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GSK Medicine: Meningococcal serogroups A, C, W-135, Y tetanus toxoid conjugate vaccine (GSK134612)

Study Number: 114858 (MENACWY-TT-087)

Title: Immunogenicity and safety study of GSK Biologicals' meningococcal conjugate vaccine (GSK 134612) when co-administered with routine vaccines in healthy infants and toddlers. NimenrixTM- GSK134612 (MenACWY-TT): GlaxoSmithKline (GSK) Biologicals’ meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate (MenACWY-TT) vaccine (GSK134612) The study vaccine, Nimenrix or MenACWY-TT has been divested to Pfizer as of 01 October 2015. At the time of conduct of the study, Nimenrix was owned by GSK Biologicals. This is reflected in the study title.

Rationale: The purpose of this study was to generate immunogenicity and safety data of MenACWY-TT when co-administered with Synflorix™ and Infanrix™-IPV/Hiberix™ vaccines, according to three-dose priming at 2, 4 and 6 monthsor one dose priming at 6 months of age (primary phase), followed by a booster dose (booster phase) in the second year of life (15-18 months of age). In addition, this study evaluated the immunogenicity and safety of MenACWY-TT when given as a single dose at 15-18 months of age.

Synflorix™(10PN): GSK Biologicals’ pneumococcal 10-valent polysaccharide conjugate vaccine Synflorix Infanrix™-IPV/Hiberix™ (DTPa-IPV/Hib): GSK Biologicals’ combined diphtheria, tetanus, acellular pertussis, inactivated polio and Haemophilus influenzae type b (DTPa-IPV/Hib) vaccine Infanrix-IPV/Hiberix This CTRS presents the demography, safety and immunogenicity results for the MenACWY-TT and Synflorix vaccines until study end and will be updated when additional data become available.

Phase: III

Study Period: 27 January 2012 to 19 October 2015

Study Design: open label, randomized (2: 1: 1), controlled, multi-country study with three parallel groups

Centres: 3 centres in 2 countries: Lebanon and Mexico

Indication: Active immunisation of healthy infants to prevent invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, W-135 and Y in the first year of life followed by a booster in the second year of life Treatment: The study groups were as follows:

• ACWY3+1 Group: 4 doses of MenACWY-TT vaccine. Primary and booster vaccination (3 doses at 2, 4 and 6 months of age followed by a booster dose at 15-18 months of age)

• ACWY1+1 Group: 2 doses of MenACWY-TT vaccine. Primary and booster vaccination (1 dose at 6 months of age followed by a booster dose at 15-18 months of age).

• ACWY1 Control Group: 1 dose of MenACWY-TT at 15-18 months of age All subjects were to receive Synflorix and Infanrix as study vaccines at 2, 4, 6 and 15-18 months of age, which are part of the routine infant immunisation in the participating countries. All vaccines were administered intramuscularly (IM) in the anterolateral region of the thigh.

Objectives:

• To demonstrate the immunogenicity of the MenACWY-TT conjugate vaccine in terms of bactericidal antibodies to N. meningitidis serogroups A, C, W-135 and Y one-month post-dose 3 of MenACWY-TT at 7 months of age in healthy infants.

Criteria for immunogenicity: For each serogroup, one month after dose 3 of MenACWY-TT vaccination, the lower limit of the two-sided exact 95% confidence interval (CI) for the percentage of subjects with rSBA titre ≥ 1:8 is greater than or equal to the pre-defined clinical limit of 80%.

Primary Outcome Variable(s): Immunogenicity:

• Immunogenicity with respect to components of the investigational vaccine.

− percentage of subjects with rSBA-MenA, rSBA-MenC, rSBA-MenW-135 and rSBA-MenY titre ≥ 1:8 one-month post-dose 3 (Visit 4 at Month 5) in all subjects of group ACWY3+1.

Secondary Outcome Variable(s): Immunogenicity:

• Immunogenicity with respect to component of the investigational vaccine (on secondary read-outs)

− percentage of subjects with rSBA-MenA, rSBA-MenC, rSBA-MenW-135, and rSBA-Men-Y titres ≥1:8 prior to (Visit 5 at Month 13) and one month after the booster dose (Visit 6) in group ACWY3+1.

− percentage of subjects with rSBA-MenA, rSBA-MenC, rSBA-MenW-135, and rSBA-Men-Y titres ≥ 1:128 and the GMTs for each serogroup one month post-dose 3 (Visit 4 (at Month 5)), prior to (Visit 5 (at Month 13)) and one month after the booster dose (Visit 6) in all subjects of group ACWY3+1.

− percentage of subjects with rSBA-MenA, rSBA-MenC, rSBA-MenW-135 and rSBA-MenY ≥ 1:8, ≥ 1:128 and the GMTs for each serogroup at Visit 4 (at Month 5) (one month post-primary for group ACWY1+1), Visit 5 (at Month 13) (pre-booster for group ACWY1+1 and pre-vaccination for group ACWY1) and Visit 6 (post-booster for group ACWY1+1 and post-vaccination for group ACWY1) in all subjects of groups ACWY1+1 and ACWY1.

− percentage of subjects with rSBA-MenA, rSBA-MenC, rSBA-MenW-135 and rSBA-MenY vaccine response at Visit 6 (one month post-booster for group ACWY3+1 and ACWY1+1 and post-vaccination for group ACWY1).

− percentage of subjects with hSBA-MenA, hSBA-MenC, hSBA-MenW-135, and hSBA-Men-Y titres ≥ 1:4, ≥ 1:8 and the GMTs for each serogroup at Visit 4 (at Month 5) (one month post-primary for groups ACWY3+1 and ACWY1+1) in a randomized subset of 50% of subjects of all three groups.

− percentage of subjects with hSBA-MenA, hSBA-MenC, hSBA-MenW-135 and hSBA-MenY ≥ 1:4, ≥ 1:8 and GMTs for each serogroup at Visit 5 (at Month 13) (pre-booster for groups ACWY3+1 and ACWY1+1 and pre-vaccination for group ACWY1) and Visit 6 (one month post-booster for groups ACWY3+1 and ACWY1+1, and one month post-vaccination for group ACWY1), in a randomized subset of 75% of subjects of all three groups.

− percentage of subjects with hSBA-MenA, hSBA-MenC, hSBA-MenW-135 and hSBA-MenY vaccine response at Visit 6 (one month post-booster for group ACWY3+1 and ACWY1+1 and post-vaccination for group ACWY1) in a randomized subset of 75% of subjects of all three groups.

• Immunogenicity with respect to components of the co- administered study vaccines

− percentage of subjects with anti-pneumococcal antibody concentrations against serotypes 1, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F ≥ the proposed cut-offs/non-inferiority thresholds and Geometric Mean Concentrations (GMCs) for each serotype one month post-dose 3, prior to and one month post-booster in a randomized subset of 25% of the subjects.

− percentage of subjects with antibody concentrations/titres for anti-diphtheria ≥ 0.1IU/ml and GMC, anti-Pertussis toxoid (PT), anti-Pertactin (PRN), and anti-FHA IgG ≥ 5 EL.U/ml and GMCs, anti-polio type 1, 2 and 3 ≥ 1:8 and GMTs, and anti-PRP ≥ 0.15µg/ml, ≥ 1.0 µg/ml and GMC one month post-dose 3, in a randomized subset of 25% of the subjects.*

− percentage of subjects with antibody concentrations for anti-tetanus ≥ 0.1IU/ml and GMC at one month post-dose 3 (Visit 4 (at Month 5)), pre-booster (Visit 5 (at Month 13)) and one month post-booster (Visit 6), in a randomized subset of 25% of subjects.*

Safety: Solicited local and general symptoms

− Occurrence of each solicited local and general symptoms within 8 days (Day 0-Day 7) after each vaccine dose.

Unsolicited adverse events (AEs)

− Occurrence of unsolicited AEs within 31 days (Day 0 – Day 30) after each vaccine dose.

Serious adverse event (SAEs)

− Occurrence of SAEs throughout the study period.

Occurrence of new onset of chronic illnesses (NOCIs)

− Occurrence of NOCIs (e.g. asthma, autoimmune disorders, type 1 diabetes, allergies) throughout the study period.

*At the time of writing this CTRS, Immunogenicity data concerning diphtheria, tetanus, pertussis, polio and Heamophilus influenzae components were not available. The CTRS will be updated when these data become available.

Statistical Methods:

Cohorts for analysis:

• The Primary Total Vaccinated cohort included all vaccinated subjects during the primary phase.

• The Booster Total Vaccinated cohort included all vaccinated subjects at booster time point (Visit 5 (at Month 13))

• The According-to-Protocol (ATP) cohort for immunogenicity for each timepoint (adapted ATP) included all eligible subjects (who had not received forbidden medications, had no intercurrent medical condition which may influence immune response, had not met any elimination criteria during the study until the respective post-vaccination blood sampling), who complied with the vaccination schedule and for whom data concerning immunogenicity endpoint measures are available. These included subjects for whom assay results are available for antibodies against at least one study vaccine antigen component after at least one vaccination during the primary vaccination course.

Analysis of immunogenicity: The analysis of immunogenicity was performed on the Adapted ATP cohort for immunogenicity. The following analysis were performed:

• Number and percentage of subjects with rSBA-MenA, rSBA-MenC, rSBA-MenW-135 and rSBA-MenY titres equal to or above the cut-off values of 1:8 and 1:128 and GMTs with exact 95% Confidence Interval (CI) post primary and post booster

• number and percentage of subjects with hSBA-MenA, hSBA-MenC, hSBA-MenW-135 and hSBA-MenY titres equal to or above the cut-off values of 1:4 and 1:8 and GMTs with 95% CI post primary and post booster.

• Booster responders (groups ACWY3+1 and ACWY1+1)/ vaccine response (group ACWY1) to each Meningococcal serotype in terms of rSBA and hSBA with exact 95% CI.

• number and percentage of subjects with anti-1, anti-4, anti-5, anti-6A, anti-6B, anti-7F, anti-9V, anti-14, anti-18C, anti-19A, anti-19F and anti-23F antibody concentrations equal to or above 0.15 micrograms per ml and 0.35 micrograms per ml and GMCs were calculated with 95% CI, post primary and booster doses.

Analysis of Safety: The percentages of subjects reporting each individual solicited local (any grade, grade 3, medical advice) and general (any grade, grade 3, related, grade 3 and related, medical advice) AE during the 8-day follow-up period (Day 0 – Day 7) were tabulated with exact 95% CI after each vaccine dose and overall. The percentage of subjects reporting unsolicited symptoms classified by Medical Dictionary for Regulatory Activities (MedDRA) preferred terms within 31-day (Days 0-30) after each dose of the study vaccines was also tabulated. The percentage of subjects reporting NOCIs from first dose up to the end of the ESFU was tabulated according the MedDRA preferred terms classifications. Solicited and unsolicited symptoms experienced by at least 5 % of subjects, classified by MedDRA Primary System Organ Class and Preferred Term within the 31-day post-vaccination period after each dose and from dose one up to ESFU, including number of events reported and excluding SAEs, were tabulated. The number and percentage of subjects with at least 1 SAE occurring during entire study period as well as the number of SAEs was tabulated according to MedDRA System Organ Class and Preferred Term, for the three study groups. The table includes SAEs with causal relationship to vaccination and fatal SAEs.

Study Population: Healthy subjects (males or females) aged 6 – 12 weeks who were born after a gestation period of at least 36 weeks, who had not previously received a meningococcal, diphtheria, tetanus, pertussis, polio (with the exception of a birth dose of OPV), Haemophilus influenzae type b or Streptococcus pneumoniae vaccine, were enrolled in the study. Written informed consent was obtained from the parent(s)/LAR(s) of the subject.

Primary phase Number of Subjects: ACWY3+1

Group ACWY1+1

Group ACWY1 Group

Planned, N 376 187 187 Randomised, N (Primary Total Vaccinated cohort) 376 187 187 Completed Primary, n (%) 360 (95.7) 178 (95.2) 181 (96.8) Total Number Subjects Withdrawn, n (%) 16 (4.3) 9 (4.8) 6 (3.2) Withdrawn due to Adverse Events, n (%) 0 (0.0) 0 (0.0) 1 (0.5)

Withdrawn due to Lack of Efficacy, n (%) Not Applicable Not Applicable Not Applicable

Withdrawn for other reasons, n (%) 16 (4.3) 9 (4.8) 5 (2.7) Demographics ACWY3+1

Group ACWY1+1

Group ACWY1 Group

N (Primary Total Vaccinated cohort) 376 187 187 Females, n (%) 182 (48.4) 105 (56.1) 95 (50.8)

Males, n (%) 194 (51.6) 82 (43.9) 92 (49.2)

Mean Age, weeks (SD) 8.1 (1.6) 8.1 (1.7) 8.2 (1.7) Median Age, weeks (Minimum, Maximum) 8 (6, 12) 8 (6, 13) 8 (6, 12) White - Arabic / North African Heritage, n (%) 199 (52.9) 100 (53.5) 99 (52.9) Mixed Origin, n (%) 176 (46.8) 87 (46.5) 87 (46.5) White - Caucasian / European Heritage, n (%) 1 (0.3) 0 (0.0) 1 (0.5) Booster phase Number of Subjects: ACWY3+1

Group ACWY1+1

Group ACWY1 Group

Planned, N 376 187 187 Randomised, N (Booster Total Vaccinated cohort) 342 166 170 Completed Booster, n (%) 332 (97.1) 164 (98.8) 163 (95.9) Total Number Subjects Withdrawn, n (%) 10 (2.9) 2 (1.2) 7 (4.1) 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 (%) 10 (2.9) 2 (1.2) 7 (4.1) Demographics ACWY3+1

Group ACWY1+1

Group ACWY1 Group

N (Booster Total Vaccinated cohort) 342 166 170 Females, n (%) 167 (48.8) 95 (57.2) 88 (51.8)

Males, n (%) 175 (51.2) 71 (42.8) 82 (48.2)

Mean Age, months (SD) 15.5 (0.8) 15.5 (0.7) 15.5 (0.8) Median Age, months (Minimum, Maximum) 15 (14, 17) 15 (14, 18) 15 (14, 18) White - Arabic / North African Heritage, n (%) 185 (54.1) 94 (56.6) 93 (54.7) Mixed Origin, n (%) 156 (45.6) 72 (43.4) 76 (44.7) White - Caucasian / European Heritage, n (%) 1 (0.3) 0 1 (0.6) Primary Outcome Results: Number and percentage of subjects with rSBA-MenA, rSBA-MenC, rSBA-MenW-135 and rSBA-MenY titres equal to or above the cut-off values of 1:8 and 1:128 and GMTs (Adapted ATP cohort for immunogenicity).

≥ 1:8 ≥ 1:128 GMT 95% CI 95% CI 95% CI

Antibody Group Timing N n % LL UL n % LL UL value LL UL rSBA-MenA ACWY3+1* PIII(M5) 328 328 100 98.9 100 321 97.9 95.7 99.1 577.5 520.7 640.6 PIII(M13) 276 225 81.5 76.4 85.9 146 52.9 46.8 58.9 71.1 56.6 89.3 PIV(M14) 283 283 100 98.7 100 282 99.6 98.0 100 2366.4 2134.8 2623.1 ACWY1+1 PIII(M5) 163 161 98.8 95.6 99.9 155 95.1 90.6 97.9 1332.9 1035.2 1716.2 PIII(M13) 131 107 81.7 74.0 87.9 88 67.2 58.4 75.1 125.3 84.4 186.1 PIV(M14) 139 138 99.3 96.1 100 138 99.3 96.1 100 2762.3 2310.3 3302.8 ACWY1 PIII(M5) 163 6 3.7 1.4 7.8 6 3.7 1.4 7.8 4.8 4.1 5.5 PIII(M13) 132 19 14.4 8.9 21.6 16 12.1 7.1 18.9 7.2 5.5 9.3 PIV(M14) 135 133 98.5 94.8 99.8 132 97.8 93.6 99.5 2918.7 2264.6 3761.7 rSBA-MenC ACWY3+1* PIII(M5) 328 327 99.7 98.3 100 318 97.0 94.5 98.5 803.1 710.4 907.8 PIII(M13) 276 190 68.8 63.0 74.3 93 33.7 28.1 39.6 33.9 27.4 41.9 PIV(M14) 283 282 99.6 98.0 100 282 99.6 98.0 100 2761.2 2461.2 3097.9 ACWY1+1 PIII(M5) 163 162 99.4 96.6 100 151 92.6 87.5 96.1 591.6 482.3 725.8 PIII(M13) 131 86 65.6 56.9 73.7 39 29.8 22.1 38.4 27.4 20.6 36.6 PIV(M14) 139 138 99.3 96.1 100 137 98.6 94.9 99.8 2525.2 2102.1 3033.3 ACWY1 PIII(M5) 162 6 3.7 1.4 7.9 5 3.1 1.0 7.1 4.7 4.1 5.4 PIII(M13) 132 3 2.3 0.5 6.5 1 0.8 0.0 4.1 4.2 3.9 4.4 PIV(M14) 135 130 96.3 91.6 98.8 128 94.8 89.6 97.9 768.1 593.0 995.0 rSBA-MenW-135 ACWY3+1* PIII(M5) 327 325 99.4 97.8 99.9 313 95.7 92.9 97.6 1190.3 1019.3 1390.1 PIII(M13) 275 225 81.8 76.7 86.2 122 44.4 38.4 50.5 52.0 42.2 64.2 PIV(M14) 284 284 100 98.7 100 284 100 98.7 100 3696.9 3242.8 4214.7

ACWY1+1 PIII(M5) 163 153 93.9 89.0 97.0 151 92.6 87.5 96.1 1255.9 917.0 1720.0 PIII(M13) 131 102 77.9 69.8 84.6 65 49.6 40.8 58.5 63.3 45.6 87.9 PIV(M14) 139 139 100 97.4 100 138 99.3 96.1 100 3144.7 2636.9 3750.4 ACWY1 PIII(M5) 163 4 2.5 0.7 6.2 4 2.5 0.7 6.2 4.6 4.0 5.2 PIII(M13) 132 7 5.3 2.2 10.6 7 5.3 2.2 10.6 5.0 4.2 5.8 PIV(M14) 135 131 97.0 92.6 99.2 131 97.0 92.6 99.2 5240.7 3855.5 7123.7 rSBA-MenY ACWY3+1* PIII(M5) 328 327 99.7 98.3 100 312 95.1 92.2 97.2 647.4 566.6 739.6 PIII(M13) 275 240 87.3 82.7 91.0 121 44.0 38.0 50.1 66.3 54.3 81.0 PIV(M14) 284 284 100 98.7 100 283 99.6 98.1 100 2778.6 2472.5 3122.5 ACWY1+1 PIII(M5) 163 161 98.8 95.6 99.9 159 97.5 93.8 99.3 1469.9 1186.5 1821.0 PIII(M13) 131 116 88.5 81.8 93.4 70 53.4 44.5 62.2 106.4 76.4 148.1 PIV(M14) 139 139 100 97.4 100 137 98.6 94.9 99.8 2748.6 2301.4 3282.6 ACWY1 PIII(M5) 162 16 9.9 5.8 15.5 16 9.9 5.8 15.5 6.3 5.0 7.8 PIII(M13) 132 24 18.2 12.0 25.8 23 17.4 11.4 25.0 9.4 6.8 12.9 PIV(M14) 135 131 97.0 92.6 99.2 131 97.0 92.6 99.2 4202.5 3219.9 5485.1 GMT = geometric mean antibody titre calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with titre equal to or above specified value 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PIII(M5) = Month 5, one month after the last dose of primary vaccination for ACWY3+1 and ACWY1+1 groups with MenACWY PIII(M13) = Month 13, prior to booster vaccination for ACWY3+1 and ACWY1+1 and prior to vaccination for ACWY1 group with MenACWY PIV(M14) = Month 14, one month after the booster vaccination for ACWY3+1 and ACWY1+1 and after vaccination for ACWY1 group with MenACWY *Primarty outcome result: The immunogenicity criteria: For Men A, C, W-135 and Y, one month after 3 doses of MenACWY-TT vaccination, the lower limit of the two-sided exact 95% confidence interval (CI) for the percentage of subjects with rSBA titre ≥ 1:8 is greater than or equal to the pre-defined clinical limit of 80%

Secondary Outcome Results: Booster response for rSBA-MenA, rSBA-MenC, rSBA-MenW-135 and rSBA-MenY antibody titres, one month after the booster vaccination (Booster ATP cohort for immunogenicity)

Booster response 95% CI

Antibody

Group Pre-vaccination status

N n % LL UL

rSBA-MenA ACWY3+1 S- 51 51 100 93.0 100 S+ 224 197 87.9 82.9 91.9 Total 275 248 90.2 86.0 93.4 ACWY1+1 S- 24 24 100 85.8 100 S+ 107 84 78.5 69.5 85.9 Total 131 108 82.4 74.8 88.5 ACWY1* S- 113 111 98.2 93.8 99.8 S+ 19 14 73.7 48.8 90.9 Total 132 125 94.7 89.4 97.8 rSBA-MenC ACWY3+1 S- 85 84 98.8 93.6 100 S+ 190 186 97.9 94.7 99.4 Total 275 270 98.2 95.8 99.4 ACWY1+1 S- 45 44 97.8 88.2 99.9 S+ 86 85 98.8 93.7 100 Total 131 129 98.5 94.6 99.8 ACWY1* S- 129 123 95.3 90.2 98.3 S+ 3 3 100 29.2 100 Total 132 126 95.5 90.4 98.3 rSBA-MenW-135 ACWY3+1 S- 50 50 100 92.9 100 S+ 225 222 98.7 96.2 99.7 Total 275 272 98.9 96.8 99.8 ACWY1+1 S- 29 29 100 88.1 100 S+ 102 93 91.2 83.9 95.9

Total 131 122 93.1 87.4 96.8 ACWY1* S- 125 121 96.8 92.0 99.1 S+ 7 7 100 59.0 100 Total 132 128 97.0 92.4 99.2 rSBA-MenY ACWY3+1 S- 35 35 100 90.0 100 S+ 240 232 96.7 93.5 98.6 Total 275 267 97.1 94.3 98.7 ACWY1+1 S- 15 15 100 78.2 100 S+ 116 106 91.4 84.7 95.8 Total 131 121 92.4 86.4 96.3 ACWY1* S- 108 104 96.3 90.8 99.0 S+ 24 21 87.5 67.6 97.3 Total 132 125 94.7 89.4 97.8 S- = seronegative subjects (antibody titre < 1:8 for rSBA-MenA, rSBA-MenC, rSBA-MenW-135, rSBA-MenY) prior to booster vaccination for ACWY3+1 and ACWY1+1 and prior to vaccination for ACWY1 S+ = seropositive subjects (antibody titre ≥ 1:8 for rSBA-MenA, rSBA-MenC, rSBA-MenW-135, rSBA-MenY) prior to booster vaccination for ACWY3+1 and ACWY1+1 and prior to vaccination for ACWY1 Total = subjects either seropositive or seronegative at pre-booster vaccination for ACWY3+1 and ACWY1+1 and pre- vaccination for ACWY1 Booster response defined as: For seronegative subjects, antibody titre ≥ 1:32 at post-booster vaccination For seropositive subjects, antibody titre at post-booster vaccination ≥ 4-fold the pre-booster vaccination antibody titre For initially seropositive subjects: antibody titre at PIV(M14) ≥ 4 fold the pre-vaccination antibody titre N = number of subjects with both pre- and post-booster vaccination results available n/% = number/percentage of subjects with a booster response 95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit * vaccine response one month after the vaccination with MenACWY-TT

Secondary Outcome Results: Number and percentage of subjects with hSBA-MenA, hSBA-MenC, hSBA-MenW-135 and hSBA-MenY titres equal to or above the cut-off values of 1:4 and 1:8 and GMTs (Adapted ATP cohort for immunogenicity)

≥ 1:4 ≥ 1:8 GMT 95% CI 95% CI 95% CI

Antibody Group Timing N n % LL UL n % LL UL value LL UL hSBA-MenA ACWY3+1 PIII(M5) 136 136 100 97.3 100 136 100 97.3 100 808.0 683.8 954.6 PIII(M13) 152 131 86.2 79.7 91.2 130 85.5 78.9 90.7 64.6 48.8 85.5 PIV(M14) 173 173 100 97.9 100 173 100 97.9 100 2318.6 1991.7 2699.1 ACWY1+1 PIII(M5) 59 58 98.3 90.9 100 58 98.3 90.9 100 270.5 205.9 355.4 PIII(M13) 71 48 67.6 55.5 78.2 47 66.2 54.0 77.0 20.8 13.5 32.2 PIV(M14) 83 83 100 95.7 100 83 100 95.7 100 1415.6 1140.2 1757.5 ACWY1 PIII(M5) 51 9 17.6 8.4 30.9 8 15.7 7.0 28.6 2.6 2.2 3.1 PIII(M13) 70 18 25.7 16.0 37.6 15 21.4 12.5 32.9 3.2 2.6 3.8 PIV(M14) 73 70 95.9 88.5 99.1 69 94.5 86.6 98.5 196.3 140.5 274.2 hSBA-MenC ACWY3+1 PIII(M5) 147 147 100 97.5 100 147 100 97.5 100 3970.8 3144.0 5015.1 PIII(M13) 173 168 97.1 93.4 99.1 168 97.1 93.4 99.1 209.0 165.7 263.7 PIV(M14) 198 198 100 98.2 100 198 100 98.2 100 15919.1 13965.3 18146.2 ACWY1+1 PIII(M5) 66 66 100 94.6 100 66 100 94.6 100 523.1 381.5 717.3 PIII(M13) 78 76 97.4 91.0 99.7 75 96.2 89.2 99.2 150.8 108.5 209.5 PIV(M14) 92 92 100 96.1 100 92 100 96.1 100 13360.1 10952.9 16296.4 ACWY1 PIII(M5) 59 3 5.1 1.1 14.1 3 5.1 1.1 14.1 2.3 1.9 2.9 PIII(M13) 74 4 5.4 1.5 13.3 4 5.4 1.5 13.3 2.3 2.0 2.7 PIV(M14) 84 84 100 95.7 100 84 100 95.7 100 363.3 269.4 490.1 hSBA-MenW-135 ACWY3+1 PIII(M5) 107 107 100 96.6 100 107 100 96.6 100 1514.5 1277.2 1795.8 PIII(M13) 123 123 100 97.0 100 123 100 97.0 100 307.9 262.9 360.6 PIV(M14) 129 129 100 97.2 100 129 100 97.2 100 8761.8 7431.3 10330.5 ACWY1+1 PIII(M5) 47 41 87.2 74.3 95.2 41 87.2 74.3 95.2 136.5 78.4 237.6 PIII(M13) 53 53 100 93.3 100 53 100 93.3 100 428.6 328.4 559.2 PIV(M14) 59 59 100 93.9 100 59 100 93.9 100 9015.6 7045.2 11537.1

ACWY1 PIII(M5) 42 0 0.0 0.0 8.4 0 0.0 0.0 8.4 2.0 2.0 2.0 PIII(M13) 52 1 1.9 0.0 10.3 1 1.9 0.0 10.3 2.1 1.9 2.3 PIV(M14) 53 49 92.5 81.8 97.9 49 92.5 81.8 97.9 221.7 140.6 349.5 hSBA-MenY ACWY3+1 PIII(M5) 127 127 100 97.1 100 127 100 97.1 100 1276.2 1077.3 1511.8 PIII(M13) 138 137 99.3 96.0 100 137 99.3 96.0 100 363.2 309.9 425.7 PIV(M14) 149 149 100 97.6 100 149 100 97.6 100 5989.3 5281.0 6792.6 ACWY1+1 PIII(M5) 52 48 92.3 81.5 97.9 48 92.3 81.5 97.9 194.8 117.6 322.9 PIII(M13) 61 60 98.4 91.2 100 60 98.4 91.2 100 389.2 292.3 518.1 PIV(M14) 69 69 100 94.8 100 69 100 94.8 100 5977.6 4746.8 7527.6 ACWY1 PIII(M5) 42 1 2.4 0.1 12.6 1 2.4 0.1 12.6 2.1 1.9 2.4 PIII(M13) 49 4 8.2 2.3 19.6 4 8.2 2.3 19.6 2.6 2.0 3.5 PIV(M14) 58 52 89.7 78.8 96.1 52 89.7 78.8 96.1 281.5 171.9 460.9 GMT = geometric mean antibody titre calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with titre equal to or above specified value 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PIII(M13) = Month 13, prior to booster vaccination for ACWY3+1 and ACWY1+1 and prior to vaccination for ACWY1 group with MenACWY PIV(M14) = Month 14, one month after the booster vaccination for ACWY3+1 and ACWY1+1 and after vaccination for ACWY1 group with MenACWY

Secondary Outcome Results: Booster response for hSBA-MenA, hSBA-MenC, hSBA-MenW-135 and hSBA-MenY antibody titres, one month after the booster vaccination (Booster ATP cohort for immunogenicity)

Booster response 95% CI

Antibody

Group Pre-vaccination status

N n % LL UL

hSBA-MenA ACWY3+1 S- 21 21 100 83.9 100 S+ 116 109 94.0 88.0 97.5 Total 137 130 94.9 89.8 97.9 ACWY1+1 S- 23 23 100 85.2 100 S+ 41 38 92.7 80.1 98.5 Total 64 61 95.3 86.9 99.0 ACWY1* S- 40 37 92.5 79.6 98.4 S+ 18 14 77.8 52.4 93.6 Total 58 51 87.9 76.7 95.0 hSBA-MenC ACWY3+1 S- 5 5 100 47.8 100 S+ 158 158 100 97.7 100 Total 163 163 100 97.8 100 ACWY1+1 S- 2 2 100 15.8 100 S+ 73 71 97.3 90.5 99.7 Total 75 73 97.3 90.7 99.7 ACWY1* S- 61 61 100 94.1 100 S+ 4 4 100 39.8 100 Total 65 65 100 94.5 100 hSBA-MenW-135 ACWY3+1 S- 0 - - - - S+ 107 106 99.1 94.9 100 Total 107 106 99.1 94.9 100 ACWY1+1 S- 0 - - - - S+ 42 40 95.2 83.8 99.4 Total 42 40 95.2 83.8 99.4 ACWY1* S- 37 36 97.3 85.8 99.9 S+ 1 1 100 2.5 100 Total 38 37 97.4 86.2 99.9 hSBA-MenY ACWY3+1 S- 1 1 100 2.5 100 S+ 121 114 94.2 88.4 97.6 Total 122 115 94.3 88.5 97.7

ACWY1+1 S- 0 - - - - S+ 49 45 91.8 80.4 97.7 Total 49 45 91.8 80.4 97.7 ACWY1* S- 31 27 87.1 70.2 96.4 S+ 3 3 100 29.2 100 Total 34 30 88.2 72.5 96.7 S- = seronegative subjects (antibody titre < 1:4 for hSBA-MenA, hSBA-MenC, hSBA-MenW-135, hSBA-MenY) prior to booster vaccination for ACWY3+1 and ACWY1+1 and prior to vaccination for ACWY1 S+ = seropositive subjects (antibody titre ≥ 1:4 for hSBA-MenA, hSBA-MenC, hSBA-MenW-135, hSBA-MenY) prior to booster vaccination for ACWY3+1 and ACWY1+1 and prior to vaccination for ACWY1 Total = subjects either seropositive or seronegative at pre-booster vaccination for ACWY3+1 and ACWY1+1 and pre- vaccination for ACWY1 Booster response defined as: For seronegative subjects, antibody titre ≥ 1:8 at post-booster vaccination For seropositive subjects, antibody titre at post-booster vaccination ≥ 4-fold the pre-booster vaccination antibody titre For initially seropositive subjects: antibody titre at PIV(M14) ≥ 4 fold the pre-vaccination antibody titre N = number of subjects with both pre- and post-booster vaccination results available n/% = number/percentage of subjects with a booster response 95% CI = exact 95% confidence interval, LL = Lower Limit, UL = Upper Limit * vaccine response one month after the vaccination with MenACWY-TT

Secondary Outcome Results: Number and percentage of subjects with anti-1, anti-4, anti-5, anti-6A, anti-6B, anti-7F, anti-9V, anti-14, anti-18C, anti-19A, anti-19F and anti-23F antibody concentrations equal to or above 0.15 micrograms per mL and 0.35 micrograms per mL and GMCs (Adapted ATP cohort for immunogenicity)

≥ 0.15 µg/mL ≥ 0.35 µg/mL GMC (µg/mL) 95% CI 95% CI 95% CI

Antibody Group Timing N n % LL UL n % LL UL value LL UL anti-1 ACWY3+1 PIII(M5) 82 82 100 95.6 100 76 92.7 84.8 97.3 1.3 1.1 1.6 PIII(M13) 57 36 63.2 49.3 75.6 12 21.1 11.4 33.9 0.2 0.1 0.2 PIV(M14) 61 61 100 94.1 100 61 100 94.1 100 2.1 1.6 2.6 ACWY1+1 PIII(M5) 42 42 100 91.6 100 41 97.6 87.4 99.9 1.4 1.1 1.8 PIII(M13) 32 19 59.4 40.6 76.3 5 15.6 5.3 32.8 0.2 0.1 0.2 PIV(M14) 30 29 96.7 82.8 99.9 29 96.7 82.8 99.9 1.7 1.2 2.5 ACWY1 PIII(M5) 37 37 100 90.5 100 34 91.9 78.1 98.3 1.5 1.1 2.1 PIII(M13) 27 19 70.4 49.8 86.2 8 29.6 13.8 50.2 0.2 0.2 0.3 PIV(M14) 29 29 100 88.1 100 28 96.6 82.2 99.9 2.2 1.5 3.2 anti-4 ACWY3+1 PIII(M5) 82 82 100 95.6 100 81 98.8 93.4 100 1.7 1.5 2.0 PIII(M13) 57 38 66.7 52.9 78.6 17 29.8 18.4 43.4 0.2 0.2 0.3 PIV(M14) 61 61 100 94.1 100 58 95.1 86.3 99.0 2.4 1.8 3.1 ACWY1+1 PIII(M5) 42 42 100 91.6 100 41 97.6 87.4 99.9 1.8 1.4 2.2 PIII(M13) 33 22 66.7 48.2 82.0 5 15.2 5.1 31.9 0.2 0.1 0.2 PIV(M14) 30 30 100 88.4 100 29 96.7 82.8 99.9 1.8 1.3 2.5 ACWY1 PIII(M5) 37 37 100 90.5 100 37 100 90.5 100 2.0 1.6 2.5 PIII(M13) 27 20 74.1 53.7 88.9 10 37.0 19.4 57.6 0.3 0.2 0.4 PIV(M14) 29 29 100 88.1 100 29 100 88.1 100 3.1 2.3 4.2 anti-5 ACWY3+1 PIII(M5) 82 81 98.8 93.4 100 72 87.8 78.7 94.0 0.6 0.6 0.7 PIII(M13) 57 32 56.1 42.4 69.3 10 17.5 8.7 29.9 0.2 0.1 0.2 PIV(M14) 61 60 98.4 91.2 100 49 80.3 68.2 89.4 0.7 0.6 0.9 ACWY1+1 PIII(M5) 42 42 100 91.6 100 32 76.2 60.5 87.9 0.6 0.5 0.7 PIII(M13) 33 18 54.5 36.4 71.9 5 15.2 5.1 31.9 0.2 0.1 0.2 PIV(M14) 30 29 96.7 82.8 99.9 23 76.7 57.7 90.1 0.5 0.4 0.7 ACWY1 PIII(M5) 37 37 100 90.5 100 28 75.7 58.8 88.2 0.7 0.5 0.9 PIII(M13) 27 17 63.0 42.4 80.6 5 18.5 6.3 38.1 0.2 0.1 0.2 PIV(M14) 29 27 93.1 77.2 99.2 26 89.7 72.6 97.8 0.7 0.5 1.0 anti-6A ACWY3+1 PIII(M5) 69 51 73.9 61.9 83.7 36 52.2 39.8 64.4 0.3 0.3 0.4 PIII(M13) 56 44 78.6 65.6 88.4 26 46.4 33.0 60.3 0.3 0.2 0.4 PIV(M14) 51 51 100 93.0 100 47 92.2 81.1 97.8 1.7 1.3 2.3

ACWY1+1 PIII(M5) 37 31 83.8 68.0 93.8 20 54.1 36.9 70.5 0.4 0.3 0.6 PIII(M13) 32 26 81.3 63.6 92.8 10 31.3 16.1 50.0 0.3 0.2 0.4 PIV(M14) 25 25 100 86.3 100 22 88.0 68.8 97.5 1.4 0.9 2.1 ACWY1 PIII(M5) 28 22 78.6 59.0 91.7 13 46.4 27.5 66.1 0.3 0.2 0.4 PIII(M13) 26 16 61.5 40.6 79.8 11 42.3 23.4 63.1 0.2 0.2 0.4 PIV(M14) 25 24 96.0 79.6 99.9 23 92.0 74.0 99.0 1.6 1.0 2.5 anti-6B ACWY3+1 PIII(M5) 81 81 100 95.5 100 73 90.1 81.5 95.6 1.8 1.4 2.3 PIII(M13) 57 55 96.5 87.9 99.6 37 64.9 51.1 77.1 0.6 0.4 0.7 PIV(M14) 61 61 100 94.1 100 61 100 94.1 100 3.8 3.1 4.8 ACWY1+1 PIII(M5) 42 41 97.6 87.4 99.9 40 95.2 83.8 99.4 1.7 1.3 2.4 PIII(M13) 33 31 93.9 79.8 99.3 23 69.7 51.3 84.4 0.5 0.4 0.7 PIV(M14) 30 30 100 88.4 100 28 93.3 77.9 99.2 2.4 1.7 3.5 ACWY1 PIII(M5) 37 37 100 90.5 100 35 94.6 81.8 99.3 1.8 1.3 2.5 PIII(M13) 27 22 81.5 61.9 93.7 15 55.6 35.3 74.5 0.4 0.3 0.7 PIV(M14) 29 28 96.6 82.2 99.9 28 96.6 82.2 99.9 3.4 2.2 5.2 anti-7F ACWY3+1 PIII(M5) 82 82 100 95.6 100 81 98.8 93.4 100 2.5 2.2 3.0 PIII(M13) 57 55 96.5 87.9 99.6 38 66.7 52.9 78.6 0.4 0.4 0.5 PIV(M14) 61 61 100 94.1 100 61 100 94.1 100 3.5 2.9 4.2 ACWY1+1 PIII(M5) 42 42 100 91.6 100 42 100 91.6 100 2.2 1.8 2.7 PIII(M13) 33 32 97.0 84.2 99.9 17 51.5 33.5 69.2 0.4 0.3 0.5 PIV(M14) 30 29 96.7 82.8 99.9 29 96.7 82.8 99.9 2.2 1.6 3.1 ACWY1 PIII(M5) 37 37 100 90.5 100 37 100 90.5 100 2.8 2.1 3.7 PIII(M13) 27 23 85.2 66.3 95.8 14 51.9 31.9 71.3 0.4 0.3 0.6 PIV(M14) 29 29 100 88.1 100 28 96.6 82.2 99.9 3.4 2.4 4.9 anti-9V ACWY3+1 PIII(M5) 82 82 100 95.6 100 79 96.3 89.7 99.2 1.2 1.0 1.4 PIII(M13) 57 47 82.5 70.1 91.3 19 33.3 21.4 47.1 0.3 0.2 0.4 PIV(M14) 61 61 100 94.1 100 59 96.7 88.7 99.6 1.6 1.3 2.0 ACWY1+1 PIII(M5) 42 42 100 91.6 100 40 95.2 83.8 99.4 1.2 1.0 1.5 PIII(M13) 33 24 72.7 54.5 86.7 10 30.3 15.6 48.7 0.3 0.2 0.4 PIV(M14) 30 29 96.7 82.8 99.9 28 93.3 77.9 99.2 1.0 0.8 1.4 ACWY1 PIII(M5) 37 37 100 90.5 100 36 97.3 85.8 99.9 1.3 1.0 1.7 PIII(M13) 27 17 63.0 42.4 80.6 9 33.3 16.5 54.0 0.2 0.1 0.3 PIV(M14) 29 29 100 88.1 100 28 96.6 82.2 99.9 1.6 1.2 2.2 anti-14 ACWY3+1 PIII(M5) 82 82 100 95.6 100 80 97.6 91.5 99.7 5.2 4.1 6.5 PIII(M13) 57 56 98.2 90.6 100 44 77.2 64.2 87.3 1.0 0.7 1.3 PIV(M14) 61 61 100 94.1 100 61 100 94.1 100 8.4 6.8 10.4 ACWY1+1 PIII(M5) 42 42 100 91.6 100 41 97.6 87.4 99.9 6.0 4.4 8.0 PIII(M13) 33 33 100 89.4 100 28 84.8 68.1 94.9 0.8 0.6 1.0 PIV(M14) 30 30 100 88.4 100 29 96.7 82.8 99.9 6.8 4.8 9.7 ACWY1 PIII(M5) 36 36 100 90.3 100 36 100 90.3 100 7.0 4.9 10.0 PIII(M13) 27 25 92.6 75.7 99.1 21 77.8 57.7 91.4 0.9 0.5 1.4 PIV(M14) 29 29 100 88.1 100 28 96.6 82.2 99.9 9.0 6.0 13.5 anti-18C ACWY3+1 PIII(M5) 82 81 98.8 93.4 100 79 96.3 89.7 99.2 2.3 1.9 2.8 PIII(M13) 57 43 75.4 62.2 85.9 18 31.6 19.9 45.2 0.2 0.2 0.3 PIV(M14) 61 61 100 94.1 100 61 100 94.1 100 3.6 3.0 4.4 ACWY1+1 PIII(M5) 42 42 100 91.6 100 41 97.6 87.4 99.9 2.0 1.5 2.5 PIII(M13) 33 20 60.6 42.1 77.1 9 27.3 13.3 45.5 0.2 0.1 0.3 PIV(M14) 30 29 96.7 82.8 99.9 27 90.0 73.5 97.9 2.3 1.5 3.6 ACWY1 PIII(M5) 37 37 100 90.5 100 36 97.3 85.8 99.9 2.9 2.2 3.8 PIII(M13) 27 19 70.4 49.8 86.2 11 40.7 22.4 61.2 0.3 0.2 0.4 PIV(M14) 29 29 100 88.1 100 29 100 88.1 100 3.4 2.6 4.6 anti-19A ACWY3+1 PIII(M5) 82 49 59.8 48.3 70.4 28 34.1 24.0 45.4 0.2 0.2 0.3 PIII(M13) 57 41 71.9 58.5 83.0 25 43.9 30.7 57.6 0.3 0.2 0.4 PIV(M14) 61 57 93.4 84.1 98.2 52 85.2 73.8 93.0 1.2 0.8 1.7 ACWY1+1 PIII(M5) 42 26 61.9 45.6 76.4 14 33.3 19.6 49.5 0.2 0.2 0.4 PIII(M13) 33 23 69.7 51.3 84.4 15 45.5 28.1 63.6 0.3 0.2 0.4

PIV(M14) 29 27 93.1 77.2 99.2 21 72.4 52.8 87.3 1.1 0.6 1.9 ACWY1 PIII(M5) 37 27 73.0 55.9 86.2 13 35.1 20.2 52.5 0.2 0.2 0.3 PIII(M13) 27 20 74.1 53.7 88.9 5 18.5 6.3 38.1 0.2 0.1 0.3 PIV(M14) 29 27 93.1 77.2 99.2 22 75.9 56.5 89.7 0.8 0.5 1.2 anti-19F ACWY3+1 PIII(M5) 81 81 100 95.5 100 80 98.8 93.3 100 3.7 3.0 4.6 PIII(M13) 57 57 100 93.7 100 52 91.2 80.7 97.1 0.9 0.7 1.2 PIV(M14) 61 61 100 94.1 100 61 100 94.1 100 8.0 6.2 10.2 ACWY1+1 PIII(M5) 42 42 100 91.6 100 42 100 91.6 100 3.8 2.7 5.3 PIII(M13) 33 33 100 89.4 100 30 90.9 75.7 98.1 0.9 0.7 1.3 PIV(M14) 30 30 100 88.4 100 30 100 88.4 100 6.9 4.5 10.6 ACWY1 PIII(M5) 37 36 97.3 85.8 99.9 36 97.3 85.8 99.9 4.7 3.3 6.6 PIII(M13) 27 25 92.6 75.7 99.1 20 74.1 53.7 88.9 0.9 0.5 1.5 PIV(M14) 29 29 100 88.1 100 29 100 88.1 100 9.8 6.8 14.2 anti-23F ACWY3+1 PIII(M5) 71 66 93.0 84.3 97.7 62 87.3 77.3 94.0 1.4 1.0 1.9 PIII(M13) 57 42 73.7 60.3 84.5 28 49.1 35.6 62.7 0.3 0.2 0.4 PIV(M14) 45 45 100 92.1 100 45 100 92.1 100 3.4 2.6 4.5 ACWY1+1 PIII(M5) 42 42 100 91.6 100 42 100 91.6 100 1.8 1.4 2.4 PIII(M13) 33 25 75.8 57.7 88.9 14 42.4 25.5 60.8 0.3 0.2 0.4 PIV(M14) 24 23 95.8 78.9 99.9 23 95.8 78.9 99.9 2.1 1.3 3.4 ACWY1 PIII(M5) 36 35 97.2 85.5 99.9 32 88.9 73.9 96.9 1.5 1.0 2.2 PIII(M13) 26 18 69.2 48.2 85.7 12 46.2 26.6 66.6 0.2 0.2 0.4 PIV(M14) 21 21 100 83.9 100 20 95.2 76.2 99.9 2.9 1.8 4.7 GMC = geometric mean antibody concentration calculated on all subjects N = number of subjects with available results n/% = number/percentage of subjects with concentration equal to or above specified value 95% CI = 95% confidence interval; LL = Lower Limit, UL = Upper Limit PIII(M5) = Month 5, one month after the last dose of primary vaccination PIII(M13) = Month 13, prior to booster vaccination PIV(M14) = Month 14, one month after the booster vaccination

Secondary Outcome Results: Number (%) of subjects reporting each solicited local symptom during the 8-day (Days 0-7) post-vaccination period by study vaccine following each dose and across doses (Primary Total Vaccinated cohort)

ACWY3+1 Group ACWY1+1 Group ACWY1 Group 95 % CI 95 % CI 95 % CI

Symptom Product Intensity

N n % LL UL N n % LL UL N n % LL UL

Dose 1

Pain Total Any 369 220 59.6 54.4 64.7 182 115 63.2 55.7 70.2 184 108 58.7 51.2 65.9 Grade 3 369 38 10.3 7.4 13.9 182 25 13.7 9.1 19.6 184 14 7.6 4.2 12.4 MenACWY-TT Any 368 182 49.5 44.2 54.7 - - - - - - - - - - Grade 3 368 30 8.2 5.6 11.4 - - - - - - - - - - DTPa-IPV/Hib Any 369 198 53.7 48.4 58.8 182 109 59.9 52.4 67.1 184 100 54.3 46.9 61.7 Grade 3 369 32 8.7 6.0 12.0 182 22 12.1 7.7 17.7 184 11 6.0 3.0 10.4 Synflorix Any 369 201 54.5 49.2 59.6 182 110 60.4 52.9 67.6 184 106 57.6 50.1 64.8 Grade 3 369 31 8.4 5.8 11.7 182 20 11.0 6.8 16.5 184 14 7.6 4.2 12.4

Redness Total Any 369 94 25.5 21.1 30.2 182 39 21.4 15.7 28.1 184 43 23.4 17.5 30.2 >30 mm 369 1 0.3 0.0 1.5 182 0 0.0 0.0 2.0 184 0 0.0 0.0 2.0 MenACWY-TT Any 368 54 14.7 11.2 18.7 - - - - - - - - - - >30 mm 368 1 0.3 0.0 1.5 - - - - - - - - - - DTPa-IPV/Hib Any 369 72 19.5 15.6 23.9 182 32 17.6 12.3 23.9 184 33 17.9 12.7 24.3 >30 mm 369 1 0.3 0.0 1.5 182 0 0.0 0.0 2.0 184 0 0.0 0.0 2.0 Synflorix Any 369 69 18.7 14.9 23.1 182 32 17.6 12.3 23.9 184 34 18.5 13.1 24.9 >30 mm 369 1 0.3 0.0 1.5 182 0 0.0 0.0 2.0 184 0 0.0 0.0 2.0

Swelling Total Any 369 84 22.8 18.6 27.4 182 31 17.0 11.9 23.3 184 34 18.5 13.1 24.9 >30 mm 369 0 0.0 0.0 1.0 182 3 1.6 0.3 4.7 184 0 0.0 0.0 2.0 MenACWY-TT Any 368 45 12.2 9.1 16.0 - - - - - - - - - - >30 mm 368 0 0.0 0.0 1.0 - - - - - - - - - -

DTPa-IPV/Hib Any 369 57 15.4 11.9 19.5 182 25 13.7 9.1 19.6 184 30 16.3 11.3 22.5 >30 mm 369 0 0.0 0.0 1.0 182 1 0.5 0.0 3.0 184 0 0.0 0.0 2.0 Synflorix Any 369 61 16.5 12.9 20.7 182 28 15.4 10.5 21.5 184 26 14.1 9.4 20.0 >30 mm 369 0 0.0 0.0 1.0 182 3 1.6 0.3 4.7 184 0 0.0 0.0 2.0

Dose 2

Pain Total Any 363 177 48.8 43.5 54.0 181 92 50.8 43.3 58.3 181 101 55.8 48.2 63.2 Grade 3 363 33 9.1 6.3 12.5 181 11 6.1 3.1 10.6 181 16 8.8 5.1 14.0 MenACWY-TT Any 363 147 40.5 35.4 45.7 - - - - - - - - - - Grade 3 363 21 5.8 3.6 8.7 - - - - - - - - - - DTPa-IPV/Hib Any 362 163 45.0 39.8 50.3 181 86 47.5 40.1 55.1 181 98 54.1 46.6 61.6 Grade 3 362 26 7.2 4.7 10.3 181 11 6.1 3.1 10.6 181 14 7.7 4.3 12.6 Synflorix Any 363 163 44.9 39.7 50.2 181 85 47.0 39.5 54.5 181 91 50.3 42.8 57.8 Grade 3 363 28 7.7 5.2 11.0 181 9 5.0 2.3 9.2 181 15 8.3 4.7 13.3

Redness Total Any 363 93 25.6 21.2 30.4 181 51 28.2 21.8 35.3 181 48 26.5 20.2 33.6 >30 mm 363 2 0.6 0.1 2.0 181 0 0.0 0.0 2.0 181 1 0.6 0.0 3.0 MenACWY-TT Any 363 63 17.4 13.6 21.7 - - - - - - - - - - >30 mm 363 2 0.6 0.1 2.0 - - - - - - - - - - DTPa-IPV/Hib Any 362 76 21.0 16.9 25.6 181 48 26.5 20.2 33.6 181 42 23.2 17.3 30.0 >30 mm 362 2 0.6 0.1 2.0 181 0 0.0 0.0 2.0 181 1 0.6 0.0 3.0 Synflorix Any 363 80 22.0 17.9 26.7 181 45 24.9 18.7 31.8 181 41 22.7 16.8 29.4 >30 mm 363 2 0.6 0.1 2.0 181 0 0.0 0.0 2.0 181 1 0.6 0.0 3.0

Swelling Total Any 363 76 20.9 16.9 25.5 181 47 26.0 19.7 33.0 181 42 23.2 17.3 30.0 >30 mm 363 2 0.6 0.1 2.0 181 2 1.1 0.1 3.9 181 0 0.0 0.0 2.0 MenACWY-TT Any 363 51 14.0 10.6 18.1 - - - - - - - - - - >30 mm 363 1 0.3 0.0 1.5 - - - - - - - - - - DTPa-IPV/Hib Any 362 62 17.1 13.4 21.4 181 39 21.5 15.8 28.3 181 33 18.2 12.9 24.6 >30 mm 362 2 0.6 0.1 2.0 181 2 1.1 0.1 3.9 181 0 0.0 0.0 2.0 Synflorix Any 363 63 17.4 13.6 21.7 181 42 23.2 17.3 30.0 181 32 17.7 12.4 24.0 >30 mm 363 2 0.6 0.1 2.0 181 2 1.1 0.1 3.9 181 0 0.0 0.0 2.0

Dose 3

Pain Total Any 359 148 41.2 36.1 46.5 177 73 41.2 33.9 48.9 180 93 51.7 44.1 59.2 Grade 3 359 16 4.5 2.6 7.1 177 18 10.2 6.1 15.6 180 9 5.0 2.3 9.3 MenACWY-TT Any 358 122 34.1 29.2 39.2 176 58 33.0 26.1 40.4 - - - - - Grade 3 358 12 3.4 1.7 5.8 176 11 6.3 3.2 10.9 - - - - - DTPa-IPV/Hib Any 359 137 38.2 33.1 43.4 176 64 36.4 29.3 43.9 180 91 50.6 43.0 58.1 Grade 3 359 15 4.2 2.4 6.8 176 14 8.0 4.4 13.0 180 8 4.4 1.9 8.6 Synflorix Any 359 138 38.4 33.4 43.7 177 64 36.2 29.1 43.7 180 87 48.3 40.8 55.9 Grade 3 359 16 4.5 2.6 7.1 177 16 9.0 5.3 14.3 180 9 5.0 2.3 9.3

Redness Total Any 359 74 20.6 16.5 25.2 177 46 26.0 19.7 33.1 180 42 23.3 17.4 30.2 >30 mm 359 1 0.3 0.0 1.5 177 1 0.6 0.0 3.1 180 1 0.6 0.0 3.1 MenACWY-TT Any 358 54 15.1 11.5 19.2 176 35 19.9 14.3 26.6 - - - - - >30 mm 358 1 0.3 0.0 1.5 176 0 0.0 0.0 2.1 - - - - - DTPa-IPV/Hib Any 359 65 18.1 14.3 22.5 176 40 22.7 16.8 29.6 180 39 21.7 15.9 28.4 >30 mm 359 1 0.3 0.0 1.5 176 1 0.6 0.0 3.1 180 1 0.6 0.0 3.1 Synflorix Any 359 61 17.0 13.3 21.3 177 38 21.5 15.7 28.3 180 38 21.1 15.4 27.8 >30 mm 359 1 0.3 0.0 1.5 177 1 0.6 0.0 3.1 180 1 0.6 0.0 3.1

Swelling Total Any 359 66 18.4 14.5 22.8 177 46 26.0 19.7 33.1 180 37 20.6 14.9 27.2 >30 mm 359 1 0.3 0.0 1.5 177 0 0.0 0.0 2.1 180 0 0.0 0.0 2.0 MenACWY-TT Any 358 43 12.0 8.8 15.8 176 29 16.5 11.3 22.8 - - - - - >30 mm 358 0 0.0 0.0 1.0 176 0 0.0 0.0 2.1 - - - - - DTPa-IPV/Hib Any 359 53 14.8 11.3 18.9 176 40 22.7 16.8 29.6 180 32 17.8 12.5 24.2 >30 mm 359 1 0.3 0.0 1.5 176 0 0.0 0.0 2.1 180 0 0.0 0.0 2.0 Synflorix Any 359 55 15.3 11.8 19.5 177 36 20.3 14.7 27.0 180 29 16.1 11.1 22.3 >30 mm 359 0 0.0 0.0 1.0 177 0 0.0 0.0 2.1 180 0 0.0 0.0 2.0

Across Doses Pain Total Any 369 262 71.0 66.1 75.6 182 135 74.2 67.2 80.4 184 142 77.2 70.4 83.0

Grade 3 369 65 17.6 13.9 21.9 182 36 19.8 14.3 26.3 184 33 17.9 12.7 24.3 MenACWY-TT Any 369 234 63.4 58.3 68.3 176 58 33.0 26.1 40.4 - - - - - Grade 3 369 49 13.3 10.0 17.2 176 11 6.3 3.2 10.9 - - - - - DTPa-IPV/Hib Any 369 251 68.0 63.0 72.8 182 132 72.5 65.4 78.9 184 138 75.0 68.1 81.1 Grade 3 369 57 15.4 11.9 19.5 182 33 18.1 12.8 24.5 184 29 15.8 10.8 21.8 Synflorix Any 369 246 66.7 61.6 71.5 182 129 70.9 63.7 77.4 184 134 72.8 65.8 79.1 Grade 3 369 56 15.2 11.7 19.3 182 32 17.6 12.3 23.9 184 32 17.4 12.2 23.7

Redness Total Any 369 160 43.4 38.2 48.6 182 79 43.4 36.1 50.9 184 78 42.4 35.2 49.9 >30 mm 369 4 1.1 0.3 2.8 182 1 0.5 0.0 3.0 184 2 1.1 0.1 3.9 MenACWY-TT Any 369 109 29.5 24.9 34.5 176 35 19.9 14.3 26.6 - - - - - >30 mm 369 4 1.1 0.3 2.8 176 0 0.0 0.0 2.1 - - - - - DTPa-IPV/Hib Any 369 135 36.6 31.7 41.7 182 74 40.7 33.5 48.2 184 69 37.5 30.5 44.9 >30 mm 369 4 1.1 0.3 2.8 182 1 0.5 0.0 3.0 184 2 1.1 0.1 3.9 Synflorix Any 369 138 37.4 32.4 42.6 182 70 38.5 31.4 45.9 184 69 37.5 30.5 44.9 >30 mm 369 4 1.1 0.3 2.8 182 1 0.5 0.0 3.0 184 2 1.1 0.1 3.9

Swelling Total Any 369 147 39.8 34.8 45.0 182 74 40.7 33.5 48.2 184 70 38.0 31.0 45.5 >30 mm 369 3 0.8 0.2 2.4 182 4 2.2 0.6 5.5 184 0 0.0 0.0 2.0 MenACWY-TT Any 369 92 24.9 20.6 29.7 176 29 16.5 11.3 22.8 - - - - - >30 mm 369 1 0.3 0.0 1.5 176 0 0.0 0.0 2.1 - - - - - DTPa-IPV/Hib Any 369 117 31.7 27.0 36.7 182 69 37.9 30.8 45.4 184 60 32.6 25.9 39.9 >30 mm 369 3 0.8 0.2 2.4 182 3 1.6 0.3 4.7 184 0 0.0 0.0 2.0 Synflorix Any 369 120 32.5 27.8 37.6 182 68 37.4 30.3 44.8 184 59 32.1 25.4 39.3 >30 mm 369 2 0.5 0.1 1.9 182 4 2.2 0.6 5.5 184 0 0.0 0.0 2.0

N = number of subjects with at least one documented dose n/% = number/percentage of subjects reporting the symptom at least once 95%CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit Any = incidence of a particular symptom regardless of intensity Grade 3 pain = cried when limb was moved/spontaneously painful

Secondary Outcome Results: Number (%) of subjects reporting each solicited local symptom during the 8-day (Days 0-7) post-vaccination period by study vaccine (Booster Total Vaccinated cohort)


Symptom Product Intensity N n % LL UL N n % LL UL N n % LL UL Pain Total Any 338 139 41.1 35.8 46.6 165 71 43.0 35.4 51.0 167 77 46.1 38.4 54.0

Grade 3 338 21 6.2 3.9 9.3 165 19 11.5 7.1 17.4 167 14 8.4 4.7 13.7 MenACWY-TT Any 338 112 33.1 28.1 38.4 165 63 38.2 30.7 46.1 167 63 37.7 30.4 45.5 Grade 3 338 14 4.1 2.3 6.9 165 13 7.9 4.3 13.1 167 8 4.8 2.1 9.2 DTPa-IPV/Hib Any 338 136 40.2 35.0 45.7 165 69 41.8 34.2 49.7 167 69 41.3 33.8 49.2 Grade 3 338 20 5.9 3.7 9.0 165 17 10.3 6.1 16.0 167 13 7.8 4.2 12.9 Synflorix Any 337 129 38.3 33.1 43.7 165 67 40.6 33.0 48.5 167 72 43.1 35.5 51.0 Grade 3 337 18 5.3 3.2 8.3 165 16 9.7 5.6 15.3 167 12 7.2 3.8 12.2

Redness Total Any 338 74 21.9 17.6 26.7 165 32 19.4 13.7 26.3 167 39 23.4 17.2 30.5 >30 mm 338 1 0.3 0.0 1.6 165 1 0.6 0.0 3.3 167 3 1.8 0.4 5.2 MenACWY-TT Any 338 50 14.8 11.2 19.0 165 22 13.3 8.5 19.5 167 26 15.6 10.4 22.0 >30 mm 338 1 0.3 0.0 1.6 165 0 0.0 0.0 2.2 167 1 0.6 0.0 3.3 DTPa-IPV/Hib Any 338 66 19.5 15.4 24.2 165 25 15.2 10.1 21.5 167 33 19.8 14.0 26.6 >30 mm 338 1 0.3 0.0 1.6 165 1 0.6 0.0 3.3 167 1 0.6 0.0 3.3 Synflorix Any 337 62 18.4 14.4 23.0 165 26 15.8 10.6 22.2 167 33 19.8 14.0 26.6 >30 mm 337 1 0.3 0.0 1.6 165 0 0.0 0.0 2.2 167 2 1.2 0.1 4.3

Swelling Total Any 338 55 16.3 12.5 20.6 165 29 17.6 12.1 24.3 167 33 19.8 14.0 26.6 >30 mm 338 2 0.6 0.1 2.1 165 1 0.6 0.0 3.3 167 3 1.8 0.4 5.2 MenACWY-TT Any 338 34 10.1 7.1 13.8 165 21 12.7 8.1 18.8 167 22 13.2 8.4 19.3 >30 mm 338 1 0.3 0.0 1.6 165 0 0.0 0.0 2.2 167 1 0.6 0.0 3.3 DTPa-IPV/Hib Any 338 48 14.2 10.7 18.4 165 22 13.3 8.5 19.5 167 29 17.4 11.9 24.0 >30 mm 338 1 0.3 0.0 1.6 165 1 0.6 0.0 3.3 167 1 0.6 0.0 3.3 Synflorix Any 337 40 11.9 8.6 15.8 165 21 12.7 8.1 18.8 167 27 16.2 10.9 22.6

>30 mm 337 2 0.6 0.1 2.1 165 1 0.6 0.0 3.3 167 2 1.2 0.1 4.3 N = number of subjects with the documented dose n/% = number/percentage of subjects reporting the symptom at least once 95%CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit Any = incidence of a particular symptom regardless of intensity Grade 3 pain = cried when limb was moved/spontaneously painful

Secondary Outcome Results: Number (%) of subjects reporting each solicited general symptom during the 8-day (Days 0-7) post-vaccination period following each dose and across doses (Primary Total Vaccinated cohort)


Symptom Intensity/Relationship


Dose 1 Drowsiness Any 369 177 48.0 42.8 53.2 182 93 51.1 43.6 58.6 184 84 45.7 38.3 53.1

Grade 3 369 18 4.9 2.9 7.6 182 10 5.5 2.7 9.9 184 2 1.1 0.1 3.9 Related 369 160 43.4 38.2 48.6 182 84 46.2 38.8 53.7 184 79 42.9 35.7 50.4

Irritability Any 369 200 54.2 49.0 59.4 182 107 58.8 51.3 66.0 184 99 53.8 46.3 61.2 Grade 3 369 19 5.1 3.1 7.9 182 9 4.9 2.3 9.2 184 10 5.4 2.6 9.8 Related 369 188 50.9 45.7 56.2 182 96 52.7 45.2 60.2 184 89 48.4 41.0 55.8

Loss of appetite Any 369 109 29.5 24.9 34.5 182 62 34.1 27.2 41.4 184 42 22.8 17.0 29.6 Grade 3 369 7 1.9 0.8 3.9 182 5 2.7 0.9 6.3 184 3 1.6 0.3 4.7 Related 369 99 26.8 22.4 31.7 182 55 30.2 23.6 37.5 184 35 19.0 13.6 25.4

Temperature/(Rectally)

≥38°C 369 126 34.1 29.3 39.2 182 62 34.1 27.2 41.4 184 58 31.5 24.9 38.8 >40.0 °C 369 0 0.0 0.0 1.0 182 0 0.0 0.0 2.0 184 1 0.5 0.0 3.0 Related 369 109 29.5 24.9 34.5 182 56 30.8 24.2 38.0 184 53 28.8 22.4 35.9

Dose 2

Drowsiness Any 363 116 32.0 27.2 37.0 181 72 39.8 32.6 47.3 181 67 37.0 30.0 44.5 Grade 3 363 9 2.5 1.1 4.7 181 8 4.4 1.9 8.5 181 8 4.4 1.9 8.5 Related 363 109 30.0 25.4 35.0 181 69 38.1 31.0 45.6 181 62 34.3 27.4 41.7




≥38°C 363 119 32.8 28.0 37.9 181 64 35.4 28.4 42.8 181 63 34.8 27.9 42.2 >40.0 °C 363 0 0.0 0.0 1.0 181 0 0.0 0.0 2.0 181 0 0.0 0.0 2.0 Related 363 116 32.0 27.2 37.0 181 59 32.6 25.8 39.9 181 54 29.8 23.3 37.1

Dose 3 Drowsiness Any 359 102 28.4 23.8 33.4 177 54 30.5 23.8 37.9 180 64 35.6 28.6 43.0

Grade 3 359 11 3.1 1.5 5.4 177 8 4.5 2.0 8.7 180 4 2.2 0.6 5.6 Related 359 95 26.5 22.0 31.3 177 54 30.5 23.8 37.9 180 60 33.3 26.5 40.7




≥38°C 359 109 30.4 25.6 35.4 177 51 28.8 22.3 36.1 180 41 22.8 16.9 29.6 >40.0 °C 359 2 0.6 0.1 2.0 177 0 0.0 0.0 2.1 180 0 0.0 0.0 2.0 Related 359 96 26.7 22.2 31.6 177 46 26.0 19.7 33.1 180 36 20.0 14.4 26.6

Across Doses Drowsiness Any 369 217 58.8 53.6 63.9 182 121 66.5 59.1 73.3 184 118 64.1 56.7 71.1

Grade 3 369 30 8.1 5.6 11.4 182 19 10.4 6.4 15.8 184 13 7.1 3.8 11.8 Related 369 205 55.6 50.3 60.7 182 116 63.7 56.3 70.7 184 114 62.0 54.5 69.0

Irritability Any 369 254 68.8 63.8 73.5 182 128 70.3 63.1 76.9 184 126 68.5 61.2 75.1

Grade 3 369 42 11.4 8.3 15.1 182 27 14.8 10.0 20.8 184 18 9.8 5.9 15.0 Related 369 246 66.7 61.6 71.5 182 125 68.7 61.4 75.3 184 121 65.8 58.4 72.6


Temperature (Rectally)

≥38°C 369 203 55.0 49.8 60.2 182 102 56.0 48.5 63.4 184 101 54.9 47.4 62.2 >40.0 °C 369 2 0.5 0.1 1.9 182 0 0.0 0.0 2.0 184 1 0.5 0.0 3.0 Related 369 193 52.3 47.1 57.5 182 97 53.3 45.8 60.7 184 93 50.5 43.1 58.0

N = number of subjects with at least one documented dose n/% = number/percentage of subjects reporting the symptom at least once 95%CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit Any = incidence of a particular symptom regardless of intensity or relationship to vaccination Grade 3 Drowsiness = event that prevented normal activities Grade 3 Irritability = crying that could not be comforted/event that prevented normal activities Grade 3 Loss of Appetite= not eating at all Related = general symptom assessed by the investigator as causally related to the study vaccination

Secondary Outcome Results: Number (%) of subjects reporting each solicited general symptom during the 8-day (Days 0-7) post-vaccination period (Booster Total Vaccinated cohort)


Symptom Intensity/Relationship


Drowsiness Any 338 79 23.4 19.0 28.3 165 46 27.9 21.2 35.4 167 43 25.7 19.3 33.1 Grade 3 338 4 1.2 0.3 3.0 165 7 4.2 1.7 8.5 167 5 3.0 1.0 6.8 Related 338 75 22.2 17.9 27.0 165 42 25.5 19.0 32.8 167 43 25.7 19.3 33.1



Temperature/(Rectally) ≥38°C 338 68 20.1 16.0 24.8 165 35 21.2 15.2 28.2 167 27 16.2 10.9 22.6 >40.0°C 338 2 0.6 0.1 2.1 165 1 0.6 0.0 3.3 167 0 0.0 0.0 2.2 Related 338 62 18.3 14.4 22.9 165 32 19.4 13.7 26.3 167 24 14.4 9.4 20.6

N = number of subjects with the documented dose n/% = number/percentage of subjects reporting the symptom at least once 95%CI = Exact 95% confidence interval; LL = lower limit, UL = upper limit Any = incidence of a particular symptom regardless of intensity or relationship to vaccination Grade 3 Drowsiness = event that prevented normal activities Grade 3 Irritability = crying that could not be comforted/event that prevented normal activities Grade 3 Loss of Appetite= not eating at all Related = general symptom assessed by the investigator as causally related to the study vaccination

Secondary Outcome Results: Number (%) of subjects reporting NOCIs from first dose up to end of ESFU (Primary Total Vaccinated cohort)

NOCIs ACWY3+1 Group N = 376

ACWY1+1 Group N = 187

ACWY1 Group N = 187

Subjects with any AE(s), n (%) 16 (4.3) 8 (4.3) 4 (2.1) Drug hypersensitivity 8 (2.1) 5 (2.7) 2 (1.1) Rhinitis allergic 3 (0.8) 1 (0.5) 1 (0.5) Asthma 2 (0.5) 1 (0.5) - Milk allergy 2 (0.5) - - Atopy - 1 (0.5) - Bronchial hyperreactivity 1 (0.3) - - Dermatitis atopic - - 1 (0.5) Epilepsy 1 (0.3) - - Food allergy 1 (0.3) - -

- : Adverse event absent

Secondary Outcome Results: Number (%) of subjects reporting unsolicited AEs during the 31-day (Days 0-30) post-vaccination period - Dose 1 (Primary Total Vaccinated cohort)

Most frequent adverse events - On-Therapy (Occurring within Days 0-30 following vaccination)



ACWY1 Group N = 187

Subjects with any AE(s), n (%) 67 (17.8) 36 (19.3) 34 (18.2) Nasopharyngitis 15 (4.0) 7 (3.7) 9 (4.8) Diarrhoea 13 (3.5) 1 (0.5) 5 (2.7) Abdominal pain 6 (1.6) 6 (3.2) 4 (2.1) Cough 7 (1.9) 2 (1.1) 1 (0.5) Pharyngitis 4 (1.1) 2 (1.1) 4 (2.1) Gastroenteritis 2 (0.5) 2 (1.1) 2 (1.1) Bronchiolitis 2 (0.5) 2 (1.1) 1 (0.5) Upper respiratory tract infection 2 (0.5) 1 (0.5) 2 (1.1) Vomiting 2 (0.5) 2 (1.1) 1 (0.5) Conjunctivitis 3 (0.8) 1 (0.5) - Gastrooesophageal reflux disease 2 (0.5) 1 (0.5) 1 (0.5) Bronchitis 2 (0.5) 1 (0.5) - Constipation 2 (0.5) 1 (0.5) - Productive cough 2 (0.5) 1 (0.5) - Application site haematoma - 1 (0.5) 1 (0.5) Dermatitis diaper 2 (0.5) - - Influenza - 1 (0.5) 1 (0.5) Oral candidiasis - 1 (0.5) 1 (0.5) Otitis media - - 2 (1.1) Rash - 1 (0.5) 1 (0.5) Rhinorrhoea - 2 (1.1) - Abdominal distension - - 1 (0.5) Dermatitis - 1 (0.5) - Drug hypersensitivity - - 1 (0.5) Gastritis - 1 (0.5) - Headache - 1 (0.5) - Pain in extremity - 1 (0.5) - Rhinitis - 1 (0.5) - -:Counting rule applied: As there were more than 30 subjects per treatment group and ≤ 3 groups, only the 10 most frequent

events in each treatment group were listed. -: Implies that AE was not reported in the particular group or that the AE was reported in the particular group but did not fall within the pre-defined counting rule of 5 most frequent events for that group.


Most frequent adverse events - On-Therapy (Occurring within Days 0-30 following vaccination)



ACWY1 Group N = 182

Subjects with any AE(s), n (%) 70 (19.0) 34 (18.7) 28 (15.4) Nasopharyngitis 17 (4.6) 6 (3.3) 8 (4.4) Pharyngitis 11 (3.0) 6 (3.3) 6 (3.3) Diarrhoea 10 (2.7) 6 (3.3) 1 (0.5) Cough 7 (1.9) 2 (1.1) 2 (1.1) Upper respiratory tract infection 8 (2.2) 1 (0.5) 2 (1.1) Otitis media - 4 (2.2) 3 (1.6) Bronchiolitis 2 (0.5) - 3 (1.6) Gastroenteritis 3 (0.8) - 2 (1.1) Conjunctivitis 2 (0.5) 1 (0.5) 1 (0.5) Oral candidiasis - 2 (1.1) 1 (0.5) Roseola 3 (0.8) - -

Bronchitis - 1 (0.5) 1 (0.5) Dermatitis atopic - - 2 (1.1) Milk allergy 2 (0.5) - - Rash 2 (0.5) - - Rhinorrhoea 2 (0.5) - - Abdominal pain - 1 (0.5) - Constipation - 1 (0.5) - Head injury - 1 (0.5) - Injection site haemorrhage - - 1 (0.5) Myalgia - 1 (0.5) - Otitis media acute - - 1 (0.5) Productive cough - 1 (0.5) - Pyrexia - 1 (0.5) - Tonsillitis - 1 (0.5) - Tracheitis - 1 (0.5) - Varicella - - 1 (0.5) Vomiting - 1 (0.5) - -:Counting rule applied: As there were more than 30 subjects per treatment group and ≤ 3 groups, only the 10 most frequent

events in each treatment group were listed. -: Implies that AE was not reported in the particular group or that the AE was reported in the particular group but did not fall within the pre-defined counting rule of 5 most frequent events for that group.


Most frequent adverse events - On-Therapy (occurring within Days 0-30 following vaccination)



ACWY1 Group N = 181

Subjects with any AE(s), n (%) 97 (26.8) 49 (27.4) 45 (24.9) Nasopharyngitis 31 (8.6) 14 (7.8) 10 (5.5) Pharyngitis 17 (4.7) 13 (7.3) 12 (6.6) Diarrhoea 9 (2.5) 5 (2.8) - Bronchiolitis 5 (1.4) 2 (1.1) 3 (1.7) Cough 6 (1.7) 4 (2.2) - Upper respiratory tract infection 6 (1.7) 1 (0.6) 2 (1.1) Gastroenteritis 3 (0.8) 3 (1.7) 1 (0.6) Pneumonia 5 (1.4) - - Pyrexia 2 (0.6) - 2 (1.1) Conjunctivitis - - 3 (1.7) Teething - 2 (1.1) 1 (0.6) Bronchitis - 1 (0.6) 1 (0.6) Dermatitis diaper - 1 (0.6) 1 (0.6) Oral candidiasis - 1 (0.6) 1 (0.6) Rash - 1 (0.6) 1 (0.6) Rhinitis - 1 (0.6) 1 (0.6) Varicella 2 (0.6) - - Aphthous stomatitis - - 1 (0.6) Application site haematoma - - 1 (0.6) Cerebral atrophy - - 1 (0.6) Dermatitis - - 1 (0.6) Dermatosis - - 1 (0.6) Drug hypersensitivity - 1 (0.6) - Ear pain - - 1 (0.6) Haematoma - - 1 (0.6) Hypersensitivity - 1 (0.6) - Ichthyosis - - 1 (0.6) Injection site haemorrhage - 1 (0.6) - Injection site induration - - 1 (0.6)

Nasal congestion - - 1 (0.6) Otitis media acute - - 1 (0.6) Pharyngotonsillitis - 1 (0.6) - Rhinorrhoea - - 1 (0.6) Thermal burn - 1 (0.6) - Umbilical hernia - - 1 (0.6) Urinary tract infection - 1 (0.6) - Viral infection - - 1 (0.6) Vomiting - 1 (0.6) - -:Counting rule applied: As there were more than 30 subjects per treatment group and ≤ 3 groups, only the 10 most frequent

events in each treatment group were listed.

-: Implies that AE was not reported in the particular group or that the AE was reported in the particular group but did not fall

within the pre-defined counting rule of 5 most frequent events for that group.

Secondary Outcome Results: Number (%) of subjects reporting unsolicited AEs during the 31-day (Days 0-30) post-vaccination period (Booster Total Vaccinated cohort)

Most frequent adverse events - On-Therapy (occurring within days 0-30 following vaccination)



ACWY1 Group N = 170

Subjects with any AE(s), n (%) 58 (17.0) 32 (19.3) 36 (21.2) Nasopharyngitis 17 (5.0) 12 (7.2) 7 (4.1) Pharyngitis 10 (2.9) 4 (2.4) 10 (5.9) Diarrhoea 6 (1.8) 4 (2.4) 4 (2.4) Gastroenteritis 5 (1.5) 4 (2.4) 2 (1.2) Rhinorrhoea 5 (1.5) 2 (1.2) 2 (1.2) Pharyngotonsillitis 4 (1.2) 2 (1.2) 1 (0.6) Cough 4 (1.2) - 2 (1.2) Dermatitis diaper 2 (0.6) 1 (0.6) - Injection site haemorrhage - - 3 (1.8) Injection site induration - 3 (1.8) - Oral candidiasis 3 (0.9) - - Otitis media - 2 (1.2) 1 (0.6) Pyrexia - 1 (0.6) 1 (0.6) Vomiting 2 (0.6) - - Arthropod bite - - 1 (0.6) Bronchiolitis - - 1 (0.6) Bronchitis - 1 (0.6) - Dermatitis contact - - 1 (0.6) Injection site haematoma - 1 (0.6) - Laryngitis - 1 (0.6) - Oral herpes - - 1 (0.6) Pneumonia - - 1 (0.6) Productive cough - - 1 (0.6) Seizure - - 1 (0.6) Sinusitis - - 1 (0.6) Skin disorder - 1 (0.6) - Urinary tract infection - 1 (0.6) - -:Counting rule applied: As there were more than 30 subjects per treatment group and ≤ 3 groups, only the 10 most frequent

events in each treatment group were listed.

-: Implies that AE was not reported in the particular group or that the AE was reported in the particular group but did not fall

within the pre-defined counting rule of 5 most frequent events for that group.

Secondary Outcome Results: Please refer to the SAE table below in Safety Section for SAEs for entire study period.

Safety Results: Solicited and unsolicited symptoms experienced by at least 5 % of subjects, classified by MedDRA Primary System Organ Class and Preferred Term within the 31-day (Days 0-30) post-vaccination period from Dose 1 up to ESFU, including number of events reported - SAE excluded (Primary Total vaccinated cohort)



ACWY1 Group N = 187

95% CI 95% CI 95% CI

Primary System Organ Class (CODE)

Preferred Term (CODE)

n* n % LL UL n* n % LL UL n* n % LL UL

At least one symptom

3348 334 88.8 85.2 91.8 1750 169 90.4 85.2 94.2 1727 169 90.4 85.2 94.2

Gastrointestinal disorders (10017947)

Diarrhoea (10012735)

38 36 9.6 6.8 13.0 16 15 8.0 4.6 12.9 10 10 5.3 2.6 9.6

General disorders and administration site conditions (10018065)

Pain (10033371)

684 273 72.6 67.8 77.1 351 142 75.9 69.2 81.9 379 145 77.5 70.9 83.3

Pyrexia (10037660)

426 215 57.2 52.0 62.2 214 112 59.9 52.5 67.0 192 111 59.4 51.9 66.5

Swelling (10042674)

281 157 41.8 36.7 46.9 153 83 44.4 37.1 51.8 146 78 41.7 34.6 49.1

Infections and infestations (10021881)

Nasopharyngitis (10028810)

83 65 17.3 13.6 21.5 42 27 14.4 9.7 20.3 35 26 13.9 9.3 19.7

Pharyngitis (10034835)

42 39 10.4 7.5 13.9 25 17 9.1 5.4 14.2 32 27 14.4 9.7 20.3

Metabolism and nutrition disorders (10027433)

Decreased appetite (10061428)

343 185 49.2 44.0 54.4 192 95 50.8 43.4 58.2 175 95 50.8 43.4 58.2

Nervous system disorders (10029205)

Somnolence (10041349)

475 224 59.6 54.4 64.6 265 124 66.3 59.1 73.0 258 120 64.2 56.8 71.0

Psychiatric disorders (10037175)

Irritability (10022998)

616 262 69.7 64.8 74.3 316 130 69.5 62.4 76.0 323 130 69.5 62.4 76.0

Respiratory, thoracic and mediastinal disorders (10038738)

Cough (10011224)

25 23 6.1 3.9 9.0 8 8 4.3 1.9 8.3 5 5 2.7 0.9 6.1

Skin and subcutaneous tissue disorders (10040785)

Erythema (10015150)

335 177 47.1 41.9 52.3 168 87 46.5 39.2 53.9 172 87 46.5 39.2 53.9

At least one symptom = at least one symptom experienced (regardless of the MedDRA Preferred Term) N = number of subjects with the administered dose n* = number of events reported n/% = number/percentage of subjects reporting the symptom at least once

Safety Results: Number (%) of subjects with SAEs reported from first study dose up to end of the ESFU (Primary Total Vaccinated cohort)

ACWY3+1 Group

N = 376

ACWY1+1 Group

N = 187

ACWY1 Group

N = 187

Type of Event

Primary System Organ Class Preferred Term (CODE) n* n % n* n % n* n %

SAE At least one symptom 58 35 9.3 23 14 7.5 23 14 7.5 Blood and lymphatic system

disorders (10005329) Anaemia (10002034) 2 2 0.5 0 0 0.0 0 0 0.0

Gastrointestinal disorders (10017947)

Diarrhoea (10012735) 2 2 0.5 0 0 0.0 1 1 0.5

Ileus paralytic (10021333) 1 1 0.3 0 0 0.0 0 0 0.0

General disorders and administration site conditions (10018065)

Sudden infant death syndrome (10042440)

0 0 0.0 0 0 0.0 1 1 0.5

Immune system disorders (10021428)

Anaphylactic shock (10002199)

0 0 0.0 1 1 0.5 0 0 0.0

Drug hypersensitivity (10013700)

1 1 0.3 2 1 0.5 0 0 0.0

Milk allergy (10027633) 1 1 0.3 0 0 0.0 0 0 0.0 Infections and infestations

(10021881) Amoebic dysentery (10001986)

0 0 0.0 1 1 0.5 0 0 0.0

Bronchiolitis (10006448) 7 5 1.3 1 1 0.5 3 3 1.6 Bronchitis (10006451) 3 3 0.8 0 0 0.0 1 1 0.5 Conjunctivitis (10010741) 0 0 0.0 0 0 0.0 1 1 0.5 Ear infection (10014011) 0 0 0.0 0 0 0.0 1 1 0.5 Escherichia urinary tract

infection (10052238) 2 1 0.3 2 2 1.1 0 0 0.0

Gastroenteritis (10017888) 4 4 1.1 1 1 0.5 3 3 1.6 Gastroenteritis rotavirus

(10017913) 1 1 0.3 0 0 0.0 0 0 0.0

Gastroenteritis viral (10017918)

2 2 0.5 0 0 0.0 1 1 0.5

Measles (10027011) 1 1 0.3 0 0 0.0 0 0 0.0 Nasopharyngitis (10028810) 0 0 0.0 0 0 0.0 2 2 1.1 Neurological infection

(10051295) 1 1 0.3 0 0 0.0 0 0 0.0

Otitis media (10033078) 0 0 0.0 1 1 0.5 0 0 0.0 Pharyngitis (10034835) 1 1 0.3 1 1 0.5 0 0 0.0 Pharyngotonsillitis

(10049140) 1 1 0.3 1 1 0.5 0 0 0.0

Pneumonia (10035664) 16 13 3.5 2 2 1.1 3 3 1.6 Pneumonia viral (10035737) 1 1 0.3 0 0 0.0 0 0 0.0 Roseola (10039222) 1 1 0.3 0 0 0.0 0 0 0.0 Upper respiratory tract

infection (10046306) 0 0 0.0 1 1 0.5 0 0 0.0

Urinary tract infection (10046571)

2 2 0.5 2 2 1.1 0 0 0.0

Viral infection (10047461) 1 1 0.3 0 0 0.0 0 0 0.0 Injury, poisoning and procedural

complications (10022117) Burns first degree (10006797)

1 1 0.3 0 0 0.0 0 0 0.0

Burns second degree (10006802)

1 1 0.3 0 0 0.0 0 0 0.0

Foreign body (10070245) 0 0 0.0 0 0 0.0 1 1 0.5 Head injury (10019196) 0 0 0.0 2 2 1.1 0 0 0.0 Skull fracture (10061365) 0 0 0.0 1 1 0.5 0 0 0.0 Subdural haematoma

(10042361) 0 0 0.0 1 1 0.5 0 0 0.0

Toxicity to various agents (10070863)

0 0 0.0 0 0 0.0 1 1 0.5

Metabolism and nutrition disorders (10027433)

Dehydration (10012174) 2 2 0.5 1 1 0.5 1 1 0.5

Nervous system disorders (10029205)

Epilepsy (10015037) 1 1 0.3 0 0 0.0 0 0 0.0

Febrile convulsion (10016284)

1 1 0.3 1 1 0.5 0 0 0.0

Hyponatraemic seizure (10073183)

0 0 0.0 0 0 0.0 1 1 0.5

Seizure (10039906) 0 0 0.0 1 1 0.5 2 1 0.5

Respiratory, thoracic and mediastinal disorders (10038738)

Lung disorder (10025082) 1 1 0.3 0b b

0 0.0 0 0 0.0

Related SAE At least one symptom 0 0 0.0 0 0 0.0 0 0 0.0 Fatal SAE At least one symptom 0 0 0.0 0 0 0.0 1 1 0.5 General disorders and

administration site conditions (10018065)

Sudden infant death syndrome (10042440)

0 0 0.0 0 0 0.0 1 1 0.5

Related fatal SAE

At least one symptom 0 0 0.0 0 0 0.0 0 0 0.0

At least one symptom = at least one symptom experienced (regardless of the MedDRA Preferred Term) N = number of subjects with the administered dose n* = number of events reported n/% = number/percentage of subjects reporting the symptom at least once

Conclusion: The primary objective to demonstrate the immunogenicity of the MenACWY-TT conjugate vaccine in terms of bactericidal antibodies to N. meningitidis serogroups A, C, W-135 and Y one month post-dose 3 of MenACWY-TT at 7 months of age in healthy infants was met since for each serogroup, one month after dose 3 of MenACWY-TT vaccination, the lower limit of the two-sided exact 95% confidence interval (CI) for the percentage of subjects with rSBA titre ≥ 1:8 is greater than or equal to the pre-defined clinical limit of 80%. At Month 5, the percentage of subjects with rSBA-MenA, rSBA-MenC, rSBA-MenW-135 and rSBA-MenY titre ≥ 1:8 one-month post-dose 3 (Visit 4 at Month 5) in all subjects of group ACWY3+1 was 100%, 99.7%, 99.4% and 99.7%, respectively. During the 30-day period (Days 0-29) following vaccination with Dose 1, at least one unsolicited AE was reported in 67 (17.8%), 36 (19.3%) and 34 (18.2%) subjects in the ACWY3+1, ACWY1+1 and ACWY1 groups, respectively. During the 30-day period (Days 0-29) following vaccination with Dose 2, at least one unsolicited AE was reported in 70 (19.0%), 34 (18.7%) and 28 (15.4%) subjects in the ACWY3+1, ACWY1+1 and ACWY1 groups, respectively. During the 30-day period (Days 0-29) following vaccination with Dose 3, at least one unsolicited AE was reported in 97 (26.8%), 49 (27.4%) and 45 (24.9%) subjects in the ACWY3+1, ACWY1+1 and ACWY1 groups, respectively. During the 30-day period (Days 0-29) following the booster vaccination, at least one unsolicited AE was reported in 58 (17.0%), 32 (19.3%) and 36 (21.2%) subjects in the ACWY3+1, ACWY1+1 and ACWY1 groups, respectively. During the entire study period i.e. from first study dose up to end of ESFU, SAEs were reported in 35 (9.3%) subjects in the ACWY3+1 Group, 14 (7.5%) subjects in the ACWY1+1 Group and 14 (7.5%) subjects in the ACWY1 Group. One fatal SAE that was assessed by the investigator as not related to the study vaccination was reported in the ACWY1 Group.

Date updated: 02-Aug-2017

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