COMPARISON OF THE SAFETY AND IMMUNOGENICITY OF 3- AND 4-DOSE SCHEDULES OF A MENINGOCOCCAL MenACWY CONJUGATE VACCINE IN HEALTHY INFANTS Block S L1, Shepard J2, Garfield H3, Xie F4, Han L4, Smolenov I4, Dull P M5 Kentucky Pediatric and Adult Research, Bardstown, KY; 2Ohio Pediatric Research Association, Dayton, OH; 3Resolve Research Solutions, Ontario, Canada; 4Novartis Pharma B.V., Arnhem, The Netherlands; 5Novartis Vaccines and Diagnostics, Inc., Cambridge, MA
1
BACKGROUND & OBJECTIVES n Neisseria meningitidis is a leading cause of bacterial meningitis and sepsis worldwide, with high rates of morbidity and mortality even with early antibiotic treatment. n Young children are particularly vulnerable to meningococcal disease, especially in the first year of life1,2. n The quadrivalent meningococcal CRM197 glycoconjugate vaccine, MenACWY-CRM (Menveo®, Novartis Vaccines), has been shown to be highly immunogenic and well tolerated in all age groups3 and is currently licensed in the US for use in persons aged 2 months to 55 years. n The present study was designed to assess the immunogenicity of a 3-dose MenACWY-CRM vaccination schedule in young infants compared to a 4-dose schedule; and to evaluate concomitant administration with Prevnar 13 (PCV-13, 13-valent pneumococcal conjugate vaccine). n Primary objectives were to demonstrate a sufficient immune response after 4 doses of MenACWY-CRM at 2, 4, 6 and 12 months of age, and to demonstrate immunological non-inferiority of a 3-dose series (at 2, 4 and 12 months of age) versus a 4-dose series (at 2, 4, 6 and 12 months of age) in CWY serogroups. n Secondary objectives included (1) assessment of immune response following each of 3 doses of MenACWY-CRM in the first 6 months of life, (2) evaluation of the immune response to PCV-13 with concomitant administration of MenACWY-CRM vs. PCV-13 alone (at 7 and 13 months of age), and (3) assessment of the safety and tolerability of MenACWY-CRM when administered concomitantly with routine infant vaccines.
n At 7 months of age, the immune responses to PCV-13 in the ACWY4 or ACWY3 group were considered noninferior to those of the Routine group if the lower limits of the 2-sided 95% CI for group differences in the percentage of subjects with IgG ≥0.35 µg/mL against each PCV-13 serotype (ACWY4 minus Routine/ACWY3 minus Routine) were greater than –10%.
This was a Phase IIIb, open-label, multi-center study performed at 37 sites in the United States and 3 sites in Canada from October 2010 to May 2012. The study was registered on clinicaltrials.gov as NCT01214837.
STUDY DESIGN n 751 healthy full-term infants aged 55–89 days were enrolled and randomized into the following groups: l ACWY3 group (n=249) received MenACWY-CRM at 2, 4 and 12 months of age l ACWY4 group (n=256) received MenACWY-CRM at 2, 4, 6 and 12 months of age l Routine group (n=246) did not receive a MenACWY-CRM vaccination n All subjects received routine infant vaccinations at 2, 4, 6 and 12 months. n All subjects had a total of four blood draws. Each group had an initial blood draw at one of the following timepoints: at 2 months (baseline; Routine group), 3 months (ACWY4a group*), 4 months (ACWY4b group*), or 5 months (ACWY3 group) of age. All groups then had subsequent blood draws at 7, 12 and 13 months of age.
n Immune responses against MenACWY-CRM antigens were measured in terms of percentage of subjects with hSBA titers ≥8 and as hSBA geometric mean titers (GMTs) using a serum bactericidal assay with human complement (hSBA). n Immunogenicity against vaccine antigens at 13 months of age (one month after completing the 4-dose vaccination series) was considered sufficient if the lower limits of the two-sided 95% confidence interval (CI) for the percentage of subjects with hSBA titers ≥8 were >80% against serogroup A, and >85% against serogroups C, W and Y. n Non-inferiority of the 3-dose versus the 4-dose schedule was established if the lower limit of the two-sided 95% CI for the difference in percentages of subjects with hSBA titers ≥8 against serogroups C, W and Y (ACWY3 minus ACWY4) at 13 months was greater than –10%. n Bactericidal antibodies against serogroups A, C, W and Y were described at baseline (2 months), one and two months after the 2 month vaccinations (at 3 and 4 months), one month after the 4 month vaccinations (at 5 months), one month after the 6 month vaccinations (at 7 months), as well as immediately prior to, and one month after, the 12 month vaccinations (at 12 and 13 months).
n Immunogenicity against PCV-13 antigens was measured in terms of percentage subjects with IgG antibody concentration ≥ 0.35 µg/mL against each serotype at 7 months of age, and as geometric mean concentrations (GMC) of antipneumococcal antibodies at 13 months of age. n At 13 months of age, non-inferior immune responses to PCV-13 antigens was established between subjects who received MenACWY-CRM vaccinations concomitantly (along with other routine vaccines), and subjects who received only PCV-13 and routine vaccinations. Non-inferiority was based on the lower limit of the 95% CI for the ratio of GMCs ([groups ACWY4 or ACWY3]/ Routine group) being greater than 0.5.
3
4
43
n Reports of medically attended and serious AEs (SAEs) were collected throughout the study. 50
28
RESULTS
5
20 15 6A
n A total of 751 subjects were enrolled in this study (249 in the ACWY3 group, 256 in the ACWY4 group, and 246 in the Routine vaccine group), of which 181 (24%) withdrew prematurely from the study, primarily due to withdrawal of consent. Overall, 472 subjects (63%) were included in the per protocol set (PPS) at the 13 month timepoint for analyses of the primary objectives.
n At 13 months of age, a sufficient immune response for all four serogroups was demonstrated after a 4-dose vaccination series: 96% of subjects had hSBA titers ≥8 against serogroup A, and 99% of subjects had hSBA titers ≥8 against serogroups C, W and Y (lower limits of 95% CI were above pre-specified margins for all 4 serogroups). The sufficiency criteria were also reached for all 4 serogroups after a 3-dose vaccination series (Table 1). n Noninferiority of a 3-dose vaccination series versus a 4-dose vaccination series at 13 months of age, as determined by the percentage of subjects with hSBA titers ≥8, was established, for all 3 serogroups considered (C, W and Y; Table 1). n At 13 months, hSBA GMTs were robust and similar between the ACWY4 and ACWY3 groups for serogroups C, W and Y. GMTs against serogroup A were higher in the ACWY4 group than in the ACWY3 group (Table 2). n Evaluation of the immune response (percentage of subjects with hSBA titers ≥8) to each serogroup one month after the 2, 4 and 6-month doses of MenACWY-CRM showed either no increase (serogroups W and Y) or a modest increase from baseline values (serogroups A and C) after the first vaccination (ACWY4); this was followed by a robust immune response after the second and third vaccinations (all serogroups; Figure 1 and Table 3).
9
9
6B
0 Serogroup A
Serogroup C
Serogroup W
n Baseline (2 Months; Routine; N=166) n Post-Dose 1 (3 Months; ACWY4; N=82)
Serogroup
A
C
W
Y
ACWY3
ACWY4
N=146
N=141
129 (88%) (82%-93%)
135 (96%) (91%-98%)
N=160
N=152
152 (95%) (90%-98%)
150 (99%) (95%-100%)
N=153
N=138
152 (99%) (96%-100%)
137 (99%) (96%-100%)
N=154
N=146
154 (100%) (98%-100%)
145 (99%) (96%-100%)
Vaccine Group Difference
–7% (–14%,–1%) –4% (–8%,0%) 0% (–3%,3%)
Serogroup
Baseline/2 Month (Pre-1st Dose) Routine
3 Month (Post-1st Dose) ACWY4a
5 Month (Post-2nd Dose) ACWY3
7 Month (Post-3rd Dose) ACWY4b
2.18 (2.05-2.33) N=166
2.63 (2.2-3.15) N=82
7.09 (5.62-8.94) N=157
28 (23-35) N=157
19A
2.52 (2.28-2.78) N=167
4.79 (3.71-6.19) N=85
50 (39-64) N=170
86 (70-104) N=176
C
W
3.32 (2.82-3.9) N=157
3 (2.48-3.61) N=84
55 (42-71) N=162
90 (77-104) N=162
Y
2.47 (2.25-2.7) N=150
2.5 (2.14-2.93) N=80
20 (15-26) N=152
52 (43-64) N=163
Figure 2: Percentage of subjects with hSBA titers ≥8 (95%CI) against N meningitidis serogroups A, C, W, and Y at prior to and one month after the 12 Month Dose (PPS)
100
96
88
95
99
Y
N=141
59 (45-77)
94 (76-117)
N=160
N=152
124 (99-156)
160 (130-198)
N=153
N=138
248 (202-303)
244 (195-305)
N=154
N=146
212 (175-258)
254 (203-318)
1
66 4
0.63 (0.48-0.84) 0.78 (0.6-1.01) 1.02 (0.79-1.31) 0.84 (0.65-1.07)
19
6 1
1
6A
3
1
3
1
6B
1
0 Serogroup A
ACWY3 : ACWY4
25
22
Yes
Yes
5
33
Yes
Ratio of GMTs
N=146
99
Serotypes
3
50
Table 2: hSBA GMT values (95%CI) and ratio of GMTs against N meningitis serogroups A, C, W, and Y at 13 months following 3 or 4 doses of MenACWY-CRM
W
100
99
n Routine – Month 12 n Routine – Month 13
Serogroup C
n ACWY3 – Month 12 n ACWY3 – Month 13
Serogroup W
Ratio of GMCs
ACWY3
ACWY4
Routine
N=145
N=116
N=123
2 (1.7-2.36)
2.16 (1.83-2.56)
2.14 (1.8-2.54)
N=139
N=113
N=118
0.88 (0.74-1.05)
0.97 (0.81-1.15)
0.77 (0.64-0.93)
N=146
N=117
N=123
1.19 (0.99-1.42)
1.45 (1.21-1.75)
1.53 (1.27-1.86)
N=140
N=114
N=117
1.29 (1.11-1.49)
1.35 (1.16-1.57)
1.26 (1.08-1.48)
N=146
N=117
N=124
6.89 (5.78-8.21)
9.01 (7.52-11)
8.16 (6.77-9.82)
N=147
N=117
N=124
4.29 (3.6-5.11)
5.23 (4.36-6.27)
5.04 (4.18-6.08)
N=147
N=116
N=123
3.96 (3.42-4.58)
5.14 (4.41-5.98)
4.95 (4.23-5.78)
N=146
N=117
N=123
1.37 (1.17-1.61)
1.85 (1.56-2.18)
1.73 (1.46-2.05)
N=147
N=117
N=124
7.76 (6.51-9.26)
7.86 (6.55-9.43)
7.54 (6.25-9.09)
N=146
N=116
N=123
1.52 (1.28-1.8)
2.34 (1.96-2.79)
2.13 (1.78-2.55)
N=144
N=114
N=124
5.51 (4.61-6.6)
5.23 (4.34-6.3)
5.39 (4.45-6.51)
N=147
N=117
N=124
5.79 (4.9-6.85)
6.19 (5.21-7.35)
5.8 (4.86-6.92)
N=147
N=117
N=124
4.21 (3.49-5.09)
4.84 (3.98-5.89)
5.44 (4.45-6.65)
ACWY3 : Routine
ACWY4 : Routine
0.94 (0.77-1.13)
1.02 (0.83-1.25)
1.14 (0.93-1.4)
1.25 (1.01-1.55)
0.77 (0.62-0.96)
0.94 (0.75-1.18)
1.02 (0.86-1.21)
1.07 (0.89-1.29)
0.85 (0.69-1.04)
1.1 (0.88-1.37)
0.85 (0.69-1.05)
1.04 (0.83-1.3)
0.8 (0.67-0.95)
1.04 (0.87-1.25)
1.02 (0.83-1.27)
0.97 (0.77-1.21)
1.03 (0.84-1.27)
1.04 (0.83-1.3)
0.72 (0.59-0.87)
n Out of 751 enrolled subjects, 733 (98%) were exposed to at least one study vaccine, 708 (94%) provided solicited safety data and 733 (98%) provided unsolicited safety data. n Reactogenicity profiles for all groups were comparable; the majority of subjects reported solicited AEs (mostly mild or moderate), with frequencies decreasing with subsequent vaccinations (Table 6). n The most commonly reported solicited local AE was tenderness, with 30–36%, 25–28%, 19–24% and 24–31% experiencing this reaction across groups after the first, second, third and fourth vaccinations, respectively. n The most commonly reported systemic AE was irritability, with 46–54%, 41–47%, 36–39% and 36–43% experiencing this AE across groups after the first, second, third and fourth vaccinations respectively. n Unsolicited AEs were reported by the majority of subjects (87–90%) across groups, with 4–13% considered possibly related to the study vaccines. The percentages of reported unsolicited AEs were comparable between subjects who received MenACWY-CRM and those who received routine vaccines alone. n 5–8% of subjects across groups reported at least 1 SAE, although no SAEs were considered related to the study vaccinations. n A single subject from the Routine group experienced a SAE of anoxic encephalopathy following cardio-respiratory arrest that led to death 49 days after the first set of routine vaccinations. The event was assessed as unrelated to vaccination.
Table 6: Overview of solicited local and systemic adverse effects (AEs) reported within 7 days of each vaccination, as well as medically attended, unsolicited and serious AEs after any vaccination
Number (%) of Subjects ACWY3
1.02 (0.83-1.27) 1 (0.82-1.22) 0.77 (0.62-0.97)
Serogroup Y
n ACWY4 – Month 12 n ACWY4 – Month 13
EFFECT OF CONCOMITANT ADMINISTRATION OF MENACWY-CRM ON IMMUNE RESPONSES TO PCV-13 ANTIGENS n At 13 months of age, immune responses to all 13 PCV-13 antigens in both ACWY groups were noninferior to those in the Routine group (Table 4). n Overall, at 7 months of age, the lower limit of the 2-sided 95% CI for the group difference of percentage of subjects with anti-pneumococcal antibodies ≥0.35 µg/mL was greater than the prespecified margin of –10% for 11 out of 13 serotypes (not serotypes 3 and 5) in the ACWY3 group, and for 12 out of 13 serotypes (not serotype 19A) in the ACWY4 group (Table 5). n When the ACWY3 and ACWY4 groups were pooled and collectively compared with the Routine group in a post-hoc exploratory analysis, the lower limit of the 2-sided 95% CIs around the vaccine group differences for the ACWY pooled group versus the Routine group was greater than –10% for all 13 PCV-13 serotypes at 7 months of age. Similarly, at 13 months of age, the lower limit of the 2-sided 95% CIs around the ratios of GMCs for the pooled ACWY group versus the Routine group was greater than 0.5 for all 13 antigens.
7F
9V
14
18C
19A
19F
23F
Geometric Mean Concentration (95% CI)
Routine
First N=235
Second N=224
Third N=204
Fourth N=179
First N=240
Second N=219
Third N=200
Fourth N=181
First N=225
Second N=213
Third N=194
Fourth N=167
Solicited Any
201 (86%)
175 (78%)
143 (70%)
129 (72%)
203 (85%)
173 (79%)
136 (68%)
123 (68%)
181 (80%)
149 (70%)
129 (66%)
117 (70%)
Local
106 (45%)
88 (39%)
81 (40%)
77 (43%)
121 (50%)
89 (41%)
73 (37%)
74 (41%)
102 (45%)
95 (45%)
76 (39%)
76 (46%)
Systemic
178 (76%)
156 (70%)
122 (60%)
111 (62%)
176 (73%)
145 (66%)
107 (54%)
104 (57%)
165 (73%)
123 (58%)
104 (54%)
98 (59%)
Medically attended
0.97 (0.77-1.21)
ACWY4
Vaccination
1.1 (0.89-1.36)
1.07 (0.86-1.32)
Unsolicited Any Possibly Related
0.89 (0.7-1.13)
Serious AEs Possibly Related
210 (87%)
220 (87%)
209 (87%)
219 (90%)
220 (87%)
209 (87%)
24 (10%)
32 (13%)
10 (4%)
11 (5%)
19 (8%)
11 (5%)
0
0
0
Note: For the ACWY4 group, each ‘vaccination’ included MenACWY-CRM plus concomitant routine vaccines including PCV-13. For the ACWY3 group, the first, second and fourth ‘vaccination’ included MenACWY-CRM plus routine vaccines while the third ‘vaccination’ included routine vaccines only. For the Routine group, each ‘vaccination’ included routine vaccines only. Local reactions were assessed only for groups and visits where MenACWY-CRM was given. For groups and visits where MenACWY-CRM was not given, local reactions were assessed for the PCV-13 injection site.
Table 5: Number (%) of subjects with IgG antibody concentration ≥ 0.35 μg/mL against pneumococcal capsular polysaccharides at 7 months after concomitant administration of 2 or 3 doses of MenACWY-CRM and PCV-13
Values assessed in ACWY4a group. bValues assessed in ACWY4b group.
a
99
Geometric Mean Concentration (95% CI)
Values in bold indicate that the lower limit of the 2-sided 95% CI around the ratio of GMCs was > 0.5.
NAa
serogroups C, W and Y.
ACWY4
23F
48
Both groups met sufficiency criteria, with lower limits of the two-sided 95% CI for the percentage of subjects with hSBA ≥1:8 being >80% against serogroup A and >85% against each of
ACWY3
19F
55
Immune response to serogroup A was not included in the noninferiority criterion assessment.
hSBA GMT values (95% CI)
14
18C
A
1 1% (–2%,4%)
9V
Number (%) of Subjects with hSBA ≥1:8
ACWY3 – ACWY4
a
C
7F
Table 3: hSBA GMT values (95%CI) against N meningitidis serogroups A, C, W, and Y at baseline (2 months) and one month after 1st, 2nd and 3rd dose of MenACWY-CRM (PPS)
Noninferiority criterion met
Note: Values in bold indicate that the criterion for noninferiority was met; i.e. the lower limit of the 2-sided 95% CI for vaccine group differences was greater than -10%.
Serogroup
Serogroup Y
n Post -Dose 2 (5 Months; ACWY3; N=157) n Post -Dose 3 (7 Months; ACWY4; N=152)
Table 1: Noninferior seroconversion rates of a 3-dose MenACWY-CRM vaccination schedule compared to a 4-dose schedule: Subjects with hSBA ≥1:8 (95% CI) against N meningitidis serogroups A, C, W, and Y at 13 months of age
Number (%) of Subjects with hSBA ≥1:8
8
7
4
n Demographics and other baseline characteristics were comparable for all vaccine groups. Slightly more males (53%) were enrolled, and most subjects were Caucasian (58%). The mean age at enrollment was 66.6 days. The mean weight and height were 5.39 kg and 58.3 cm, respectively. Overall, 571 (76%) enrolled subjects completed the study.
A
EFFECT OF CONCOMITANT ADMINISTRATION OF MenACWY-CRM ON IMMUNE RESPONSES TO PCV-13 ANTIGENS
1
n A diary card was then used by parents/legal representatives to document any solicited local and systemic AEs and any unsolicited AEs for 7 days after each study vaccination.
VACCINES
IMMUNOGENICITY AGAINST N. MENINGITIDIS SEROGROUPS A, C, W, Y
86
n All subjects were observed for 30 minutes after each vaccination for any immediate postvaccination adverse events (AEs).
n At 12 months of age (immediately prior to the final dose in both ACWY groups), a higher percentage of subjects had hSBA titers ≥8 in the ACWY4 group (22–66%) compared to the ACWY3 group (6–33%; Figure 2). The percentage of subjects with hSBA titers ≥8 in both ACWY groups at this time point, however, was much higher than the Routine group.
n Routine infant vaccines included: PCV-13 (Prevnar 13 , Pfizer Inc), DTaP, IPV, Hib, Hepatitis B vaccine, measles, mumps and rubella (MMR) and Varivax or Proquad, rotavirus vaccines. At Canadian sites where Men C vaccine is recommended in the second year of life, the Men C vaccine was administered at 13 months of age, at the time of the final blood draw.
Serotypes
94
REACTOGENICITY AND SAFETY
Table 4: Immune response against pneumococcal capsular polysaccharides at 13 months after concomitant administration of MenACWY-CRM and PCV-13
67
*The ACWY4 group was divided into two subgroups for blood draws at either 3 or 4 months of age.
®
86
84
REACTOGENICITY AND SAFETY
n Immune responses were observed against all four serogroups (84–99% of subjects achieved hSBA titers ≥8) one month after the 3rd dose of MenACWY-CRM (at 7 months of age), and against serogroups C, W and Y (67–86%) one month after the 2nd dose (at 5 months of age).
n The MenACWY-CRM vaccine contains oligosaccharides of each of the four serogroups: serogroups A (10 µg), C, W and Y (5 µg each), conjugated to a non-toxic mutant of diphtheria toxin, CRM197.
99
95 100
IMMUNOGENICITY OF 3- AND 4-DOSE MENACWY-CRM VACCINATION SERIES
METHODS
Figure 1: Percentage of subjects with hSBA titers ≥8 (95%CI) against N meningitidis serogroups A, C, W, and Y at baseline and one Month After the first, second and third MenACWY-CRM Vaccination (PPS)
Ratio of GMCs
ACWY3
ACWY4
Routine
N=159
N=136
N=156
149 (93.7%) (88.7%-96.9%)
136 (100%) (97.3%-100%)
147 (94.2%) (89.3%-97.3%)
N=150
N=129
N=147
119 (79.3%) (72%-85.5%)
113 (87.6%) (80.6%-92.7%)
121 (82.3%) (75.2%-88.1%)
N=160
N=137
N=157
151 (94.4%) (89.6%-97.4%)
133 (97.1%) (92.7%-99.2%)
152 (96.8%) (92.7%-99%)
N=156
N=133
N=154
131 (84%) (77.3%-89.4%)
124 (93.2%) (87.5%-96.9%)
136 (88.3%) (82.2%-92.9%)
N=159
N=136
N=156
156 (98.1%) (94.6%-99.6%)
135 (99.3%) (96%-100%)
153 (98.1%) (94.5%-99.6%)
N=160
N=137
N=157
135 (84.4%) (77.8%-89.6%)
130 (94.9%) (89.8%-97.9%)
133 (84.7%) (78.1%-90%)
N=158
N=136
N=156
158 (100%) (97.7%-100%)
136 (100%) (97.3%-100%)
155 (99.4%) (96.5%-100%)
N=159
N=136
N=157
142 (89.3%) (83.4%-93.6%)
131 (96.3%) (91.6%-98.8%)
145 (92.4%) (87%-96%)
N=158
N=136
N=158
157 (99.4%) (96.5%-100%))
136 (100%) (97.3%-100%)
154 (97.5%) (93.6%-99.3%)
N=158
N=136
N=157
154 (97.5%) (93.6%-99.3%)
133 (97.8%) (93.7%-99.5%)
157 (100%) (97.7%-100%)
N=158
N=135
N=156
151 (95.6%) (91.1%-98.2%)
125 (92.6%) (86.8%-96.4%)
153 (98.1%) (94.5%-99.6%)
N=159
N=136
N=158
159 (100%) (97.7%-100%)
136 (100%) (97.3%-100%)
157 (99.4%) (96.5%-100%)
N=158
N=136
N=158
147 (93%) (87.9%-96.5%)
130 (95.6%) (90.6%-98.4%)
144 (91.1%) (85.6%-95.1%)
ACWY3 : Routine
ACWY4 : Routine
–0.5% (–6.1%,5%)
5.8% (3%,10.5%)
–3%* (–11.9%,6%)
5.3% (–3.3%,13.7%)
–2.4% (–7.5%,2.3%)
0.3% (–4.4%,4.7%)
–4.3%* (–12.1%,3.4%)
4.9% (–1.9%,11.8%)
0.04% (–3.7%,3.8%)
1.2% (–2.2%,4.8%)
–0.3% (–8.4%,7.7%)
10.2% (3.4%,17.2%)
0.6% (–1.7%,3.5%)
0.6% (–2.1%,3.5%)
–3.1% (–9.7%,3.4%)
4% (–1.5%,9.7%)
1.9% (–1.2%,5.7%)
2.5% (–0.2%,6.3%)
-2.5% (–6.3%,0.2%)
–2.2% (–6.2%,0.2%)
–2.5% (–7.1%,1.6%)
–5.5%* (–11.3%,-0.9%)
0.6% (–1.7%,3.4%)
0.6% (–2.1%,3.4%)
Values in bold indicate that the lower limit of 2-sided 95% CI around the difference between groups was greater than -10%.
1.9% (–4.2%,8.2%)
CONCLUSIONS n At 13 months of age, both the 3- and 4-dose MenACWY-CRM schedules were immunogenic against each vaccine serogroup, as determined by both the percentage of subjects achieving hSBA titers ≥8 and hSBA GMTs. n By 13 months of age (one month after final MenACWY-CRM vaccination in both groups), the 3-dose schedule was established as non-inferior to the 4-dose schedule for serogroups C, W and Y. n Immunogenicity against all four serogroups was established one month after the 3rd dose of MenACWY-CRM (at 7 months of age), and against serogroups C, W and Y (67–86%) one month after the 2nd dose (at 5 months of age). n At 13 months of age, immunogenicity against all 13 PCV serotypes following completion of a 4-dose PCV-13 series was determined as noninferior in both ACWY groups compared to the Routine group. At 7 months of age, however, the lower limit of the 2-sided 95% CIs around the vaccine group differences for the ACWY groups versus the Routine group was greater than -10% for 11 out of 13 serotypes in the ACWY3 group (not serotypes 3 and 5) and for 12 out of 13 serotypes in group ACWY4 (not serotype 19A). n When the ACWY3 and ACWY4 groups were pooled and collectively compared with the Routine group in a post-hoc exploratory analysis, the lower limit of the 2-sided 95% CIs around the vaccine group differences for the ACWY pooled group versus the Routine group was greater than -10% for all 13 PCV-13 serotypes at 7 months of age. Similarly, at 13 months of age, the lower limit of the 2-sided 95% CIs around the ratios of GMCs for the pooled ACWY group versus the Routine group was greater than 0.5 for all 13 antigens. n MenACWY-CRM vaccination, co-administered with routine childhood vaccines including PCV-13, was well tolerated without increased reactogenicity or any safety concerns.
REFERENCES 1
Pace D. MenACWY-CRM, a novel quadrivalent glycoconjugate vaccine against Neisseria meningitidis for the prevention of meningococcal infection. Current opinion in molecular therapeutics. 2009;11:692-706.
2
Cohn AC, MacNeil JR, Harrison LH, Hatcher C, Theodore J, Schmidt M, et al. Changes in Neisseria meningitidis disease epidemiology in the United States, 1998-2007: implications for prevention of meningococcal disease. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2010;50:184-91.
3
Trotter CL, Chandra M, Cano R, Larrauri A, Ramsay ME, Brehony C, et al. A surveillance network for meningococcal disease in Europe. FEMS microbiology reviews. 2007;31:27-36.
4.5% (–1.4%,10.5%)
*for these comparisons, the lower limit of 2-sided 95% CI around the difference between groups was not greater than -10%
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