Bexsero - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Bexsero - Scientific Information

Manufacture: GlaxoSmithKline
Country: Canada
Condition: Meningococcal Meningitis Prophylaxis
Class: Vaccine combinations
Form: Liquid solution, Intramuscular (IM), Intravenous (IV)
Ingredients: recombinant Neisseria meningitidis group B NHBA fusion protein, recombinant Neisseria meningitidis group B NadA protein, recombinant Neisseria meningitidis group B fHbp fusion protein, Outer Membrane Vesicles Neisseria meningitidis group B strain NZ98/254, Sodium chloride, histidine, sucrose, water for injections

Pharmaceutical Information

Drug Substance

Proper name: Multicomponent Meningococcal B Vaccine (recombinant, adsorbed)

Product Characteristics

BEXSERO is a multicomponent Meningococcal B Vaccine and appears as white opalescent liquid suspension for intramuscular injection in a prefilled syringe (see Product Information, DESCRIPTION).

Clinical Trials

Study Demographics and Trial Design

The safety and immunogenicity profile of BEXSERO is based on data from 15 clinical studies (see Table 1).

Table 1 - Study Demographics and Trial Designs
Study No. Age at Enrollment Trial design Dosage, route of administration and schedule No. of subjects enrolled
(No. receiving BEXSEROa)
Mean age of enrolled subjects (range) Gender of enrolled subjects (% male)
V72P4
Phase 2
18-50 yrs Open-label, multicenter
Safety, immunogenicity in at-risk adults
0.5mL, IM
Schedule: 0, 2, 6 mos
54(53) 31.8 (21-46) yrs 50%
V72P5
Phase 2
18-40 yrs Observer-blind single center, randomized
Safety, immunogenicity in healthy adults
0.5mL, IM
Schedule: 0, 1, 2 mos
70(28) 32.1 (18-40) yrs 66%
V72P6
Phase 2
2 mos Open-label, multicenter, randomized, controlled
Safety, immunogenicity of infant primary series + fourth dose
0.5mL, IM
Schedule: 2, 4, 6 12 mos of age
147 (74) (50: 4-doses; 24: one dose at 12 mos of age) 60.2 (55-85) days 58%
V72P6E1
Phase 2
40-60 mos Open-Label, single center, extension
Antibody persistence, safety and immunogenicity of booster doses in children who received 1 or 4 doses as infants in study V72P6
0.5mL, IM
Schedule: 5th dose boost at 40 mos; 2 doses at 40, 42 mos after one dose at 12 mos; 2 catch up doses in naive children at 40, 42 mos.
113 (69) (19: 5th dose; 8: 2-doses after one dose at 12 mos; 42: 2-doses in naпve) 41.5 (40-44) mos 50%
V72P9
Phase 2
6-8 mos Single-blind, single center, randomized
Safety, immunogenicity of infant primary series + third dose
0.5mL, IM
Schedule: 6, 8 12 mos of age
60(30) 7.1 (6-8) mos 47%
V72P9E1
Phase 2
40-60 mos Open-label, single center, extension
Antibody persistence, safety, and immunogenicity of booster dose in children who received a 3-dose series as infants in Study V72P9
0.5mL, IM
Schedule: 4th dose boost at 40 mos; 2 catch up doses in naive children at 40,42 or 60,62 mos
120 (103) (14: 4th dose; 89: 2-doses in naпve) 50.0 (39-62) mos 48%
V72P10
Phase 2b/3
11-17 yrs Observer-blind, multicenter, randomized, placebo controlled
Safety, immunogenicity, schedule finding
0.5mL, IM
Schedule: mos 0; mos 6; mos 0, 1; mos 0, 2; mos 0, 6; mos 0, 1, 2; mos 0, 1, 6; mos 0, 2, 6
1631 (1622) 13.8 (10-17) yrs 44%
V72P10E1
Phase 2b/3
13-19 yrs Multi-Center, Extension Antibody Persistence n.ab 817 (n.a) 15.9 (13-20) yrs 43%
V72P12
Phase 2b
2 mos Open-label, multicenter, randomized, controlled
Safety, immunogenicity, schedule finding
0.5mL, IM
Schedule: 2, 4, 6 and 2, 3, 4 mos of age
1885 (1570) 68.7 (50-107) days 51%
V72P12E1
Phase 2b
12, 18, 24 mos Open-label, multicenter, extension
Safety, immunogenicity of booster in subjects who received a 3-dose series as infants in Study V72P12
0.5mL, IM
Schedule: 4th dose booster at 12, 18, or 24 mos of age; 2 catch up doses at 12, 14 or 18, 20 or 24, 26 mos of age
1588 (1519) (1174: 4th dose; 345: 2-doses in naпve) 17.1 (11-26) mos 52%
V72P13
Phase 3
2 mos Partially blinded, multicenter, randomized controlled
Safety, immunogenicity, lot consistency
0.5mL, IM
Schedule: 2, 4, 6 mos of age
3630 (2480) 73.5 (54-132) days 51%
V72P13E1
Phase 3
12 mos Open-label, multicenter, randomized
Safety, immunogenicity of fourth dose, 2 catch-up doses starting at 12 or 13 mo for original control group in V72P13
0.5mL, IM
Schedule: 4th dose at 12 mos; 1 or 2 catch-up doses starting at 12 or 13, mos of age
2249 (2247) (1555: 4th dose; 692: 1 or 2 catch-up doses) 12.3 (11-15) mos 51%
V72P13E2
Phase 3
24-27 mos Open label, randomized, multi-center, extension study 0.5mL, IM
Schedule: 3rd dose boost at 12 mos after 2 catch up doses at 13 and 15 mos or 12 and 14 mos; 2 catch up doses in naive children (less than 2 years of age) at 24, 26 mos of age
508 (193) (85: 3rd dose; 108: 2-doses in naпve) 25.4 (23-30) mos 52%
V72P16
Phase 2
2 mos Partially observer-blind, randomized, controlled, multicenter dose-ranging and formulation-finding Safety and immunogenicity 0.5mL, IM
Schedule: 2, 3, 4, 12 mos of age
1507 (736) 74.6 (54-91) days 52%
V72_41
Phase 3
11-17 yrs Observer-blind, multicenter, randomized Safety and immunogenicity, lot consistency 0.5mL, IM
Schedule: 0, 1 mos
344 (342) 13.7 (11-17) yrs 55%

aNumber of subjects in the BEXSERO safety population. Defined as those subjects who were vaccinated with BEXSERO and who provided some post-baseline safety data;

bNo investigational vaccine was administered in the V72P10E1 study. Only blood samples were obtained for meningococcal serology from all the subjects
IM: intramuscular;
mos: months;
yrs: years.

Table 2 - Study Results
Study Primary Immunogenicity
Objectives
Prospectively Defined
Criterion
Outcome
V72P12

Phase 2b
– Demonstration of a sufficient immune response to BEXSERO when given concomitantly with routine vaccines to healthy infants at either 2, 4 and 6 or 2, 3 and 4 months of age, by evaluation of hSBA at 1 month after the third vaccination. – The immune response was considered sufficient if the lower limit of the two-sided 95% CI for the percentage of subjects with hSBA ≥1:5 at 1 month following the third vaccination was ≥70% for all 3 reference strains H44/76, NZ98/254 and 5/99. Objective was met.

– The lower limits of the two-sided 95% CI for the percentage of subjects with hSBA ≥1:5 for the 2, 4, 6-month schedule were: 98% for strain H44/76, 98% for stain 5/99 and 75% for strain NZ98/254.

– The lower limits of thetwo-sided 95% CI for the percentage of subjects with hSBA ≥1:5 for the 2,3,4-month schedule were: 97% for strain H44/76, 99% for strain 5/99 and 76% for strain NZ98/254.
V72P13
Phase 3
Two Co-primary Objectives:

– To show the consistency of the immune response from 3 lots of BEXSERO, by hSBA GMTs, when administered to healthy infants at 2, 4 and 6 months of age, at 1 month after the third vaccination.

– Demonstration of a sufficient immune response to BEXSERO (3 lots combined) when given concomitantly with routine vaccines to healthy infants at 2, 4 and 6 months of age, by evaluation of hSBA at 1 month after the third vaccination.

– The 3 BEXSERO vaccine lots were considered equivalent if for each of the reference strains H44/76, NZ98/254 and 5/99 and each pair of vaccine lots, the two-sided 95% CI of the ratio of GMTs at 1 month after the third vaccination was contained within the interval [0.50, 2.00].

– The immune response was considered sufficient immune if the lower limit of the two-sided 95% CI for the percentage of subjects with hSBA ≥ 1:5 at 1 month following the third vaccination was ≥ 70% for all 3 reference strains H44/76, NZ98/254 and 5/99, for the 3 BEXSERO lots combined.
Objectives were met.

– For each reference strain, for all 3 pairs of BEXSERO vaccine lots simultaneously, the two-sided 95% CI for the ratios of GMTs at 1 month after the third vaccination were entirely contained within the interval [0.74, 1.33], thereby meeting the criterion for lot consistency [0.50, 2.00].

– The lower limits of the two-sided 95% CI for the percentage of subjects with an hSBA ≥ 1:5 at 1 month following the third vaccination were: 100% against the H44/76 and 5/99 strains, and 84% against the NZ98/254 strain, thereby meeting the sufficient immune response criterion.
V72P13E1
Phase 3
– Demonstration of a sufficient immune response following a fourth dose of BEXSERO administered at 12 months of age, either with or without concomitant Priorix-Tetra vaccination, to children (less than 2 years of age) previously primed with three doses of BEXSERO as infants in Study V72P13. – The fourth dose immune response was considered sufficient if for the percentage of subjects with hSBA ≥1:5, the lower limit of the two-sided 95% CI was ≥75% for all 3 reference strains H44/76, NZ98/254 and 5/99. Objectives were met.

– For strains H44/76 and 5/99, 100% of the subjects had hSBA ≥1:5. The lower limit of the two-sided 95% CI was 98% in subjects with or without concomitant Priorix-Tetra vaccination.

– For strain NZ98/254, 97% and 94% of the subjects in the vaccination groups had hSBA ≥1:5. The lower limit of the two-sided 95% CI was 93% in subjects with concomitant Priorix-Tetra and 90% in subjects without concomitant Priorix-Tetra vaccination.
V72_41
Phase 3
– Demonstration of the equivalence of rMenB+OMV NZ lot 1 to rMenB+OMV NZ lot 2 when administered to adolescents, as measured by hSBA GMTs for strains H44/76, 5/99, and NZ98/254 and ELISA GMCs against vaccine antigen 287-953 approximately 30 days after a primary vaccination course of two doses administered one month apart. – The equivalence was considered a success if, at one month following the second vaccination, the two-sided 95% confidence interval (CI) of the ratio of the hSBA GMTs for each of 3 serogroup B reference strains (H44/76, 5/99, and NZ98/254) and the two-sided 95% CI of the ratio of the ELISA GMCs against vaccine antigen 287-953 are contained within the interval (0.5, 2.0) Objective was met.

– The ratios of hSBA GMTs in Lot 1_Rosia to Lot 2_Siena at one month after the second vaccination were 1.0, 0.92, and 0.81 for strains H44/76, 5/99, and NZ98/254, respectively, with corresponding two-sided 95% confidence intervals of (0.82, 1.23), (0.77, 1.10), and (0.60, 1.09).

– The ratio of ELISA GMCs against vaccine antigen 287-953 at one month after second vaccination was 0.83, with a corresponding two-sided 95% CI of (0.67, 1.02).

CI: confidence interval;
GMT: geometric mean titers
hSBA: serum bactericidal assay using human complement

Immunogenicity Data

The primary immunogenicity measure was the proportion of subjects with human serum bactericidal assay (hSBA) equal to or above the threshold of 1:4 against each of the meningococcal serogroup B reference strains. This threshold, used in early-stage clinical studies (V72P6, V72P9, V72P4, V72P5 and V72P10) and in their extensions (V72P6E1, V72P9E1, V72P10E1), is an accepted correlate of protection. A threshold of 1:5 was then set after hSBA assay validation to ensure, based on the intermediate precision of the assay, 95% certainty of a true response of 1:4, and this cutoff was used to define seropositive responses in late-stage clinical studies V72P12, V72P12E1, V72P13, V72P13E1, V72P13E2, V72P16, V72_41.

Immunogenicity was evaluated in randomized, multicenter, clinical trials that enrolled infants, children (less than 2 years of age), adolescents and adults.

In infant study V72P13, participants received three doses of BEXSERO at 2, 4 and 6 months of age. In infant study V72P12, participants received three doses of BEXSERO at either 2, 4 and 6 or 2, 3, and 4 months of age. In infant study V72P16, participants received four doses of BEXSERO at 2, 3, 4 and 12 months of age. Sera were obtained both before vaccination and one month after the third vaccination (Table 3). Subjects who received three doses of BEXSERO in V72P12 and V72P13 received a fourth dose at either 12 months of age in the extension studies V72P12E1 and V72P13E1 (Table 4) or 18 and 24 months of age in study V72P12E1. In studies V72P16, V72P12E1 and V72P13E1 sera were obtained before and one month after the fourth vaccination.

Previously unvaccinated children (less than 2 years of age) in the above mentioned studies received 2 doses in the second year of life (Table 5). The immunogenicity after two doses has been also documented in another study in infants (V72P9) aged 6 months at enrolment (Table 5).

Vaccine-naive children enrolled in studies V72P6E1, V72P9E1 and V72P13E2 received two doses of BEXSERO with a two month-interval between doses. Sera were obtained both before vaccination and one month after the second vaccination.

In the adolescents studies, participants received two doses of BEXSERO with a one month (V72_41) or one, two or six month (V72P10)-interval between doses, as shown in Table 6. Sera were obtained both before vaccination and one month after each vaccination.

In other studies in adults (V72P4 and V72P5), data were also obtained after two doses of BEXSERO with a one month or two month interval between doses (Table 6). Sera were obtained both before vaccination and one month after each vaccination.

Immunogenicity in infants 2 months to 6 months of age

Immunogenicity results at one month after three doses of BEXSERO administered at 2, 3, 4 and 2, 4, 6 months of age are summarized in Table 3.

Persistence and data after a fourth dose administered at 12 months of age (following administration at 2, 3, 4 months of age in Study V72P12E1 and at 2, 4, 6 months of age in Study V72P13E1) are summarized in Table 4.

Baseline Geometric Mean Titers (GMT) were uniformly low against all strains in the BEXSERO (ranging from 1.02 to 1.49 for fHbp, NadA and PorA P1.4 antigens and from 3.15 to 3.51 for NHBA) and the control groups (ranging from 1.01 to 1.28 for fHbp, NadA and PorA P1.4 antigens and was 3.91 for NHBA) across studies. The responses one month after the third vaccination at a 2, 4, 6-month schedule were high against all antigens in the BEXSERO groups (Table 3). In contrast, the mean hSBA GMTs remained low and similar with respect to the baseline in the control groups (ranging from 1.04 to 1.25).

Table 3 - Serum Bactericidal Antibody Responses at 1 Month Following the Third Dose of BEXSERO given at 2, 3, 4 or 2, 4, 6 Months of Age
Antigen Study V72P13
2, 4, 6 months
Study V72P12
2, 3, 4 months
Study V72P16
2, 3, 4 months
fHbp % seropositivea
(95% CI)
N=1149
100% (99-100)
N=273
99% (97-100)
N=170
100% (98-100)
hSBA GMT
(95% CI)
91
(87-95)
82
(75-91)
101
(90-113)
NadA % seropositivea
(95% CI)
N=1152
100% (99-100)
N=275
100% (99-100)
N=165
99% (97-100)
hSBA GMT
(95% CI)
635
(606-665)
325
(292-362)
396
(348-450)
PorA P1.4 % seropositivea
(95% CI)
N=1152
84% (82-86)
N=274
81% (76-86)
N=171
78% (71-84)
hSBA GMT
(95% CI)
14
(13-15)
11
(9.14-12)
10
(8.59-12)
NHBA % seropositivea
(95% CI)
N=100
84% (75-91)
N=112
37% (28-46)
N=35
43% (26-61)
hSBA GMT
(95% CI)
16
(13-21)
3.24
(2.49-4.21)
3.29
(1.85-5.83)

a%seropositive = the percentage of subjects who achieved an hSBA ≥ 1:5

hSBA = Serum Bactericidal Assay using human complement

GMT = Geometric Mean Titer.

As compared with study V72P13 (2, 4, 6- month schedule), percentages of subjects with hSBA ≥1:5 against NHBA and GMTs against NHBA, NadA and PorA P1.4 were significantly lower in study V72P12 and V72P16 (2, 3, 4- month schedule) at one month after the third vaccination.

A modest response was demonstrated following vaccinations with BEXSERO at the 2, 3, 4-month schedule in studies V72P12 and V72P16 as the percentages of subjects with hSBA ≥1:5 against NHBA was 36% vs. 6%; 43% vs. 20% for the BEXSERO vs. control groups, respectively.

The antibodies against PorA and fHbp rapidly declined in infants 6 and 12 months after the third dose, respectively. However a booster response was observed following a fourth vaccine dose administered during the second year of life, consistent with adequate priming with a three-dose primary series.

Table 4 - Serum Bactericidal Antibody Responses Following a Booster at 12 Months After a Primary Series Administered at 2, 3 and 4 or 2, 4 and 6 Months of Age, and Persistence of Bactericidal Antibody One Year After the Booster
Antigen 2, 3, 4, 12 months 2, 4, 6, 12 months
fHbp pre-boostera
% seropositiveb (95% CI)
hSBA GMT (95% CI)
N=81
58% (47-69)
5.79 (4.54-7.39)
N=426
82% (78-85)
10 (9.55-12)
1 month after booster
% seropositiveb (95% CI)
hSBA GMT (95% CI)
N=83
100% (96-100)
135 (108-170)
N=422
100% (99-100)
128 (118-139)
12 months after booster
% seropositiveb (95% CI)
hSBA GMT (95% CI)
- N=299
62% (56-67)
6.5 (5.63-7.5)
NadA pre-boostera
% seropositiveb (95% CI)
hSBA GMT (95% CI)
N=79
97% (91-100)
63 (49-83)
N=423
99% (97-100)
81 (74-89)
1 month after booster
% seropositiveb (95% CI)
hSBA GMT (95% CI)
N=84
100% (96-100)
1558 (1262-1923)
N=421
100% (99-100)
1465 (1350-1590)
12 months after booster
% seropositiveb (95% CI)
hSBA GMT (95% CI)
- N=298
97% (95-99)
81 (71-94)
PorA P1.4 pre-boostera
% seropositiveb (95% CI)
hSBA GMT (95% CI)
N=83
19% (11-29)
1.61 (1.32-1.96)
N=426
22% (18-26)
2.14 (1.94-2.36)
1 month after booster
% seropositiveb (95% CI)
hSBA GMT (95% CI)
N=86
97% (90-99)
47 (36-62)
N=424
95% (93-97)
35 (31-39)
12 months after booster
% seropositiveb (95% CI)
hSBA GMT (95% CI)
- N=300
17% (13-22)
1.91 (1.7-2.15)
NHBA pre-boostera
% seropositiveb (95% CI)
hSBA GMT (95% CI)
N=69
25% (15-36)
2.36 (1.75-3.18)
N=100
61% (51-71)
8.4 (6.4-11)
1 month after booster
% seropositiveb (95% CI)
hSBA GMT (95% CI)
N=67
76% (64-86)
12 (8.52-17)
N=100
98% (93-100)
2 (36-50)
12 months after booster
% seropositiveb (95% CI)
hSBA GMT (95% CI)
- N=291
36% (31-42%)
3.35 (2.88-3.9)

apre-booster time point represents persistence of bactericidal antibody at 8 months after BEXSERO vaccination at 2, 3and 4 months of age and 6 months after BEXSERO vaccination at 2, 4 and 6 months of age.

b% seropositive = the percentage of subjects who achieved an hSBA ≥ 1:5

hSBA = Serum Bactericidal Assay using human complement
GMT = Geometric Mean Titer

Concomitant use of BEXSERO with routine vaccines

Concomitant administration of BEXSERO was studied with any of the following vaccine antigens, either as monovalent or as combination vaccines: diphtheria, tetanus, acellular pertussis, Haemophilus influenzae type b, inactivated poliomyelitis, hepatitis B, heptavalent pneumococcal conjugate, measles, mumps, rubella, and varicella.

Clinical study V72P12 demonstrated that the percentage of subjects with hSBA ≥1:5 for strain NZ98/254 was lower in the group that concomitantly administered BEXSERO and the routine vaccines (combined DTaP-IPV-HBV/Hib vaccine and heptavalent pneumococcal conjugate vaccine) than the group where they were administered separately at 1 month after the third dose. When administered alone, BEXSERO also elicited higher hSBA GMTs for all strains as compared to the concomitant group. The clinical implication of these differences remains unknown.

Inconsistent results were seen across studies for responses to inactivated poliovirus type 2 and pneumococcal conjugate serotype 6B; lower antibody titers to the pertussis pertactin antigen were also noted.
%In addition, concomitant use of BEXSERO and MMRV demonstrated non-inferiority of seroconversion (≥ 1.25 gpELISA units/mL), but not of seroprotection (≥ 5 gpELISA units/mL) for varicella after the first dose, although the difference between the groups was only 2% (95% CI, -11%, 7%). The clinical implication of these differences remains unknown.

In a clinical trial, prophylactic use of acetaminophen had no impact on the immune responses of BEXSERO and for most antigens in routine vaccines after the primary series. These data do not suggest any clinically significant interference also considering that no impact was observed on the immune responses after the booster doses.

Immunogenicity in infants aged 6 to 11 months, children aged 12 to 23 months and 2 through 10 years of age

The immunogenicity after two doses in infants and children has been documented in three studies whose results are summarized in Table 5.

Baseline GMTs were uniformly low against all three strains in the studies in 6 to 11 and 12 to 23 months of age (ranging from 1.00 to 1.70) and increased following vaccination. The increase in hSBA titers for vaccine antigens was similar in additional groups of children following BEXSERO vaccination at 12-14 and 18-20 m%onths of age. In these additional groups a similar response was also observed in terms of percentages of seropositive subjects (100% against fHbp antigen; 98-100% against NadA antigen; 93-99% against PorA P1.4 antigen; 74-86% against NHBA antigen).

In 24 to 26 months old children baseline GMTs were also low (ranging from 1.01 to 2.32 across all vaccine antigens). Additional data relative to the administration of two BEXSERO doses 2 months apart in children at 40-42 and 60-62 months of age (Studies V72P6E1, V72P9E1) were in line with the responses presented in Table 5.

Table 5 - Serum Bactericidal Antibody Responses Following BEXSERO Vaccination at 6 and 8 Months of Age (V72P9), 13 and 15 Months of Age (V72P13E1) or 24 and 26 Months of Age (V72P13E2) and Persistence of Bactericidal Antibody One Year After the Two Doses at 13 and 15 Months of Age (V72P13E2)
Antigen Age range
6 to 11
months of age
12 to 23
months of age
2 to 10
years of age
Age of vaccination
6, 8 months 13, 15 months 24, 26 months
fHbp 1 month after 2nd dose
% seropositivea
hSBA GMT
N=23
100%
250
N=163
100% (98-100)b
271 (237-310)b
N=105
100% (97-100)b
220 (186-261)b
12 months after 2nd dose
% seropositivea
hSBA GMT
- N=68
74% (61-83)b
14 (9.4-20)b
-
NadA 1 month after 2nd dose
% seropositivea
hSBA GMT
N=23
100%
534
N=164
100% (98-100)b
599 (520-690)b
N=103
99% (95-100)b
455 (372-556)b
12 months after 2nd dose
% seropositivea
hSBA GMT
- N=68
97% (90-100)b
70 (47-104)b
-
PorA P1.4 1 month after 2nd dose
% seropositivea
hSBA GMT
N=22
95%
27
N=164
100% (98-100)b
43 (38-49)b
N=108
98% (93-100)b
27 (23-32)b
12 months after 2nd dose
% seropositivea
hSBA GMT
- N=68
18% (9-29)b
1.65 (1.2-2.28)b
-
NHBA 1 month after 2nd dose
% seropositivea
hSBA GMT
- N=46
63% (48-77)b
11 (7.07-16)b
N=100
97% (91-99)b
38 (32-45)b
12 months after 2nd dose
% seropositivea
hSBA GMT
- N=65
38% (27-51)b
3.7 (2.15-6.35)b
-

a% seropositive = the percentage of subjects who achieved an hSBA ≥ 1:4 (in the 6 to 11 months range of age) and hSBA ≥ 1:5 (in the 12 to 23 months and 2 to 10 years ranges of age).
b95% Confidence Intervals are reported in brackets only for data generated from clinical studies V72P13E1 and V72P13E2 in the age range 12 to 23 months and 2 to 10 years of age.
hSBA = Serum Bactericidal Assay using human complement
GMT = Geometric Mean Titer.

Table 6 - Serum Bactericidal Antibody Responses in Adolescents or Adults One Month After Two Doses ofBEXSERO Administered According to Different Two-Dose Schedules
Antigen Adolescents Adults
V72_41
0, 1 months
V72P10
0, 1 months
V72P10
0, 2 months
V72P10
0, 6 months
V72P5
0, 1 months
V72P4
0, 2 months
fHbp %
seropositivea
N=298
99% (98-100)b
N=638
100% (99-100)b
N=319
100% (99-100)b
N=86
100% (99-100)b
N=28
100%
N=46
100%
hSBA GMT 117
(105-130)b
210
(193-229)b
234
(209-263)b
218
(157-302)b
100 93
NadA %
seropositivea
N=299
100% (99-100)b
N=639
100% (99-100)b
N=320
99% (98-100)b
N=86
99% (94-100)b
N=28
100%
N=46
100%
hSBA GMT 179
(163-197)b
490
(455-528)b
734
(653-825)b
880
(675-1147)b
566 144
PorA P1.4 %
seropositivea
N=298
75% (70-80)b
N=639
100% (99-100)b
N=319
100% (99-100)b
N=86
100% (96-100)b
N=28
96%
N=46
91%
hSBA GMT 10
(8.77-12)b
92
(84-102)b
123
(107-142)b
140
(101-195)b
47 32
NHBA %
seropositivea
- N=46
100% (92-100)b
N=46
100% (92-100)b
- - -
hSBA GMT - 99
(76-129)b
107
(82-140)b
- - -

a% seropositive = the percentage of subjects who achieved an hSBA ≥ 1:4 (in clinical studies V72P5, V72P4, and V72P10) and hSBA ≥ 1:5 (in clinical study V72_41).
b95% Confidence Intervals are reported in brackets only for clinical studies V72P10 and V72_41.
hSBA = Serum Bactericidal Assay using human complement.
GMT = Geometric Mean Titer.

In study V72P10, subjects were stratified by pre-vaccination titer baseline hSBA <1:4 or ≥1:4. The percentage of subjects with at least a 4-fold increase in hSBA titer from baseline one month after the last dose of BEXSERO is summarized in Table 7.

Table 7 - Percentage of Adolescents With Seroresponse and at Least 4-Fold Rise in Bactericidal Titers One Month After Two Doses of BEXSERO Administered According to Different Two-Dose Schedules - Stratified by Pre-Vaccination Titers
Antigen 0, 1 months 0, 2 months 0, 6 months
fHbp % seropositivea
(95% CI)
pre-vaccination
titer <1:4
N=369
100% (98-100)
N=179
100% (98-100)
N=55
100% (94-100)
pre-vaccination
titer ≥1:4
N=269
100% (99-100)
N=140
100% (97-100)
N=31
100% (89-100)
% 4-fold increase
(95% CI)
pre-vaccination titer
<1:4
N=369
100% (98-100)
N=179
100% (98-100)
N=55
100% (94-100)
pre-vaccination titer
≥1:4
N=268
90% (86-93)
N=140
86% (80-92)
N=31
90% (74-98)
NadA % seropositivea
(95% CI)
pre-vaccination
titer <1:4
N=427
100% (99-100)
N=211
99% (97-100)
N=64
98% (92-100)
pre-vaccination
titer ≥1:4
N=212
100% (98-100)
N=109
100% (97-100)
N=22
100% (85-100)
% 4-fold increase
(95% CI)
pre-vaccination titer
<1:4
N=426
99% (98-100)
N=211
99% (97-100)
N=64
98% (92-100)
pre-vaccination titer
≥1:4
N=212
96% (93-98)
N=109
95% (90-98)
N=22
95% (77-100)
PorA P1.4 % seropositivea
(95% CI)
pre-vaccination
titer <1:4
N=427
100% (98-100)
N=208
100% (98-100)
N=64
100% (94-100)
pre-vaccination
titer ≥1:4
N=212
100% (98-100)
N=111
100% (97-100)
N=22
100% (85-100)
% 4-fold increase
(95% CI)
pre-vaccination titer
<1:4
N=426
99% (98-100)
N=208
100% (98-100)
N=64
100% (94-100)
pre-vaccination titer
≥1:4
N=211
81% (75-86)
N=111
77% (68-84)
N=22
82% (60-95)
NHBA % seropositivea
(95% CI)
pre-vaccination
titer <1:4
N=2
100% (16-100)
N=9
100% (66-100)
-
pre-vaccination
titer ≥1:4
N=44
100% (92-100)
N=37
100% (91-100)
-
% 4-fold increase
(95% CI)
pre-vaccination titer
<1:4
N=2
100% (16-100)
N=9
89% (52-100)
-
pre-vaccination titer
≥1:4
N=44
30% (17-45)
N=37
19% (8-35)
-

a% seropositive = the percentage of subjects who achieved an hSBA ≥ 1:4

Detailed Pharmacology

Duration of Effect

The data on duration of immune status is not yet established.

Toxicology

Table 8 - Nonclinical Toxicology Studies
Study type, gender,
and species
Route and regimen Results
Single and repeat dose toxicity and local tolerability, male and female rabbits One or five 0.5 mL or 1 mL intramuscular doses of rMenB±OMV d(50 µg or 100 µg of each recombinant protein NHBA, NadA and fHbpa, and 25 µg of OMV NZ or NW in 1.5 mg or 3 mg Al(OH)3) two weeks apart for eight weeks No systemic adverse effects and well tolerated locally
Pilot reproductive & developmental toxicity female rabbits Five 0.5 mL or 1 mL intramuscular doses of rMenB±OMVd approx. two weeks apart. Three doses before mating and two during gestation (1Ч dose in 0.5 mL: 50 µg of each recombinant protein NHBA, NadA and fHbpa, 25 µg of OMV NZ in 1.5 mg Al(OH)3; or 2Ч dose in 1 mL, administered 0.5 mL in each leg) No systemic toxicity in maternal rabbits and no teratogenic effects
Pivotal reproductive & developmental toxicity female rabbits Five 0.5 mL intramuscular doses of rMenB±OMVd two weeks apart. Three doses before mating and two during gestation (50 µg of each recombinant protein NHBA, NadA and fHbpa, 25 µg of OMV NZ in 1.5 mg Al(OH)3) No systemic toxicity in maternal rabbits and no reproductive, embryofetal, or postnatal developmental effects
In vitro toxicity non-GLP studies in human cells HBMEC, HUVEC cellsb, human plasma or whole blood and platelet-rich plasma treated with vaccine components at various incubation times No effects on cytotoxicity, binding to human cells, cytokines production, coagulationc, platelet activation, platelet-leukocyte aggregation
Single and repeat dose toxicity and local tolerability male and female rabbits One or five 0.5 mL intramuscular doses of MenB protein 287±OMV (50 µg MenB recombinant 287 ± 25 µg OMV in 1.65 mg Al(OH)3) two weeks apart No systemic adverse effects and well tolerated locally
Reproductive & developmental toxicity female rabbits Eight 0.5 mL intramuscular doses of MeNZBTM. Three doses two weeks apart before mating and five doses every 3 to 4 days during gestation (25 µg OMV in 0.5 mL with 1.65 mg Al(OH)3 before mating; 6.25 µg, 25 µg or 50 µg OMV in 0.13 to 1 mL with Al(OH)3 during gestation) No systemic toxicity in maternal rabbits and no teratogenic effects

aproteins NHBA, NadA and fHbp also named antigens 287-953, 961c, and 936-741;
bhuman umbilical vein endothelial cells and human brain microvascular endothelial cells;
cPT, PTT and activated Protein C;
PT: prothrombin time;
PTT: partial thromboplastin time;drMenB+OMV NZ corresponds to BEXSERO