables were generated according to the booster phase treatment groups, for each pneumococcal serotype, for anti- PD, anti-diphtheria, anti-tetanus toxoids, anti-prp, anti-pt, anti-fha, anti-prn and anti-hbs and for the following blood sampling time points: post-dose 3 blood sample (primary phase), pre-booster vaccination blood sample (booster phase), post-booster vaccination blood sample (booster phase). GMCs or GMTs with 95% CIs and seropositivity/seroprotection rates with exact 95% CIs were tabulated. Analysis of safety Analysis of the SAEs between the end of the primary study up to booster dose was done on the Primary total vaccinated cohort. The other safety analyses were performed on the Total vaccinated cohort for the booster phase. Standardized asymptotic 95% CI for the difference between groups (- minus ), in terms of percentage of subjects with rectal temperature > 39.0 C, within 4 days (Day 0-3) after booster vaccination, was computed. The primary objective was reached if the upper limit of the 95% CI for the difference between groups (- minus ) was < 10%. The percentage of subjects with each individual solicited local and general symptom during the 4-day (Day 0-3) solicited follow-up period was tabulated with exact 95% CI. The same calculations were performed for symptoms rated as grade 3 and for general symptoms with causal relationship to vaccination. The proportion of subjects with at least one report of unsolicited AE classified by the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms and reported within 31 days (Day 0-30) after vaccination was tabulated. SAEs were also tabulated according to MedDRA preferred terms; 3 tables were generated: (1) one from priming up to booster dose, (2) one for SAEs occurring within 31 days after the booster dose and (3) one from the booster dose up to the end of the extended safety follow-up period, therefore also including the SAEs of the previous table.. Study Population: Approximately 1200 male or female subjects between and including, 12 and 18 months of age at the time of the booster vaccination, who participated in the primary vaccination study 10PN-PD-DIT-001 (105553) and received at least one dose of either pneumococcal conjugate vaccines (-PD-DIT or vaccine) were to be enrolled in this study. The other subjects who had participated in the study were invited to take part in a separate booster study 10PN-PD-DIT-022 BST:001. Subjects were free of obvious health problems as established by medical history and clinical examination before entering into the study. Subjects who were administered any additional pneumococcal or DTPa-combined vaccines since the end of the primary study 10PN-PD-DIT-001 (105553) were excluded. Written informed consent was obtained from the parent or guardian of the subject prior to the performance of any study-specific procedures. Active Phase Number of subjects - Group Group Group Planned, N Randomised, N (Total Vaccinated Cohort) Completed, n (%) 736 (99.9) 91 (98.9) 282 (99.6) Total Number Subjects Withdrawn, n (%) 1 (0.1) 1 (1.1) 1 (0.4) Withdrawn due to Adverse Events, n (%) 0 (0.0) 0 (0.0) 0 (0.0) Withdrawn due to Lack of Efficacy, n (%) Not applicable Not applicable Not applicable Withdrawn for other reasons, n (%) 1 (0.1) 1 (1.1) 1 (0.4) Demographics - Group Group Group N (Total Vaccinated Cohort) Females:Males 377:360 42:50 149:134 Mean Age, months (SD) 15.3 (2.08) 14.2 (2.26) 14.2 (2.23) White Caucasian/European heritage, n (%) 713 (96.7) 91 (98.9) 278 (98.2) Number of subjects - Group Group Group Subjects in Total Vaccinated Cohort (active phase), N) Subjects in ESFU cohort, n (%) Subjects not contacted for ESFU phase, n (%) 11 (1.5) 1 (1.1) 1 (0.4) Not contacted due to consent withdrawal, n (%) 0 (0.0) 0 (0.0) 0 (0.0) Not contacted due to lost to follow up, n (%) 11 (1.5) 1 (1.1) 1 (0.4) Extended Safety follow-up Demographics - Group Group Group N (ESFU cohort) Females:Males 368:358 42:49 148:134 Mean Age, months (SD) 21.6 (2.22) 20.3 (2.38) 20.5 (2.42) White - Caucasian / European heritage, n (%) 702 (96.7) 90 (98.9) 277 (98.2) Primary Efficacy Results:

4 Difference between groups (- minus ) in percentage of subjects with rectal temperature > 39.0 C during the 4-day (Day 0-3) post-vaccination period (Total vaccinated cohort) Symptoms Type - Group Group Difference in percentage (- Group minus Group) N n % N n % % 95% CI LL UL Fever (rectal temperature) > 39.0 C * N = number of subjects with the documented dose n (%) = number (percentage) of subjects with rectal temperature > 39.0 C 95% CI = standardized asymptotic 95% confidence interval, LL = Lower Limit, UL = Upper Limit * The primary objective was reached as the upper limit of the 95% CI for the difference between groups (- minus ), in terms of percentage of subjects reporting fever with rectal temperature > 39.0 C after the booster vaccination, was below the pre-defined limit of 10%. Seropositivity rates and GMCs for anti-1, anti-4, anti-5, anti-6b, anti-7f, anti-9v, anti-14, anti-18c, anti-19f and anti-23f antibodies (22F-inhibition ELISA) (ATP cohort for persistence) Antibody Group Timing N 0.05 μg/ml 0.2 μg/ml GMC (μg/ml) n % 95% CI n % 95% CI Value 95% CI LL UL LL UL LL UL Anti-1 - PIII(M3) Pre-booster PIII(M3) Pre-booster Anti-4 - PIII(M3) Pre-booster PIII(M3) Pre-booster Anti-5 - PIII(M3) Pre-booster PIII(M3) Pre-booster Anti-6B - PIII(M3) Pre-booster PIII(M3) Pre-booster Anti-7F - PIII(M3) Pre-booster PIII(M3) Pre-booster Anti-9V - PIII(M3) Pre-booster PIII(M3) Pre-booster Anti-14 - PIII(M3) Pre-booster PIII(M3) Pre-booster Anti-18C - PIII(M3) Pre-booster PIII(M3) Pre-booster Anti-19F - PIII(M3) Pre-booster PIII(M3)

5 Pre-booster Anti-23F - PIII(M3) Pre-booster PIII(M3) Pre-booster Seropositivity rates and GMTs for opsono-1, opsono-4, opsono-5, opsono-6b, opsono-7f, opsono-9v, opsono-14, opsono-18c, opsono-19f and opsono-23f (ATP cohort for persistence) Antibody Group Timing N 8 GMT n % 95% CI Value 95% CI LL UL LL UL Opsono-1 - PIII(M3) Pre-booster PIII(M3) Pre-booster Opsono-4 - PIII(M3) Pre-booster PIII(M3) Pre-booster Opsono-5 - PIII(M3) Pre-booster PIII(M3) Pre-booster Opsono-6B - PIII(M3) Pre-booster PIII(M3) Pre-booster Opsono-7F - PIII(M3) Pre-booster PIII(M3) Pre-booster Opsono-9V - PIII(M3) Pre-booster PIII(M3) Pre-booster Opsono-14 - PIII(M3) Pre-booster PIII(M3) Pre-booster Opsono-18C - PIII(M3) Pre-booster PIII(M3) Pre-booster Opsono-19F - PIII(M3) Pre-booster PIII(M3) Pre-booster Opsono-23F - PIII(M3) Pre-booster PIII(M3)

6 Pre-booster n (%) = number (percentage) of subjects with antibody titre within the specified range Seropositivity rates and GMCs for anti-pd antibodies (ATP cohort for persistence) Group Timing N 100 EL.U/mL GMC (EL.U/mL) n % 95% CI Value 95% CI LL UL LL UL - PIII(M3) Pre-booster PIII(M3) Pre-booster n (%) = number(percentage) of subjects with antibody concentration within the specified range Seropositivity rates and GMCs for anti-1, anti-4, anti-5, anti-6b, anti-7f, anti-9v, anti-14, anti-18c, anti-19f and anti-23f antibodies (22F-inhibition ELISA) (ATP cohort for immunogenicity) Antibody Group Timing N 0.05 μg/ml 0.2 μg/ml GMC (μg/ml) n % 95% CI n % 95% CI Value 95% CI LL UL LL UL LL UL Anti-1 Anti-4 Anti-5 Anti-6B PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster

7 Anti-7F Anti-9V Anti Anti-18C - Anti-19F Anti-23F - - Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster

8 PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Post-booster = post-booster vaccination blood sample (booster phase) Seropositivity rates and GMTs for opsono-1, opsono-4, opsono-5, opsono-6b, opsono-7f, opsono-9v, opsono-14, opsono-18c, opsono-19f and opsono-23f (ATP cohort for immunogenicity) Antibody Group Timing N 8 GMT n % 95% CI Value 95% CI LL UL LL UL Opsono-1 - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Opsono-4 - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Opsono-5 - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Opsono-6B - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Opsono-7F - PIII(M3)

9 Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Opsono-9V - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Opsono-14 - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Opsono-18C - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Opsono-19F - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Opsono-23F - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster

10 Post-booster = post-booster vaccination blood sample (booster phase) Seropositivity rates and GMCs for anti-pd antibodies (ATP cohort for immunogenicity) Group Timing N 100 EL.U/mL GMC (EL.U/mL) n % 95% CI Value 95% CI LL UL LL UL - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Post-booster = post-booster vaccination blood sample (booster phase) Seroprotection rates and GMCs for anti-diphtheria and anti-tetanus antibodies (ATP cohort for immunogenicity) Antibody Group Timing N 0.1 IU/mL GMC (IU/mL) n % 95% CI Value 95% CI LL UL LL UL Antidiphtheria Antitetanus - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Post-booster = post-booster vaccination blood sample (booster phase) Seropositivity rates and GMCs for anti-pt, anti-fha and anti-prn antibodies (ATP cohort for immunogenicity) Antibody Group Timing N 5 EL.U/mL GMC (EL.U/mL)

11 n % 95% CI Value 95% CI LL UL LL UL Anti-PT - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Anti-FHA - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Anti-PRN - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Post-booster = post-booster vaccination blood sample (booster phase) Seroprotection rates and GMCs for anti-hbs antibodies (ATP cohort for immunogenicity) Group Timing N 10 miu/ml GMC (miu/ml) n % 95% CI Value 95% CI LL UL LL UL - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Post-booster = post-booster vaccination blood sample (booster phase)

12 Seroprotection rates and GMTs for anti-polio 1, anti-polio 2 and anti-polio 3 (ATP cohort for immunogenicity) Antibody Group Timing N 8 GMT n % 95% CI Value 95% CI LL UL LL UL Anti-polio 1 - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Anti-polio 2 - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Anti-polio 3 - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster Post-booster = post-booster vaccination blood sample (booster phase) Seroprotection rates and GMCs for anti-prp antibodies (ATP cohort for immunogenicity) Group Timing N 0.15 μg/ml 1 μg/ml GMC (μg/ml) n % 95% CI n % 95% CI Value 95% CI LL UL LL UL LL UL - PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster PIII(M3) Pre-booster Post-booster

13 Post-booster = post-booster vaccination blood sample (booster phase) Booster vaccine response for anti-pt, anti-fha and anti-prn antibody concentrations, one month after booster dose (ATP cohort for immunogenicity) Antibody Group Pre-vaccination status Number of Responders subjects* n % 95% CI LL UL Anti-PT - S S Total S S Total S S Total Anti-FHA - S S Total S S Total S S Total Anti-PRN - S S Total S S Total S S Total * number of subjects with both pre and post vaccination results available n (%) = number (percentage) of responders S-/S+ = seronegative/seropositive subjects at pre-booster vaccination Total = subjects either seropositive or seronegative at pre-booster vaccination Booster vaccine response defined as : For initially seronegative subjects, antibody concentration at Post-booster 5 EL.U/mL For initially seropositive subjects, antibody concentration at Post-booster 2 fold the pre-booster vaccination antibody concentration 95% CI = exact 95% confidence interval; LL = lower limit, UL = upper limit Incidence of solicited local symptoms reported during the 4-day (Day 0-3) post-vaccination period (Total vaccinated cohort) Symptom Intensity - Group Group Group N n % 95% CI N n % 95% CI N n % 95% CI LL UL LL UL LL UL Pain Any Grade Redness Any > 30 mm Swelling Any

14 > 30 mm N = number of subjects with the documented dose n (%) = number (percentage) of subjects for whom the symptom was reported at least once 95%CI = exact 95% confidence interval; LL = lower limit, UL = upper limit Any = occurrence of any solicited general symptom regardless of their intensity grade. Grade 3 pain = cried when limb was moved/ was spontaneously painful. Incidence of solicited general symptoms reported during the 4-day (Day 0-3) post-vaccination period (Total vaccinated cohort) Symptom Intensity/ relationship - Group Group Group N n % 95% CI N n % 95% CI N n % 95% CI LL UL LL UL LL UL Drowsiness Any Grade Related Fever 38.0 C (rectal > 39.0 C temperature) > 40.0 C Related Irritability Any Grade Loss of appetite Related Any Grade Related N = number of subjects with the documented dose n (%) = number (percentage) of subjects for whom the symptom was reported at least once 95%CI = exact 95% confidence interval; LL = lower limit, UL = upper limit Any = occurrence of any solicited general symptom regardless of their intensity grade or relationship to study vaccination. Grade 3 drowsiness = drowsiness that prevented normal activity. Grade 3 irritability = crying that could not be comforted/ prevented normal activity. Grade 3 loss of appetite = did not eat at all. Related = general symptom considered by the investigator to be causally related to the study vaccination. Safety Results: Number (%) of subjects with unsolicited adverse events (Total vaccinated cohort) Most frequent* adverse events - On-Therapy (occurring within Day 0-30 following vaccination) - Group N = 737 Group N = 92 Group N = 283 Subjects with any AE(s), n (%) 188 (25.5) 32 (34.8) 99 (35.0) Rhinitis 28 (3.8) 4 (4.3) 19 (6.7) Upper respiratory tract infection 25 (3.4) 5 (5.4) 13 (4.6) Otitis media 16 (2.2) 4 (4.3) 11 (3.9) Pyrexia 14 (1.9) 3 (3.3) 12 (4.2) Diarrhoea 15 (2.0) 1 (1.1) 10 (3.5) Cough 7 (0.9) 3 (3.3) 14 (4.9) Bronchitis 11 (1.5) 4 (4.3) 7 (2.5) Injection site induration 1 (0.1) 7 (7.6) 7 (2.5) Nasopharyngitis 8 (1.1) 2 (2.2) 4 (1.4) Conjunctivitis 8 (1.1) 1 (1.1) 4 (1.4) Ear infection 6 (0.8) 2 (2.2) 5 (1.8) Gastroenteritis 9 (1.2) 2 (2.2) 2 (0.7) Pharyngitis 10 (1.4) 2 (2.2) 1 (0.4) Exanthema subitum 5 (0.7) 2 (2.2) 2 (0.7) Rash 5 (0.7) 2 (2.2) 0 (0.0) Teething 2 (0.3) 0 (0.0) 5 (1.8) * Detail of unsolicited AEs counting rule: > 30 subjects/treatment group and > = 3 groups, display the most frequent 10 primary preferred terms in each group. Safety Results: Number (%) of subjects with Serious Adverse Events (SAEs) between the end of the primary vaccination

15 study and the booster vaccination (Primary Total vaccinated cohort) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] All SAEs (between the end of the - Group primary vaccination study and the N = 827 booster vaccination) Group & Group pooled N = 415 Subjects with any SAE(s), n (%) [n related] 59 (7.1) [0] 23 (5.5) [0] Pharyngitis 8 (1.0) [0] 5 (1.2) [0] Gastroenteritis 10 (1.2) [0] 2 (0.5) [0] Bronchitis chronic 5 (0.6) [0] 6 (1.4) [0] Diarrhoea 6 (0.7) [0] 2 (0.5) [0] Gastroenteritis rotavirus 4 (0.5) [0] 2 (0.5) [0] Bronchopneumonia 5 (0.6) [0] 0 (0.0) [0] Ear infection 5 (0.6) [0] 0 (0.0) [0] Pneumonia 3 (0.4) [0] 2 (0.5) [0] Urinary tract infection 4 (0.5) [0] 1 (0.2) [0] Bronchitis 3 (0.4) [0] 1 (0.2) [0] Febrile convulsion 2 (0.2) [0] 2 (0.5) [0] Nasopharyngitis 3 (0.4) [0] 1 (0.2) [0] Respiratory tract infection 2 (0.2) [0] 2 (0.5) [0] Head injury 3 (0.4) [0] 0 (0.0) [0] Laryngitis 2 (0.2) [0] 1 (0.2) [0] Otitis media acute 2 (0.2) [0] 1 (0.2) [0] Pyelonephritis 3 (0.4) [0] 0 (0.0) [0] Thermal burn 3 (0.4) [0] 0 (0.0) [0] Upper respiratory tract infection 1 (0.1) [0] 2 (0.5) [0] Dyspepsia 2 (0.2) [0] 0 (0.0) [0] Enteritis 2 (0.2) [0] 0 (0.0) [0] Oral herpes 1 (0.1) [0] 1 (0.2) [0] Otitis media 1 (0.1) [0] 1 (0.2) [0] Rash 2 (0.2) [0] 0 (0.0) [0] Skull fracture 2 (0.2) [0] 0 (0.0) [0] Anaemia 1 (0.1) [0] 0 (0.0) [0] Brain neoplasm 1 (0.1) [0] 0 (0.0) [0] Bronchiolitis 0 (0.0) [0] 1 (0.2) [0] Concussion 1 (0.1) [0] 0 (0.0) [0] Conjunctivitis 1 (0.1) [0] 0 (0.0) [0] Contusion 0 (0.0) [0] 1 (0.2) [0] Dehydration 1 (0.1) [0] 0 (0.0) [0] Dermatitis allergic 1 (0.1) [0] 0 (0.0) [0] Eczema infantile 0 (0.0) [0] 1 (0.2) [0] Enterocolitis haemorrhagic 1 (0.1) [0] 0 (0.0) [0] Foreign body aspiration 1 (0.1) [0] 0 (0.0) [0] Gastro oesophageal reflux disease 0 (0.0) [0] 1 (0.2) [0] Infantile spasms 1 (0.1) [0] 0 (0.0) [0] Intertrigo 1 (0.1) [0] 0 (0.0) [0] Intussusception 1 (0.1) [0] 0 (0.0) [0] Psychomotor retardation 1 (0.1) [0] 0 (0.0) [0] Pyrexia 1 (0.1) [0] 0 (0.0) [0] Skin exfoliation 1 (0.1) [0] 0 (0.0) [0] Subcutaneous haematoma 1 (0.1) [0] 0 (0.0) [0] Talipes 1 (0.1) [0] 0 (0.0) [0] Tongue neoplasm 1 (0.1) [0] 0 (0.0) [0] Tonic convulsion 1 (0.1) [0] 0 (0.0) [0] Tonsillitis 1 (0.1) [0] 0 (0.0) [0] Urticaria 1 (0.1) [0] 0 (0.0) [0]

16 Vomiting 1 (0.1) [0] 0 (0.0) [0] Wound 1 (0.1) [0] 0 (0.0) [0] Wound complication 1 (0.1) [0] 0 (0.0) [0] Fatal SAEs - Group N = 1214 Subjects with fatal SAEs, n (%) [related] 0 (0.0) [0] 0 (0.0) [0] Safety Results: Number (%) of subjects with SAEs within 31 days after booster dose (Total vaccinated cohort) Serious adverse event, n (%) [n considered by the investigator to be related to study medication] Group & Group pooled N = 409 All SAEs (occurring within Day 0-30 following vaccination) - Group N = 737 Group N = 92 Group N = 283 Subjects with any SAE(s), n (%) [n related] 12(1.6) [0] 1 (1.1) [0] 4 (1.4) [1] Asthma 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Gastroenteritis 3 (0.4) [0] 0 (0.0) [0] 1 (0.4) [0] Bronchitis 1 (0.1) [0] 1 (1.1) [0] 1 (0.4) [0] Bronchitis chronic 0 (0.0) [0] 0 (0.0) [0] 2 (0.7) [0] Pharyngitis 2 (0.3) [0] 0 (0.0) [0] 0 (0.0) [0] Dehydration 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Dermatitis atopic 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Drug toxicity 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Ear infection 0 (0.0) [0] 1 (1.1) [0] 0 (0.0) [0] Febrile convulsion 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Gastritis 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Gastroenteritis rotavirus 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Laryngitis 0 (0.0) [0] 1 (1.1) [0] 0 (0.0) [0] Microcytic anaemia 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Nasopharyngitis 0 (0.0) [0] 0 (0.0) [0] 1 (0.4) [0] Oedema peripheral 0 (0.0) [0] 0 (0.0) [0] 1 (0.4) [1] Pneumonia 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Respiratory tract infection 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Upper respiratory tract infection 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Fatal SAEs - Group N = 737 Group N = 92 Group N = 283 Subjects with fatal SAE(s), n (%) [n related] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] Safety Results: Number (%) of subjects with (SAEs) within the 31 days after the booster dose (reported in the previous table) and during the extended safety follow-up period (Total vaccinated cohort) All SAEs (from the booster dose up to the end of the extended safety follow-up period) - Group N = 726 Group N = 91 Group N = 282 Subjects with any SAE(s), n (%) [n related] 33 (4.5) [0] 6 (6.6) [0] 8 (2.8) [1] Bronchitis chronic 6 (0.8) [0] 0 (0.0) [0] 4 (1.4) [0] Gastroenteritis 9 (1.2) [0] 0 (0.0) [0] 1 (0.4) [0] Bronchitis 2 (0.3) [0] 1 (1.1) [0] 2 (0.7) [0] Gastroenteritis rotavirus 1 (0.1) [0] 1 (1.1) [0] 1 (0.4) [0] Laryngitis 1 (0.1) [0] 2 (2.2) [0] 0 (0.0) [0] Diarrhoea 1 (0.1) [0] 1 (1.1) [0] 0 (0.0) [0] Febrile convulsion 2 (0.3) [0] 0 (0.0) [0] 0 (0.0) [0] Nasopharyngitis 1 (0.1) [0] 0 (0.0) [0] 1 (0.4) [0] Pharyngitis 2 (0.3) [0] 0 (0.0) [0] 0 (0.0) [0] Pneumonia 2 (0.3) [0] 0 (0.0) [0] 0 (0.0) [0] Respiratory tract infection 1 (0.1) [0] 0 (0.0) [0] 1 (0.4) [0] Adenovirus infection 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Asthma 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Bronchiolitis 0 (0.0) [0] 1 (1.1) [0] 0 (0.0) [0] Concussion 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Dehydration 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Dermatitis atopic 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0]

17 Drug toxicity 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Ear infection 0 (0.0) [0] 1 (1.1) [0] 0 (0.0) [0] Gastritis 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Limb injury 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Microcytic anaemia 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Oedema peripheral 0 (0.0) [0] 0 (0.0) [0] 1 (0.4) [1] Otitis media 0 (0.0) [0] 0 (0.0) [0] 1 (0.4) [0] Purpura 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Pyelonephritis 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Stomatitis 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Thermal burn 0 (0.0) [0] 1 (1.1) [0] 0 (0.0) [0] Upper respiratory tract infection 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Weight gain poor 1 (0.1) [0] 0 (0.0) [0] 0 (0.0) [0] Fatal SAEs - Group N = 726 Group N = 91 Group N = 282 Subjects with fatal SAE(s), n (%) [n related] 0 (0.0) [0] 0 (0.0) [0] 0 (0.0) [0] Conclusion: Please refer to the publications section. Date updated: 11 September 2014