1.0
Table of Contents
Page
1.0 General Information ………..……………………………………………………………... 3
PRODUCT NAME
PRODUCT COMPOSITION
PROPOSED AGE GROUP
DOSING REGIMEN AND ROUTE OF ADMINISTRATION
2.0 Introduction and Background …………….…………………………………………..… 4
2.1 EPIDEMIOLOGY
OF MENIGOCOCCAL INFECTIONS IN ADOLESCENTS AND ADULTS 4
2.2 IMMUNE CORRELATE: SERUM BACTERICIDAL ANTIBODY 4
2.3 EGULATORY
BACKGROUND 4
3.0 Clinical Overview ………………………………………………………………………….. 5
4.0 Efficacy Data
(Immunogenicity) ………………………………………………………….. 11
4.1 MTA-02: Safety,
Immunogenicity in Adolescents 11-18 years old ……………………. 12
4.2 MTA-09: Safety, Immunogenicity in Adults 18-55 years
old ……………………….. 14
5.0 Safety Data …………………………………………………………………………………. 17
5.1 MTA-04: Expanded
Safety Study in Adolescents 11-18 years old
…………………… 19
5.2 MTA-02: Safety,
Immunogenicity in Adolescents 11-18 years old ……………………… 22
5.3 MTA-09:
Safety, Immunogenicity in Adults 18-55 years old ………………………… 23
5.4 MTA-14:
Lot consistency in Adults 18-55 years old
…………………………………. 27
5.5 Serious Adverse Events and safety assessment
6 months post-vaccination …………… 29
6.0 Concurrent Immunization …………………………………………………………………. 29
6.1 MTA-11: Concomitant Administration with TyphimViâ
Vaccine in Adults ………… 29
6.2 MTA-12: Concomitant Administration with Td vaccine in
Adolescents …………….. 38
7.0 Lot
Consistency
…………………………………………………………………………….. 46
7.1 MTA-14: Lot consistency in Adults 18-55 years
old ………………………………… 46
REFERENCES ……………………………………………………………………………………… 48
1.0
General Information
Product name
Generic name: Meningococcal (Groups
A,C,Y,W135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine
Proposed trade name: Menactra
Product composition: Each 0.5ml dose contains
·
4ug
of polysaccharide (PS) for serogroup A
·
4ug
of polysaccharide (PS) for serogroup C
·
4ug
of polysaccharide (PS) for serogroup Y
·
4ug
of polysaccharide (PS) for serogroup W135
·
48ug
diphtheria toxoid protein total (Each PS is conjugated to diphtheria toxoid)
·
0.6 mg sodium phosphate
·
4.4mg sodium chloride
The
vaccine contains neither an adjuvant nor preservative.
Sponsor: Aventis
Pasteur Inc.
Proposed indication: Active immunization of
adolescents and adults for prevention of invasive
disease caused by Neisseria meningitidis serogroups A, C, Y and W135
Proposed age group: 11-55 years old
Dosing
regimen and
Route of administration: Single dose, intramuscularly
2.0
Introduction and Background
2.1
Epidemiology of meningococcal infections in adolescents and adults
Meningitis and meningococcemia are common
manifestations of invasive disease due to Neisseria meningitidis (N.
meningitidis). Other clinical
presentations of meningococcal disease include pneumonia and occult
bacteremia. During 1991-1998, increased
numbers of meningococcal cases were reported in the United States among persons
aged 18-23 years old (1.4/106 population), compared with the general
population (1.1/ 106 population).1 The highest rate of meningococcal disease
continues to occur in children younger than one year of age. Approximately 50% of meningococcal disease
in this age group is due to serogroup B.1
The epidemiology of meningococcal disease in the
United States has changed in the last 15 years.
The
proportion of meningococcal disease due to serogroup Y increased from 2%,
during 1989-1991, to 30% during 1992-1996.2 There have also been increased reports of
localized serogroup C outbreaks. Eight
outbreaks occurred during a two-year timeframe [1991-1993], compared with 13
outbreaks in the previous decade [1980-1990].3 Cases of serogroup W135 meningococcal
disease were also reported in association with an outbreak among travelers
returning from the Hajj, in 2000-2001.4 The mortality rate due to meningococcal disease overall is 7 to
19%, and for meningococcemia, 18-53%.
The case-fatality rate due to serogroup W135, C and Y, during 1992-1996
was 21%, 14%, and 9%, respectively.2 Despite susceptibility of N. meningitidis to many
antibiotics, approximately 10-20% of individuals
with meningococcal disease experience permanent sequelae (e.g. limb loss,
neurosensory hearing loss, cognitive deficits, seizure disorder).5-7
2.2
Immune Correlate: Serum Bactericidal Antibody
The presence of bactericidal antibody has been shown to correlate with
both natural and vaccine-induced protection against meningococcal disease. The basis for accepting serum bactericidal
antibody as an immunologic correlate originated from studies conducted in the
1960’s. 8,9 Military recruits with naturally acquired bactericidal
antibody were shown to be protected from meningococcal group C disease. The presence of bactericidal antibody was
determined using a serum bactericidal assay (SBA) with a human complement (HC)
source. A positive result, which
indicated the presence of complement mediated anti-meningococcal group C
antibody killing, was qualitatively measured at an estimated dilution of 1:
4.
In vitro measurement of bactericidal
antibody was indicative of functional activity in vivo, and serum bactericidal antibody was hence considered to be
a reliable predictor of vaccine effectiveness for serogroups A, C, Y and
W135.
2.3
Regulatory background
2.3.1
Use of Immunologic Correlates for Licensure of Meningococcal Vaccines
Demonstration of efficacy, inferred from immunogenicity data, was an
approach used as a basis for U.S. licensure of a meningococcal quadrivalent
polysaccharide (PS) vaccine, Menomuneâ. The primary measure of immune response was the proportion of
participants who achieved a four-fold or greater increase in serum bactericidal
antibody to each serogroup. Use of
immunologic correlates, as a basis of vaccine effectiveness, was discussed at a
Vaccines and Related Biological Products
Advisory Committee
(VRBPAC) meeting on September 15, 1999,10
as an
approach to support approval of new meningococcal conjugate vaccines. The outcomes of the VRBPAC meeting which pertain to the
proposed age group in this biologics license application, are as follows:
Ø
Use of an immunologic correlate to determine effectiveness
of new meningococcal conjugate vaccines is acceptable
Ø
In
individuals for which the current meningococcal PS vaccine is licensed, serum
bactericidal antibody can be used as a predictor of vaccine efficacy
2.3.2
Basis for Licensure
Proposed licensure of Menactra is based on
the following aspects
·
Demonstration of efficacy (immunogenicity) compared
to Menomuneâ
·
Demonstration of safety compared to Menomuneâ
·
Demonstration of lot consistency
3.0
Clinical Studies- Overview
The license application included safety and
immunogenicity data from six clinical studies and one supplemental study. Safety data from two additional supporting
studies was also included.
|
Study
|
Description
|
Study
|
Subjects: Menactra: Menomuneâ (Ma:Me)
|
|
Protocol:
|
|
Population
|
Planned
|
Enrolled
|
|
|
|
|
N
|
Ma:Me
|
N
|
Ma:Me
|
|
Pivotal
Studies
|
|
|
|
|
|
|
|
MTA-02
|
Safety +
|
11-18 yrs
|
812
|
406: 406
|
881
|
440: 441
|
|
USA
|
Immunogenicity
|
|
|
|
|
|
|
MTA-04
|
Safety
|
11-18 yrs
|
3178
|
2222: 956
|
3242
|
2270: 972
|
|
USA
|
|
|
|
|
|
|
|
MTA-09
|
Safety +
|
18-55 yrs
|
2455
|
1333: 1122
|
2554
|
1384: 1170
|
|
USA
|
Immunogenicity
|
|
|
|
|
|
|
MTA-14
|
|
18-55 yrs
|
2039
|
1599+
|
2040
|
1582+
|
|
USA
|
Lot
consistency
|
26-55 yrs
|
|
440
|
|
458
|
|
|
|
|
|
|
|
|
|
MTA-11
|
Concomitant
Vaccination:
|
18-55 yrs
|
890
|
Gr A: 445
|
945
|
Gr A: 469
|
|
USA
|
Typhim Vi
eval.
|
|
|
Gr B: 445
|
|
Gr B: 476
|
|
MTA-12
|
Concomitant
Vaccination:
|
11-17 yrs
|
1024
|
Gr A: 512
|
1081
|
Gr A: 509
|
|
USA
|
Td eval.
|
|
|
Gr A: 512
|
|
Gr B: 512
|
|
Supplemental
Studies- adults
|
|
|
|
|
|
|
603-01
|
Dose
escalation,
|
18-55 yrs
|
|
30*:0
|
|
30*:0
|
|
USA
|
Safety +
Immuno
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Total
11-55y:
|
|
Planned:
|
N= 10, 428
|
Enrolled:
|
N= 10, 713
|
|
|
|
|
|
Menactra: 7504
|
|
Menactra: 7672
|
|
|
|
|
|
Menomune: 2924
|
|
Menomune: 3041
|
|
+MTA-14: Menactra [n= 533 planned per lot]; [n= 527
enrolled for lots 1&3 (each), n= 528 enrolled for lot 2]
|
|
*603-01: 30 adult
participants received a 4ug dose, the dose selected for the final
formulation. Sixty additional adults
were enrolled and received a 1 or 10ug Menactra dose (n= 30 subjects/ dose).
|
Other supporting studies:
·
Study 603-02, a safety and immunogenicity study
in healthy U.S. children 2-10 years old
·
Study MTA-08, an expanded safety study in
healthy U.S. and Chilean children 2-10 years old
3.1 Control vaccine: Menomuneâ
A/C/Y/W135
The
active control vaccine implemented in the comparative immunogenicity and safety
studies was Menomuneâ A/C/Y/W135. Each 0.5 ml dose contains 50ug of “isolated
product” from each serogroup, and is formulated as lyophilized powder in a
single-dose vial. Lactose is added as a
stabilizer (2.5-5 mg). Following reconstituted
with sterile water, the vaccine appears as a clear, colorless, liquid. A single dose was administered
subcutaneously.
3.2 Menactra bactericidal antibody results, using baby rabbit and
human complement, compared to Menomuneâ:
Human sera that lack
anti-meningococcal antibodies are a difficult source of exogenous complement to
locate. In contrast, baby rabbit sera
are widely available, and assay results using this complement source are highly
reproducible. Serogroup C meningococcal
antibody titers, generated from an assay with a rabbit complement source, have
been shown to be elevated relative to results using human complement. Consequently, SBA-BR results might
overestimate efficacy against group C meningococcus. Less bactericidal antibody data, generated from assays with the
two complement sources, are available for serogroups A, Y and W135.
The sponsor was asked to test sera from Menactra and Menomuneâ participants vaccinated in
the same clinical studies, with both a bactericidal assay using baby rabbit
complement and an assay using exogeneous human complement. Analyses were based on the participants for
whom sufficient sera were available.
Pre- and post-vaccination sera were collected from 165 (Menactra n= 84,
Menomune®, n=81) non-randomized participants enrolled in study MTA-02 (11-18
years old), and 100 (n= 50 per group) participants in study MTA-09 (18-55 years
old). Antibody results for serogroups
C, Y and W135 were generated from sera obtained from study MTA-02, and data for
serogroups Y and W135, from study MTA-09.
Sera from separate subset of 102 MTA-02 participants were used for
serogroup A antibody results.
Immune responses were assessed by reverse cumulative
distribution curves, seroresponse and seroconversion rates. The seroresponse rate was defined as the
proportion of participants with > four-fold increase in SBA-BR titer
post-vaccination, compared to baseline.
Seroconversion rate was defined as the proportion of participants with SBA-BR antibody titer less
than 1:8 pre-vaccination, who subsequently achieved a four-fold or greater
increase in SBA-BR antibody titer 28 days following vaccination. For SBA-H results, seroresponse rate was
defined as the proportion of participants with SBA-H titer > 4
post-vaccination. Seroconversion rate
was also defined as the proportion of participants with SBA-H antibody titer less
than 1:4 pre-vaccination, who subsequently achieved a titer of >1: 4,
twenty-eight days following vaccination.
Menactra SBA antibody responses, compared to Menomune,
showed general agreement by comparison of reverse cumulative distributions
curves, seroresponse
and seroconversion rates. The sample
size, however, was not large enough to make definite conclusions. Assay sensitivity and specificity were not
noticeably different among two populations (adolescents, adults), serogroup (A,
C, Y, W135), or vaccine (polysaccharide, conjugate). Misclassification of seroresponders that might occur when SBA
results are generated with a rabbit complement source were similarly
represented in the two vaccine groups and results were without bias towards
Menomune® or Menactra. True
susceptible individuals, predicted by a SBA-H titer < 4, however, were not
the same susceptible individuals identified by the SBA-BR assay. Thus, the SBA-BR assay has utility as an
indicator of vaccine –induced antibody response on a population basis, and is
less predictive of individual susceptibility to meningococcal disease.
11-18 years old:
Seroresponse Rate:
SBA-BR
|
Serogroup
|
Menomune (Me)
|
Menactra (Ma)
|
Diff
|
95% CI for the Difference
|
|
(Me-Ma)
|
|
|
N
|
Proportion
|
N
|
Proportion
|
|
|
|
A
|
52
|
0.98
|
50
|
0.88
|
0.1
|
-0.00, 0.22
|
|
C
|
81
|
0.9
|
84
|
0.89
|
0.01
|
-0.09, 0.11
|
|
Y
|
62
|
0.81
|
65
|
0.94
|
-0.13
|
-0.26, -0.02
|
|
W
|
58
|
0.97
|
61
|
0.97
|
0
|
-0.09, 0.08
|
SBA-H
|
Serogroup
|
Menomune (Me)
|
Menactra (Ma)
|
Diff
|
95% CI for the Difference
|
|
(Me-Ma)
|
|
|
N
|
Proportion
|
N
|
Proportion
|
|
|
|
A
|
52
|
0.96
|
50
|
0.94
|
0.02
|
-0.08, 0.13
|
|
C
|
81
|
0.86
|
84
|
0.94
|
-0.08
|
-0.18, 0.02
|
|
Y
|
62
|
0.95
|
65
|
0.94
|
0.01
|
-0.08, 0.11
|
|
W
|
58
|
0.93
|
61
|
0.98
|
-0.05
|
-0.15, 0.03
|
Seroconversion
Rate:
SBA-BR
|
Serogroup
(11-18 yrs old)
|
Menomune (Me)
|
Menactra (Ma)
|
Diff
|
95% CI for the Difference
|
|
(Me-Ma)
|
|
|
N
|
Proportion
|
N
|
Proportion
|
|
|
|
A
|
11
|
1
|
12
|
1
|
0
|
-0.29, 0.27
|
|
C
|
62
|
0.9
|
57
|
0.95
|
-0.04
|
-0.15, 0.06
|
|
Y
|
39
|
0.9
|
41
|
0.93
|
-0.03
|
-0.18, 0.11
|
|
W
|
23
|
1
|
22
|
0.95
|
-0.05
|
-0.11, 0.23
|
SBA-H
|
Serogroup
(11-18 yrs old)
|
Menomune (Me)
|
Menactra (Ma)
|
Diff
|
95% CI for the Difference
|
|
(Me-Ma)
|
|
|
N
|
Proportion
|
N
|
Proportion
|
|
|
|
A
|
11
|
0.91
|
12
|
0.92
|
-0.01
|
-0.34, 0.31
|
|
C
|
62
|
0.82
|
57
|
0.91
|
-0.09
|
-0.22, 0.04
|
|
Y
|
39
|
0.92
|
41
|
0.93
|
-0.004
|
-0.15, 0.13
|
|
W
|
23
|
0.83
|
22
|
0.95
|
-0.13
|
-0.35, 0.08
|
18-55
year old:
SBA-BR
|
Serogroup
|
Menomune (Me)
|
Menactra (Ma)
|
Diff
|
95% CI
|
|
(Me-Ma)
|
|
|
N
|
Proportion
|
N
|
Proportion
|
|
|
|
Seroresponse
Rate
|
|
|
|
|
|
|
|
50
|
0.72
|
50
|
0.80
|
-0.08
|
-0.25, 0.09
|
|
|
50
|
0.94
|
50
|
0.96
|
-0.02
|
-0.13, 0.08
|
|
Seroconversion
Rate
|
|
|
|
|
|
|
Y
|
17
|
0.88
|
18
|
1
|
-0.12
|
-0.37, 0.08
|
|
W
|
9
|
1
|
8
|
0.89
|
0.11
|
-0.26, 0.48
|
SBA-H:
|
Serogroup
|
Menomune (Me)
|
Menactra (Ma)
|
Diff
|
95% CI
|
|
(Me-Ma)
|
|
|
N
|
Proportion
|
N
|
Proportion
|
|
|
|
Seroresponse
Rate
|
|
|
|
|
|
|
Y
|
50
|
1
|
50
|
0.96
|
0.04
|
-0.03, 0.14
|
|
W
|
50
|
1
|
50
|
1
|
0
|
-0.07, 0.07
|
|
Seroconversion
Rate
|
|
|
|
|
|
|
Y
|
17
|
1
|
18
|
0.89
|
0.11
|
-0.10, 0.35
|
|
W
|
9
|
1
|
8
|
1
|
0
|
-0.35, 0.37
|
4.0
Efficacy Data (Immunogenicity)
Immunogenicity data from the following clinical
trials were the basis of inferring the efficacy of Menactra:
·
Study MTA-02: A Comparative Trial of the Safety and Immunogenicity of Menactra
versus Menomune® A/C/Y/W-135 in Adolescents
11-18 years old
·
Study MTA-09: A Comparative Trial of the Safety and Immunogenicity of Menactra
versus Menomune® A/C/Y/W-135 in Adults 18-55
years old
Assessment of
Immunogenicity:
The primary endpoint was
the proportion of participants achieving a four-fold or greater increase in
serum bactericidal antibody, to serogroups A, C, Y, and W135. Other parameters of immune response were
also provided (seroconversion, GMT, geometric mean fold rise, reverse
cumulative distribution curve, group-specific anti-meningococcal PS antibody
measured by ELISA).
Vaccine
Administration
Menactra
was administered as a single dose intramuscularly.
Control
vaccine
The active control vaccine implemented in both studies
was Menomuneâ A/C/Y/W135. Each 0.5 ml dose contains 50ug of “isolated
product” from each serogroup, and is formulated as lyophilized powder in a
single-dose vial. Lactose is added as a
stabilizer (2.5-5 mg). Following
reconstituted with sterile water, the vaccine appears as a clear, colorless,
liquid. A single dose was
administered subcutaneously.
Surveillance (Immunogenicity):
Serum
samples were obtained pre- and 28 days post-vaccination. For all study participants, functional antibody activity
to each serogroup, was determined using a serum bactericidal assay. In a subset of 160 MTA-02 participants,
group-specific IgG and IgM antibody were measured by ELISA.
Laboratory Methods
All
assays were performed at Aventis Pasteur, Inc.
Anti-Meningococcal Antibody Determination by Serum
Bactericidal Assay
Functional antibody activity to each serogroup was
determined using a serum bactericidal assay, which is an adaptation of the CDC
method recommended by the WHO Expert Committee of the Department of Vaccines
and Biologicals.11,12 The lower limit of
detection for this assay, using baby
rabbit complement, is a titer of 1: 8.
IgG and IgM Anti-Meningococcal Antibody Determination
IgG and IgG antibody activity for anti-meningococcal
antibody to serogroups A, C, Y, and W-135 was measured using an indirect ELISA.
Populations for Analysis
Per-protocol
population for immunogenicity:
The per-protocol population included all eligible participants
who received one dose of vaccine according to the treatment assignment, who
complied with scheduled visits for blood specimens, and for whom a sufficient
quantity of paired sera was available for analysis. The primary analysis was based on the per-protocol population.
Intent-to-treat
population for immunogenicity:
The intent-to-treat
population consisted of all enrolled participants who received one dose of
vaccine and underwent the first blood draw.
Analyses were performed according to the vaccine
received.
For
analysis purposes, if the SBA-BR antibody titer to any serogroup was reported
below the limit of detection, the antibody titer assigned was a value equal to
the limit of detection.
4.1
Study MTA-02
Title: A Comparative Trial of the Safety and
Immunogenicity of One Dose of an Experimental Tetravalent (A, C, Y, and W-135)
Meningococcal Diphtheria Conjugate Vaccine versus Menomune® A/C/Y/W-135 in Healthy Adolescents in the U.S.
Immunogenicity Objectives
·
Primary objective: To describe and compare the antibody response to serogroups A, C, Y,
W135, using baby rabbit complement (SBA-BR), among healthy adolescents
immunized with Menactra with the SBA-BR responses following vaccination with a
licensed meningococcal polysaccharide vaccine.
·
Other objectives:
ü To describe and compare the SBA-BR response to each
serogroup pre- and 28 days post-vaccination for Menactra and Menomune® recipients.
ü To compare serogroup-specific IgG and IgM antibody
levels pre- and 28 days post-vaccination in a subset of Menactra and Menomune® recipients.
ü
To describe and compare
the proportion of participants who achieve seroconversion 28 days following a
single dose of either Menactra or Menomune®.
Design: The
study was a randomized, modified double blind, multi-center, active-controlled
trial. Participants were randomized in
a 1: 1 (Menactra: Menomune®) ratio. Participants were enrolled at eleven study centers
in the United States.
Primary Immunogenicity Endpoint
The
proportion of participants with a >4-fold rise in SBA-BR titer for N.
meningitidis serogroups A, C, Y and W-135 28 days post-vaccination,
compared to baseline.
Statistical
plan
Primary Hypothesis
To demonstrate that 28 days
after vaccination, Menactra is non-inferior to Menomune® by proportion of participants
with a >4-fold rise in SBA-BR titer for N. meningitidis serogroups
A, C, Y and W-135.
This hypothesis would be
supported by the data if the upper
limit of the one-sided 95% confidence interval (CI) of pMenomune® – pMenactra is less than 0.10, where p represents the
proportion of participants with a >4-fold rise in SBA-BR titer as
compared to baseline, for each serogroup, respectively. The sample size provided 90% power, overall,
to achieve the primary hypothesis for serogroups C, Y and W135. All tests of the primary hypothesis were
conducted at the 0.05 significance level.
The primary hypothesis was modified during the trial to include demonstration of equivalence
for serogroup A. Hence, the sample size
and power calculations do not include hypothesis testing for this
serogroup. The primary analysis was
based on data generated from the per-protocol population.
CBER recommendations for
non-inferiority hypothesis testing have evolved since the conduct of this
trial. Comparisons are currently based
on the upper limit of the two-sided 95% confidence interval for the difference
in two proportions.
Results
A
total of 881 (Menactra n=440, Menomune® n= 441) adolescents
were enrolled, and 871 (Menactra n=436, Menomune® n= 435) individuals
completed the study. The per protocol population
for immunogenicity included 425 Menactra and 423 Menomune® participants.
Demographic characteristics: The distribution of participants, based on age, gender, race and
ethnicity, was similar among the two vaccine groups. The study population enrolled was predominately Caucasian
(95.2%), but also included African American (3.3%), Hispanic (0.3%), Asian
populations (0.2%) and individuals with mixed racial background (0.9%).
|
MTA-02: Primary Hypothesis Testing
Number and Proportion of Participants 11-18 Years Old with a
>Four-fold Increase in SBA-BR Titer
|
|
|
Menomune®
|
Menactra
|
|
Upper Limit of the
|
Upper Limit of the
|
|
Serogroup
|
N= 423
|
N= 423
|
Difference
|
1-sided 95% CI
|
2-sided 95% CI
|
|
|
n*
|
pMenomune®†
|
|
