Vaccines and Related Biological Products Advisory Committee

**Meeting Date: September 22, 2004**

**FDA Clinical Briefing Document for**

**Aventis Pasteur Inc.**

**Menactra^TM^: Tetravalent Meningococcal Conjugate Vaccine**

**Lucia H. Lee, M.D.**

**CBER/FDA**

1.  

## Table of Contents

#  Page

**1.0 General Information**
................................................................................\...
**3**

PRODUCT NAME

PRODUCT COMPOSITION

PROPOSED INDICATION

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 TyphimVi^^ 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.  **General Information**

> **[Product name]{.underline}**
>
> **Generic name:** Meningococcal (Groups A,C,Y,W135) Polysaccharide
> Diphtheria Toxoid Conjugate Vaccine
>
> **Proposed trade name:** Menactra
>
> **[Product composition:]{.underline}** 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:]{.underline}** Aventis Pasteur Inc.
>
> **[Proposed indication:]{.underline}** 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]{.underline} 

> **[Route of administration:]{.underline}** Single dose,
> intramuscularly

2.  **Introduction and Background**

    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 (1.4/10^6^ population), compared with the general population (1.1/
10^6^ 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.  **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.

3.  **Regulatory background**

    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, Menomune^^. 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:

-   Use of an immunologic correlate to determine effectiveness of new
    meningococcal conjugate vaccines is acceptable

-   In individuals for which the current meningococcal PS vaccine is
    licensed, serum bactericidal antibody can be used as a predictor of
    vaccine efficacy

    1.  **Basis for Licensure**

Proposed licensure of Menactra is based on the following aspects

-   Demonstration of efficacy (immunogenicity) compared to Menomune^^

-   Demonstration of safety compared to Menomune^^

-   Demonstration of lot consistency

3.  **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:                                   
                                                      Menomune**^^                               
                                                      **(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       18-55 yrs        890             Gr A: 445   945             Gr A: 469
                   Vaccination:                                                                   

  USA              Typhim Vi eval.                                    Gr B: 445                   Gr B: 476

  **MTA-12**       Concomitant       11-17 yrs        1024            Gr A: 512   1081            Gr A: 509
                   Vaccination:                                                                   

  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                            **Planned:**                     **N= 10,    **Enrolled:**   **N= 10,
  11-55y:**                                                           428**                       713**

  ** **                              ** **                            Menactra:   ** **           Menactra:
                                                                      7504                        7672

                                                                      Menomune:                   Menomune:
                                                                      2924                        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:]{.underline}

-   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: Menomune^^ A/C/Y/W135**

The active control vaccine implemented in the comparative immunogenicity
and safety studies was Menomune^^ 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 Menomune^^:**

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 Menomune^^
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 [\>]{.underline}
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 [\>]{.underline} 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
[\>]{.underline}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.

[SBA-BR Reverse cumulative distributions curves (11-18 years
old)]{.underline}

#####  Serogroup A Serogroup C

![](media/image1.png){width="4.78740157480315in"
height="2.9543307086614172in"}![](media/image2.png){width="5.0437007874015745in"
height="2.769291338582677in"}![](media/image3.png){width="5.0437007874015745in"
height="2.9543307086614172in"}![](media/image4.png){width="5.1299212598425195in"
height="2.790944881889764in"}

###### 

###### 

###### 

###### 

###### 

###### 

###### 

###### 

###### 

###### 

###### 

######  Serogroup Y Serogroup W135

[SBA-H Reverse cumulative distributions curves (11-18 years
old):]{.underline}

[Serogroup A]{.underline} [Serogroup C]{.underline}

![](media/image5.png){width="5.119291338582677in"
height="2.7791338582677168in"}![](media/image6.png){width="5.21259842519685in"
height="2.37007874015748in"}![](media/image7.png){width="5.21259842519685in"
height="2.484645669291339in"}![](media/image8.png){width="5.309055118110236in"
height="2.8625984251968504in"}

[Serogroup Y]{.underline} [Serogroup W135]{.underline}

[11-18 years old:]{.underline}

[Seroresponse Rate:]{.underline}

[SBA-BR]{.underline}

  ----------- ---------- ------------ ---------- ------------ --------- ------------
  Serogroup   Menomune                Menactra                Diff      95% CI for
              (Me)                    (Ma)                              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                Menactra                Diff      95% CI for
              (Me)                    (Ma)                              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:]{.underline}

SBA-BR

+----------+--------+--------+------+-------+-------+---------------+
| S        | Me     |        | Mena |       | Diff  | 95% CI for    |
| erogroup | nomune |        | ctra |       |       | the           |
|          | (Me)   |        | (Ma) |       |       | Difference    |
| (11-18   |        |        |      |       |       |               |
| yrs old) |        |        |      |       |       |               |
+----------+--------+--------+------+-------+-------+---------------+
|          |        |        |      |       | (M    |               |
|          |        |        |      |       | e-Ma) |               |
+----------+--------+--------+------+-------+-------+---------------+
|          | N      | Prop   | N    | Propo |       |               |
|          |        | ortion |      | rtion |       |               |
+----------+--------+--------+------+-------+-------+---------------+
| 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

+----------+--------+--------+------+-------+-------+---------------+
| S        | Me     |        | Mena |       | Diff  | 95% CI for    |
| erogroup | nomune |        | ctra |       |       | the           |
|          | (Me)   |        | (Ma) |       |       | Difference    |
| (11-18   |        |        |      |       |       |               |
| yrs old) |        |        |      |       |       |               |
+----------+--------+--------+------+-------+-------+---------------+
|          |        |        |      |       | (M    |               |
|          |        |        |      |       | e-Ma) |               |
+----------+--------+--------+------+-------+-------+---------------+
|          | N      | Prop   | N    | Propo |       |               |
|          |        | ortion |      | rtion |       |               |
+----------+--------+--------+------+-------+-------+---------------+
| 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  | -     | -0.15, 0.13   |
|          |        |        |      |       | 0.004 |               |
+----------+--------+--------+------+-------+-------+---------------+
| W        | 23     | 0.83   | 22   | 0.95  | -0.13 | -0.35, 0.08   |
+----------+--------+--------+------+-------+-------+---------------+

[18-55 year old:]{.underline}

SBA-BR

  ---------------- ---------- ------------ ---------- ------------ --------- ---------------
  Serogroup        Menomune                Menactra                Diff      95% CI
                   (Me)                    (Ma)                              

                                                                   (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                Menactra                Diff      95% CI
                   (Me)                    (Ma)                              

                                                                   (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.  **Efficacy Data (Immunogenicity)**

Immunogenicity data from the following clinical trials were the basis of
inferring the efficacy of Menactra:

-   **[Study MTA-02:]{.underline}** 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:]{.underline}** A Comparative Trial of the Safety
    and Immunogenicity of Menactra versus Menomune^®^ A/C/Y/W-135 in
    Adults 18-55 years old

The primary endpoint, vaccine administration, surveillance, laboratory
methods, and population for analysis were the same in both trials, as
are described below:

**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]{.underline}

The active control vaccine implemented in both studies was Menomune^^
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]{.underline}

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.

1.  **[Study MTA-02]{.underline}**

**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:]{.underline} 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.

```{=html}
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-   [Other objectives:]{.underline}

```{=html}
<!-- -->
```
-   To describe and compare the SBA-BR response to each serogroup pre-
    and 28 days post-vaccination for Menactra and Menomune^®^
    recipients.

-   To compare serogroup-specific IgG and IgM antibody levels pre- and
    28 days post-vaccination in a subset of Menactra and Menomune^®^
    recipients.

-   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]{.underline}**

The proportion of participants with a [\>]{.underline}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]{.underline}**

**To demonstrate that 28 days after vaccination, Menactra is
non-inferior to Menomune^®^ by proportion of participants with a
[\>]{.underline}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 *p*~Menomune®~ --
*p*~Menactra~ is less than 0.10, where *p* represents the proportion of
participants with a [\>]{.underline}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: Pr |   |        |   |       |         |           |            |
| imary  |   |        |   |       |         |           |            |
| Hypoth |   |        |   |       |         |           |            |
| esis T |   |        |   |       |         |           |            |
| esting |   |        |   |       |         |           |            |
|        |   |        |   |       |         |           |            |
| ###    |   |        |   |       |         |           |            |
| #### N |   |        |   |       |         |           |            |
| umber  |   |        |   |       |         |           |            |
| and Pr |   |        |   |       |         |           |            |
| oporti |   |        |   |       |         |           |            |
| on of  |   |        |   |       |         |           |            |
| Partic |   |        |   |       |         |           |            |
| ipants |   |        |   |       |         |           |            |
|  11-18 |   |        |   |       |         |           |            |
|  Years |   |        |   |       |         |           |            |
|  Old w |   |        |   |       |         |           |            |
| ith a  |   |        |   |       |         |           |            |
| \>Four |   |        |   |       |         |           |            |
| -fold  |   |        |   |       |         |           |            |
| Increa |   |        |   |       |         |           |            |
| se in  |   |        |   |       |         |           |            |
| SBA-BR |   |        |   |       |         |           |            |
|  Titer |   |        |   |       |         |           |            |
+--------+---+--------+---+-------+---------+-----------+------------+
|        | * |        | * |       |         | **Upper   | **Upper    |
|        | * |        | * |       |         | Limit of  | Limit of   |
|        | M |        | M |       |         | the**     | the**      |
|        | e |        | e |       |         |           |            |
|        | n |        | n |       |         |           |            |
|        | o |        | a |       |         |           |            |
|        | m |        | c |       |         |           |            |
|        | u |        | t |       |         |           |            |
|        | n |        | r |       |         |           |            |
|        | e |        | a |       |         |           |            |
|        | ^ |        | * |       |         |           |            |
|        | ® |        | * |       |         |           |            |
|        | ^ |        |   |       |         |           |            |
|        | * |        |   |       |         |           |            |
|        | * |        |   |       |         |           |            |
+--------+---+--------+---+-------+---------+-----------+------------+
| *      | N |        | N |       | **Diffe | **1-sided | **2-sided  |
| *Serog | = |        | = |       | rence** | 95% CI**  | 95% CI**   |
| roup** | 4 |        | 4 |       |         |           |            |
|        | 2 |        | 2 |       |         |           |            |
|        | 3 |        | 3 |       |         |           |            |
+--------+---+--------+---+-------+---------+-----------+------------+
|        | * | *      | * | ***   | (*p*    | **of the  | **of the   |
|        | * | **p*~M | * | P*~Me | ~Menomu | Differ    | Diffe      |
|        | n | enomun | n | nactr | ne®\ -~ | ence^§^** | rence^§^** |
|        | * | e®~**† | * | a~**‡ | *p*~Men |           |            |
|        | * |        | * |       | actra~) |           |            |
|        | \ |        | \ |       |         |           |            |
|        | * |        | * |       |         |           |            |
+--------+---+--------+---+-------+---------+-----------+------------+
| **A**  | 3 | 0.924  | 3 | 0.926 | -0.002  | 0.027     | 0.033      |
|        | 9 |        | 9 |       |         |           |            |
|        | 1 |        | 2 |       |         |           |            |
+--------+---+--------+---+-------+---------+-----------+------------+
| **C**  | 3 | 0.886  | 3 | 0.917 | -0.031  | 0.003     | 0.009      |
|        | 7 |        | 8 |       |         |           |            |
|        | 5 |        | 8 |       |         |           |            |
+--------+---+--------+---+-------+---------+-----------+------------+
| **Y**  | 3 | 0.801  | 3 | 0.818 | -0.017  | 0.028     | 0.036      |
|        | 3 |        | 4 |       |         |           |            |
|        | 9 |        | 6 |       |         |           |            |
+--------+---+--------+---+-------+---------+-----------+------------+
| **W    | 4 | 0.952  | 4 | 0.966 | -0.014  | 0.008     | 0.013      |
| -135** | 0 |        | 0 |       |         |           |            |
|        | 3 |        | 9 |       |         |           |            |
+--------+---+--------+---+-------+---------+-----------+------------+

\*n: number of participants with ≥ 4-fold rise from baseline SBA-BR
titer. N: total number of participants with valid serology data.

† *p*~Menomune®~: proportion of Menomune^®^ participants with a ≥4-fold
rise in SBA-BR titer post-vaccination compared with baseline.

‡ *p*~Menactra:~ proportion of Menactra participants with a ≥ 4-fold
rise in SBA-BR titer post-vaccination compared with baseline.

§ CI: Confidence interval.

[Serum bactericidal antibody:]{.underline}

+---------+----+------------+---------+----+-----------+------------+
| **      |    |            |         |    |           |            |
| MTA-02: |    |            |         |    |           |            |
| Number  |    |            |         |    |           |            |
| and     |    |            |         |    |           |            |
| Per     |    |            |         |    |           |            |
| centage |    |            |         |    |           |            |
| of      |    |            |         |    |           |            |
| Parti   |    |            |         |    |           |            |
| cipants |    |            |         |    |           |            |
| 11-18   |    |            |         |    |           |            |
| Years   |    |            |         |    |           |            |
| Old     |    |            |         |    |           |            |
| Ac      |    |            |         |    |           |            |
| hieving |    |            |         |    |           |            |
| a       |    |            |         |    |           |            |
| [\      |    |            |         |    |           |            |
| >]{.und |    |            |         |    |           |            |
| erline} |    |            |         |    |           |            |
| Fo      |    |            |         |    |           |            |
| ur-fold |    |            |         |    |           |            |
| I       |    |            |         |    |           |            |
| ncrease |    |            |         |    |           |            |
| in      |    |            |         |    |           |            |
| SBA-BR  |    |            |         |    |           |            |
| A       |    |            |         |    |           |            |
| ntibody |    |            |         |    |           |            |
| Titer,  |    |            |         |    |           |            |
| with    |    |            |         |    |           |            |
| 95%CI** |    |            |         |    |           |            |
+---------+----+------------+---------+----+-----------+------------+
|         | *  |            |         | ** |           |            |
|         | *M |            |         | Me |           |            |
|         | en |            |         | na |           |            |
|         | om |            |         | ct |           |            |
|         | un |            |         | ra |           |            |
|         | e^ |            |         | ** |           |            |
|         | ®^ |            |         |    |           |            |
|         | ** |            |         |    |           |            |
+---------+----+------------+---------+----+-----------+------------+
| **Sero  | N= |            |         | N= |           |            |
| group** | 4  |            |         | 4  |           |            |
|         | 23 |            |         | 23 |           |            |
+---------+----+------------+---------+----+-----------+------------+
|         | *  | **%**†     | **95%   | *  | **%**†    | **95%      |
|         | *n |            | CI**    | *n |           | CI**§      |
|         | ** |            |         | ** |           |            |
|         | \* |            |         | \* |           |            |
+---------+----+------------+---------+----+-----------+------------+
| > **A** | 3  | 92.4%      | 89.5,   | 3  | 92.7%     | 89.8, 95.0 |
|         | 91 |            | 94.8    | 92 |           |            |
+---------+----+------------+---------+----+-----------+------------+
| > **C** | 3  | 88.7%      | 85.2,   | 3  | 91.7%     | 88.7, 94.2 |
|         | 75 |            | 91.5    | 88 |           |            |
+---------+----+------------+---------+----+-----------+------------+
| > **Y** | 3  | 80.1%      | 76.0,   | 3  | 81.8%     | 77.8, 85.4 |
|         | 39 |            | 83.8    | 46 |           |            |
+---------+----+------------+---------+----+-----------+------------+
| > **    | 4  | 95.3%      | 92.8,   | 4  | 96.7%     | 94.5, 98.2 |
| W-135** | 03 |            | 97.1    | 09 |           |            |
+---------+----+------------+---------+----+-----------+------------+

\*n: number of participants with ≥ 4-fold rise from baseline SBA-BR
titer. N: total number of participants with valid serology data.

† %: percentage of participants with a ≥4-fold rise in SBA-BR titer
post-vaccination compared with baseline.

§ CI: Confidence interval.

[Seroconversion rate]{.underline} 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. In both groups, all
participants with serogroup A SBA-BR antibody less than 1:8
pre-vaccination, achieved seroconversion. For serogroup C,
seroconversion was observed in 98.7% \[153/155\] of Menactra recipients
and 99.3% \[151/152\] of Menomune^®^ recipients. For the remaining
serogroups, of those participants who received Menactra, 98.4% \[60/61\]
and 98.2% \[161/164\] responded with a [\>]{.underline}4-fold antibody
rise to serogroups Y and W135, respectively, compared with 100%
\[47/47\] and 83% \[138/139\] of individuals who received Menomune^®^.

[Serogroup-specific IgG and IgM antibody:]{.underline}

Serogroup-specific IgG and IgM antibody levels, measured by ELISA, were
assessed in a subset of 161 participants \[Menactra n=82, Menomune^®^
n=79\].

+--------+--------------+----------+--------+-----------+------------+
| **M    |              |          |        |           |            |
| TA-02: |              |          |        |           |            |
| Comp   |              |          |        |           |            |
| arison |              |          |        |           |            |
| of     |              |          |        |           |            |
| Serogr |              |          |        |           |            |
| oup-sp |              |          |        |           |            |
| ecific |              |          |        |           |            |
| IgG    |              |          |        |           |            |
| and    |              |          |        |           |            |
| SBA-BR |              |          |        |           |            |
| GMT    |              |          |        |           |            |
| Post-v |              |          |        |           |            |
| accina |              |          |        |           |            |
| tion** |              |          |        |           |            |
+--------+--------------+----------+--------+-----------+------------+
| *      | **Vaccine**  | **       |        |           |            |
| *Serog |              | Post-vac |        |           |            |
| roup** |              | cination |        |           |            |
|        |              | r        |        |           |            |
|        |              | esults** |        |           |            |
+--------+--------------+----------+--------+-----------+------------+
|        | **Group**    | **IgG    | **95%  | **SBA-BR  | **95% CI** |
|        |              | (        | CI**   | GMT**     |            |
|        |              | µg/mL)** |        |           |            |
+--------+--------------+----------+--------+-----------+------------+
| >      | Menomune^®^  | 11.6     | 8.8,   | 3245.7    | 2910.0,    |
|  **A** |              |          | 15.3   |           | 3620.1     |
+--------+--------------+----------+--------+-----------+------------+
| >      | #####        | 18.1     | 13.6,  | 5483.2    | 4920.1,    |
|        | ### Menactra |          | 24.1   |           | 6110.7     |
+--------+--------------+----------+--------+-----------+------------+
| >      | Menomune^®^  | 8.1      | 5.4,   | 1638.9    | 1405.6,    |
|  **C** |              |          | 12.2   |           | 1910.9     |
+--------+--------------+----------+--------+-----------+------------+
| >      | #####        | 5.5      | 3.9,   | 1924.4    | 1662.1,    |
|        | ### Menactra |          | 8.0    |           | 2228.0     |
+--------+--------------+----------+--------+-----------+------------+
| >      | Menomune^®^  | 9.2      | 6.6,   | 1228.3    | 1088.2,    |
|  **Y** |              |          | 12.8   |           | 1386.4     |
+--------+--------------+----------+--------+-----------+------------+
| >      | #####        | 4.4      | 2.7,   | 1322.3    | 1161.9,    |
|        | ### Menactra |          | 7.1    |           | 1504.8     |
+--------+--------------+----------+--------+-----------+------------+
| > **W  | Menomune^®^  | 4.9      | 3.5,   | 1545.0    | 1383.6,    |
| -135** |              |          | 7.0    |           | 1725.2     |
+--------+--------------+----------+--------+-----------+------------+
| >      | #####        | 3.0      | 2.0,   | 1407.2    | 1232.8,    |
|        | ### Menactra |          | 4.3    |           | 1607.3     |
+--------+--------------+----------+--------+-----------+------------+

Note: The SBA-BR GMT analysis was based on 846 participants \[Menactra
n=423, Menomune**^®^** n=423\] with valid serology data.

+------------+-------------------------+------------+-----------------+
| **MTA-02:  |                         |            |                 |
| Serogrou   |                         |            |                 |
| p-specific |                         |            |                 |
| IgM        |                         |            |                 |
| Geometric  |                         |            |                 |
| Mean       |                         |            |                 |
| Conc       |                         |            |                 |
| entrations |                         |            |                 |
| Post-va    |                         |            |                 |
| ccination, |                         |            |                 |
| with 95%   |                         |            |                 |
| CI**       |                         |            |                 |
+------------+-------------------------+------------+-----------------+
| **S        | **Vaccine**             | ** **      | ** **           |
| erogroup** |                         |            |                 |
+------------+-------------------------+------------+-----------------+
|            | **Group**               | **IgM      | **95% CI**      |
|            |                         | (µg/mL)**  |                 |
+------------+-------------------------+------------+-----------------+
| #### A     | Menomune^®^             | 12.0       | 9.7, 14.9       |
+------------+-------------------------+------------+-----------------+
| >          | Menactra                | 17.8       | 14.7, 21.6      |
+------------+-------------------------+------------+-----------------+
| > **C**    | Menomune^®^             | 1.7        | 1.4, 2.1        |
+------------+-------------------------+------------+-----------------+
| >          | Menactra                | 1.6        | 1.2, 2.0        |
+------------+-------------------------+------------+-----------------+
| > **Y**    | Menomune^®^             | 3.5        | 2.9, 4.2        |
+------------+-------------------------+------------+-----------------+
| >          | Menactra                | 3.5        | 2.8, 4.3        |
+------------+-------------------------+------------+-----------------+
| >          | Menomune^®^             | 1.7        | 1.4, 2.0        |
|  **W-135** |                         |            |                 |
+------------+-------------------------+------------+-----------------+
| >          | Menactra                | 1.9        | 1.6, 2.3        |
+------------+-------------------------+------------+-----------------+

1.  **[Study MTA-09:]{.underline}**

**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:]{.underline}

```{=html}
<!-- -->
```
-   To compare the bactericidal antibody response to serogroups A, C, Y,
    W135, using baby rabbit complement (SBA-BR), among healthy adults
    immunized with Menactra with the SBA-BR responses following
    vaccination with a licensed meningococcal polysaccharide vaccine.

```{=html}
<!-- -->
```
-   [Other objectives:]{.underline}

```{=html}
<!-- -->
```
-   To describe and compare the SBA-BR response to each serogroup pre-
    and 28 days post-vaccination for Menactra and Menomune^®^
    recipients.

-   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. Enrollment was stratified by two age groups
(18-25 years, 26-55 years) to ensure adequate representation of
participants in each age group. Participants were randomized in a 1: 1
(Menactra: Menomune^®^) ratio. Participants were enrolled at
thirty-three study centers in the United States.

**Primary Immunogenicity Endpoint**

The proportion of participants with a [\>]{.underline}4-fold rise in
SBA-BR titer for *N. meningitidis* serogroups A, C, Y and W-135.

**Secondary Immunogenicity endpoint**

SBA-BR GMT for serogroups A,C,Y,W135 in the Menactra group, compared to
corresponding GMTs in the Menomune group.

**Statistical plan**

**[Primary hypothesis:]{.underline}**

**To demonstrate that 28 days after vaccination, Menactra is
non-inferior to Menomune^®^ by proportion of participants with a
[\>]{.underline}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 bound of the
two-sided 95% CI of *p*~Menomune®~-- *p*~Menactra~ is less than 0.10,
where *p* represents the proportion of participants with a
[\>]{.underline}4-fold rise in SBA-BR titer as compared to baseline, for
each serogroup, respectively. The sample size provided 99.9% power,
overall, to achieve the primary hypothesis for serogroups A, C, Y and
W135. All tests of the primary hypothesis used a type I error of 0.025.
The primary analysis was based on data generated from the per-protocol
population.

The confidence interval used for primary immunogenicity hypothesis
testing was modified during the trial, from a two-sided 90% CI to a
two-sided 95% CI, due to changed criteria preferred by CBER for
one-sided equivalence trials.

**Secondary Hypothesis:** To demonstrate that 28 days after vaccination,
the GMT for serogroups A,C,Y,W135 in the Menactra group is non-inferior
to corresponding GMTs in the Menomune group. This hypothesis would be
supported by the data if the upper limit of the two-sided 95% CI of
GMT~Menactra~/ GMT~Menomune~ \<log~2~ (2) for each serogroup. GMTs are
calculated as a log base 2 titer, and adjusted for baseline disparities
in pre-existing antibody, using an analysis of covariance with baseline
outcome as a covariate. Analyses of the secondary point were performed
on both per-protocol and intent-to-treat populations.

**Results**

A total of 2554 (Menactra n=1384, Menomune^®^ n= 1170) adults were
enrolled, and 2400 (Menactra n=1301, Menomune^®^ n= 1099) individuals
completed the study. The per protocol population for immunogenicity
included 1280 Menactra and 1098 Menomune^®^ participants.

[Immunogenicity population:]{.underline}

One hundred forty-six (Menactra n=84, Menomune^®^ n=62) of
301participants with a protocol violation were considered evaluable for
the per-protocol analysis, since the violation related to safety data
collection, rather than sera collection or processing. Forty-three
participants, for whom Day 8 safety follow-up was either outside the
window or not done, were considered evaluable for the per-protocol
analysis; of these participants, 81% \[35/43\] were enrolled at a single
study site. Twelve Menactra participants and 9 Menomune participants,
while not listed for protocol violations, were excluded from the
per-protocol population.

*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
(85.0%), but also included African American (5.1%), Hispanic (5.8%),
Asian populations (2.7%) and individuals with mixed racial background
(1.4%).

+--------+------+-------+------+---------+-------------+--------------+
| **M    |      |       |      |         |             |              |
| TA-09: |      |       |      |         |             |              |
| P      |      |       |      |         |             |              |
| rimary |      |       |      |         |             |              |
| Hypo   |      |       |      |         |             |              |
| thesis |      |       |      |         |             |              |
| Tes    |      |       |      |         |             |              |
| ting** |      |       |      |         |             |              |
|        |      |       |      |         |             |              |
| **     |      |       |      |         |             |              |
| Number |      |       |      |         |             |              |
| and    |      |       |      |         |             |              |
| Prop   |      |       |      |         |             |              |
| ortion |      |       |      |         |             |              |
| of     |      |       |      |         |             |              |
| Partic |      |       |      |         |             |              |
| ipants |      |       |      |         |             |              |
| 18-55  |      |       |      |         |             |              |
| Years  |      |       |      |         |             |              |
| Old    |      |       |      |         |             |              |
| with a |      |       |      |         |             |              |
| [\>]   |      |       |      |         |             |              |
| {.unde |      |       |      |         |             |              |
| rline} |      |       |      |         |             |              |
| Fou    |      |       |      |         |             |              |
| r-fold |      |       |      |         |             |              |
| In     |      |       |      |         |             |              |
| crease |      |       |      |         |             |              |
| in     |      |       |      |         |             |              |
| SBA-BR |      |       |      |         |             |              |
| T      |      |       |      |         |             |              |
| iter** |      |       |      |         |             |              |
+--------+------+-------+------+---------+-------------+--------------+
|        | **M  |       | **Me |         |             | **Upper      |
|        | enom |       | nact |         |             | Limit of     |
|        | une^ |       | ra** |         |             | the**        |
|        | ®^** |       |      |         |             |              |
+--------+------+-------+------+---------+-------------+--------------+
| *      | **N= |       | **N= |         | **D         | **2-sided    |
| *Serog | 10   |       | 12   |         | ifference** | 95% CI**     |
| roup** | 98** |       | 80** |         |             |              |
+--------+------+-------+------+---------+-------------+--------------+
|        | **n  | ***p  | **n  | ***p    | (*p*~M      | **of the     |
|        | **\* | *~Men | **\* | *~Menac | enomune®~ - | Dif          |
|        |      | omune |      | tra~**‡ | *p*         | ference^§^** |
|        |      | ®~**† |      |         | ~Menactra~) |              |
+--------+------+-------+------+---------+-------------+--------------+
| >      | 929  | 0.846 | 1030 | 0.805   | 0.041       | 0.072        |
|  **A** |      |       |      |         |             |              |
+--------+------+-------+------+---------+-------------+--------------+
| >      | 985  | 0.897 | 1133 | 0.885   | 0.012       | 0.037        |
|  **C** |      |       |      |         |             |              |
+--------+------+-------+------+---------+-------------+--------------+
| >      | 872  | 0.794 | 941  | 0.735   | 0.059       | 0.093        |
|  **Y** |      |       |      |         |             |              |
+--------+------+-------+------+---------+-------------+--------------+
| > **W  | 1036 | 0.944 | 1144 | 0.894   | 0.050       | 0.072        |
| -135** |      |       |      |         |             |              |
+--------+------+-------+------+---------+-------------+--------------+

\*n: number of participants with ≥ 4-fold rise in SBA-BR titer from
baseline. N: total number of participants with valid serology data.

† *p*~Menomune®~: proportion of Menomune^®^ participants with a ≥4-fold
rise in SBA-BR titer post-vaccination compared with baseline.

‡ *p*~Menactra:~ proportion of Menactra participants with a ≥ 4-fold
rise in SBA-BR titer post-vaccination compared with baseline.

§ CI: Confidence interval.

[Serum bactericidal antibody:]{.underline}

+---------+-----+--------+-----------+-----+-----------+-------------+
| **      |     |        |           |     |           |             |
| MTA-09: |     |        |           |     |           |             |
| Number  |     |        |           |     |           |             |
| and     |     |        |           |     |           |             |
| Per     |     |        |           |     |           |             |
| centage |     |        |           |     |           |             |
| of      |     |        |           |     |           |             |
| Parti   |     |        |           |     |           |             |
| cipants |     |        |           |     |           |             |
| 18-55   |     |        |           |     |           |             |
| Years   |     |        |           |     |           |             |
| Old     |     |        |           |     |           |             |
| Ac      |     |        |           |     |           |             |
| hieving |     |        |           |     |           |             |
| a       |     |        |           |     |           |             |
| [\      |     |        |           |     |           |             |
| >]{.und |     |        |           |     |           |             |
| erline} |     |        |           |     |           |             |
| Fo      |     |        |           |     |           |             |
| ur-fold |     |        |           |     |           |             |
| I       |     |        |           |     |           |             |
| ncrease |     |        |           |     |           |             |
| in      |     |        |           |     |           |             |
| SBA-BR  |     |        |           |     |           |             |
| A       |     |        |           |     |           |             |
| ntibody |     |        |           |     |           |             |
| Titer,  |     |        |           |     |           |             |
| with    |     |        |           |     |           |             |
| 95%CI** |     |        |           |     |           |             |
+---------+-----+--------+-----------+-----+-----------+-------------+
|         | **M |        |           | **M |           |             |
|         | eno |        |           | ena |           |             |
|         | mun |        |           | ctr |           |             |
|         | e^® |        |           | a** |           |             |
|         | ^** |        |           |     |           |             |
+---------+-----+--------+-----------+-----+-----------+-------------+
| **Sero  | N=  |        |           | N=  |           |             |
| group** | 1   |        |           | 1   |           |             |
|         | 098 |        |           | 280 |           |             |
+---------+-----+--------+-----------+-----+-----------+-------------+
|         | *   | **%**† | **95%     | *   | **%**†    | **95% CI**§ |
|         | *n* |        | CI**      | *n* |           |             |
|         | *\* |        |           | *\* |           |             |
+---------+-----+--------+-----------+-----+-----------+-------------+
| > **A** | 929 | 84.6%  | 82.3,     | 1   | 80.5%     | 78.2, 82.6  |
|         |     |        | 86.7      | 030 |           |             |
+---------+-----+--------+-----------+-----+-----------+-------------+
| > **C** | 985 | 89.7%  | 87.8,     | 1   | 88.5%     | 86.6, 90.2  |
|         |     |        | 91.4      | 133 |           |             |
+---------+-----+--------+-----------+-----+-----------+-------------+
| > **Y** | 872 | 79.4%  | 76.9,     | 941 | 73.5%     | 71.0, 75.9  |
|         |     |        | 81.8      |     |           |             |
+---------+-----+--------+-----------+-----+-----------+-------------+
| > **    | 1   | 94.4%  | 92.8,     | 1   | 89.4%     | 87.6, 91.0  |
| W-135** | 036 |        | 95.6      | 144 |           |             |
+---------+-----+--------+-----------+-----+-----------+-------------+

\*n: number of participants with ≥ 4-fold rise in SBA-BR from baseline.
N: total number of participants with valid serology data.

† %: percentage of participants with a ≥4-fold rise in SBA-BR titer
post-vaccination, compared with baseline.

§ CI: Confidence interval.

[SBA-BR GMT:]{.underline}

+---------+--------+-------+---------------+------+----------------+
| **      |        |       |               |      |                |
| MTA-09: |        |       |               |      |                |
| SBA-BR  |        |       |               |      |                |
| Ge      |        |       |               |      |                |
| ometric |        |       |               |      |                |
| Mean    |        |       |               |      |                |
| A       |        |       |               |      |                |
| ntibody |        |       |               |      |                |
| Titer   |        |       |               |      |                |
| Pre-    |        |       |               |      |                |
| and 28  |        |       |               |      |                |
| days    |        |       |               |      |                |
| Post    |        |       |               |      |                |
| -vaccin |        |       |               |      |                |
| ation** |        |       |               |      |                |
+---------+--------+-------+---------------+------+----------------+
| ** **   | ** **  | **Men |               | **Me |                |
|         |        | omune |               | nact |                |
|         |        | ^®^** |               | ra** |                |
+---------+--------+-------+---------------+------+----------------+
| ** **   | ** **  | **N=  |               | **N= |                |
|         |        | 1     |               | 12   |                |
|         |        | 098** |               | 80** |                |
+---------+--------+-------+---------------+------+----------------+
|         |        | **SBA | ** **         | **   | ** **          |
|         |        | -BR** |               | SBA- |                |
|         |        |       |               | BR** |                |
+---------+--------+-------+---------------+------+----------------+
| **Sero  | *      | **    | **95% CI**    | **G  | **95% CI**     |
| group** | *Timep | GMT** |               | MT** |                |
|         | oint** |       |               |      |                |
+---------+--------+-------+---------------+------+----------------+
| > **A** | Day 0  | 203.6 | 180.3, 229.9  | 2    | 200.1, 250.4   |
|         |        |       |               | 23.8 |                |
+---------+--------+-------+---------------+------+----------------+
| >       | Day 28 | 4     | 3832.2,       | 38   | 3647.0, 4164.0 |
|         |        | 114.1 | 4416.8        | 96.9 |                |
+---------+--------+-------+---------------+------+----------------+
| > **C** | Day 0  | 51.7  | 45.4, 56.0    | 56.8 | 50.2, 64.4     |
+---------+--------+-------+---------------+------+----------------+
| >       | Day 28 | 3     | 3148.4,       | 32   | 2954.9, 3533.2 |
|         |        | 469.4 | 3823.1        | 31.1 |                |
+---------+--------+-------+---------------+------+----------------+
| > **Y** | Day 0  | 127.2 | 111.8, 144.8  | 1    | 109.1, 139.0   |
|         |        |       |               | 23.2 |                |
+---------+--------+-------+---------------+------+----------------+
| >       | Day 28 | 2     | 2237.0,       | 17   | 1597.0, 1918.5 |
|         |        | 448.6 | 2680.2        | 50.4 |                |
+---------+--------+-------+---------------+------+----------------+
| > **    | Day 0  | 30.9  | 27.8, 34.4    | 33.1 | 29.9, 36.7     |
| W-135** |        |       |               |      |                |
+---------+--------+-------+---------------+------+----------------+
| >       | Day 28 | 1     | 1722.8,       | 1271 | 1171.9, 1378.4 |
|         |        | 871.2 | 2032.4        |      |                |
+---------+--------+-------+---------------+------+----------------+

N: total number of participants with valid serology data.

[SBA-BR geometric mean titer, using the baseline titer as a
covariate:]{.underline}

The upper limit of the two-sided 95% CI for the anti-log of the
treatment effect for each serogroup was less than log~2~ (2), which
indicated that the post-vaccination SBA-BR GMT, for each serogroup, did
not differ between the two vaccine groups when adjusted for baseline
disparities in pre-existing antibody.

+------+--------+-----+--------+----------+----------+--------------+
| *    |        |     |        |          |          |              |
| *MTA |        |     |        |          |          |              |
| -09: |        |     |        |          |          |              |
| T    |        |     |        |          |          |              |
| reat |        |     |        |          |          |              |
| ment |        |     |        |          |          |              |
| Ef   |        |     |        |          |          |              |
| fect |        |     |        |          |          |              |
| on   |        |     |        |          |          |              |
| SB   |        |     |        |          |          |              |
| A-BR |        |     |        |          |          |              |
| GMT, |        |     |        |          |          |              |
| Adju |        |     |        |          |          |              |
| sted |        |     |        |          |          |              |
| by   |        |     |        |          |          |              |
| Base |        |     |        |          |          |              |
| line |        |     |        |          |          |              |
| Cov  |        |     |        |          |          |              |
| aria |        |     |        |          |          |              |
| te** |        |     |        |          |          |              |
+------+--------+-----+--------+----------+----------+--------------+
| *    | ** **  | **B | **Es   | **Di     | **       | **95% CI for |
| * ** |        | ase | timate | fference | Anti-Log | Anti-Log**   |
|      |        | lin | of**   | of the** | of**     |              |
|      |        | e** |        |          |          |              |
+------+--------+-----+--------+----------+----------+--------------+
| *    | **Vac  | *   | **Base | **T      | **T      | **of the     |
| * ** | cine** | *SB | line** | reatment | reatment | Treatment    |
|      |        | A-B |        | Effect** | Ef       | Effect**     |
|      |        | R** |        |          | fect**\* |              |
+------+--------+-----+--------+----------+----------+--------------+
| *    | **G    | *   | **GMT  | (Meno    | (Meno    | (            |
| *Ser | roup** | *GM | Ef     | mune^®^- | mune^®^- | Menomune^®^- |
| ogro |        | T** | fect** | M        | M        | Menactra)    |
| up** |        |     |        | enactra) | enactra) |              |
+------+--------+-----+--------+----------+----------+--------------+
| > *  | **M    | 20  | -0.849 | 0.099    | 1.071    | 0.975, 1.177 |
| *A** | enomun | 3.6 |        |          |          |              |
|      | e**^®^ |     |        |          |          |              |
+------+--------+-----+--------+----------+----------+--------------+
| > *  | **Mena | 22  |        |          |          |              |
| * ** | ctra** | 3.8 |        |          |          |              |
+------+--------+-----+--------+----------+----------+--------------+
| > *  | **M    | 5   | -0.771 | 0.134    | 1.097    | 0.968, 1.244 |
| *C** | enomun | 1.7 |        |          |          |              |
|      | e**^®^ |     |        |          |          |              |
+------+--------+-----+--------+----------+----------+--------------+
| > *  | **Mena | 5   |        |          |          |              |
| * ** | ctra** | 6.8 |        |          |          |              |
+------+--------+-----+--------+----------+----------+--------------+
| > *  | **M    | 12  | -0.743 | 0.472    | 1.387    | 1.229, 1.567 |
| *Y** | enomun | 7.2 |        |          |          |              |
|      | e**^®^ |     |        |          |          |              |
+------+--------+-----+--------+----------+----------+--------------+
| > *  | **Mena | 12  |        |          |          |              |
| * ** | ctra** | 3.2 |        |          |          |              |
+------+--------+-----+--------+----------+----------+--------------+
| > *  | **M    | 3   | -0.764 | 0.581    | 1.496    | 1.339, 1.672 |
| *W-1 | enomun | 0.9 |        |          |          |              |
| 35** | e**^®^ |     |        |          |          |              |
+------+--------+-----+--------+----------+----------+--------------+
| > *  | **Mena | 3   |        |          |          |              |
| * ** | ctra** | 3.1 |        |          |          |              |
+------+--------+-----+--------+----------+----------+--------------+

\* Anti-Log of the treatment effect is calculated as 2 to the treatment
effect (Menomune-Menactra) power.

[Seroconversion rate]{.underline} 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 after vaccination. All Menactra recipients with
SBA-BR antibody titer less than 1:8 pre-vaccination, and 99.3%
\[143/144\] of corresponding Menomune^®^ recipients achieved this
criterion for serogroup A. For serogroup C, seroconversion was observed
in 99.4% \[343/345\] of Menactra recipients and 97.7% \[297/304\] of
Menomune^®^ recipients. For the remaining serogroups, 90.7% \[253/279\]
and 96.5% \[360/373\] of Menactra participants responded with a
[\>]{.underline}4-fold antibody rise to serogroups Y and W135,
respectively, compared with 96.9% \[221/228\] and 99.1% \[325/328\] of
individuals who received Menomune^®^.

5.  **Safety Data**

The epidemiology of meningococcal disease in the United States and ACIP
recommendations for the prevention of meningococcal disease among
college freshmen projected frequent use of this vaccine in adolescents
and young adults. Hence, particular attention was given to
characterizing the safety profile in the 15-25 year old age group. The
number of participants enrolled for all studies combined is summarized
in the following table:

  ---------------------------------- ------------------- -----------------
  **Overall Safety Database**                            ** **

  ** **                              **\# Participants   
                                     enrolled**          

  **Age group**                      **Menactra**        **Menomune**^®^

  ** **                              **n**               **n**

  **11-14 years**                    1636                490

  **15-25 years**                    4078                1578

  **26-55 years**                    1957                973

  **Total for 11-55y\***             **7672**            **3041**
  ---------------------------------- ------------------- -----------------

Clinical studies MTA-04 and MTA-09 included non-inferiority comparisons
of adverse events as a primary hypothesis, and studies MTA-02 and MTA-14
included safety comparisons as a secondary hypothesis. Study design
elements that pertain to the safety assessment, and were uniform across
all studies, are the following:

**Vaccine administration**

Each group received a single dose of vaccine. Menactra was administered
intramuscularly, and the control vaccine, Menomune^®^, given
subcutaneously. Since the route of administration for the study vaccine
differed from the control vaccine, study personnel who administered the
vaccine differed from the personnel collecting the safety data.

**Monitored parameters:**

-   **Immediate reactions:** 30 minutes post-vaccination

-   **Local and systemic adverse events:** reactogenicity was assessed
    during Days 0-7 (day of vaccination = Day 0). The events were
    recorded on a diary card, and also collected by study personnel
    through telephone interview eight days after vaccination.
    Pre-specified local reactions were erythema, swelling, induration,
    pain. In studies MTA-04, MTA-09, MTA-14, information was obtained
    for fever measured by oral temperature, headache, fatigue, chills,
    arthralgia, anorexia, vomiting, diarrhea, seizures, malaise and
    rash. If rash was reported, the investigator was prompted to record
    additional details on a separate case report form. In study MTA-02,
    which was conducted early in clinical development, the same systemic
    reactions were collected except for arthalgia and chills. The
    presence of rash was assessed qualitatively, but prompts for
    additional details were not included on the case report form.

-   **Unsolicited adverse events:** Days 0-28. Information about these
    events was obtained by telephone interview eight and twenty-eight
    days after vaccination.

-   **Significant adverse events:** Day 0- 6 months. These events
    consisted of visits to an emergency room, or unexpected visits to an
    office physician were collected via scripted telephone interview.

-   **Serious adverse events** were reported and recorded during the
    6-month study period following vaccination. A serious adverse event
    was defined as any untoward medical occurrence resulting in death,
    life-threatening experience, inpatient hospitalization, prolonged
    existing hospitalization, persistent or significant
    disability/incapacity, or a congenital anomaly/birth defect. In
    addition to these events.

####### Primary Endpoint

The proportion of participants with a least one solicited systemic
reaction reported as severe during the 7-day period following
vaccination.

**Populations for analysis**

**Intent-to-treat population for safety:**

The intent-to-treat population consisted of all participants who
received one dose of vaccine and for whom safety information was
available. Analyses were performed according to the vaccine received.

**Per-protocol population for safety:**

Eligible participants who received the vaccine according to the
treatment assignment were included in the per-protocol population.
Although this population was defined, all analyses were performed on the
intent-to-treat population.

1.  **[Study MTA-04]{.underline}**

**Title: A Comparative Trial of the Safety of One Dose of an
Experimental Tetravalent (A, C, Y, and W135) Meningococcal Diphtheria
Conjugate Vaccine Versus** **Menomune® A/C/Y/W-135 in Healthy Children
in the U.S. Aged 11-18 Years**

**Objectives**

-   [Primary objective:]{.underline}

```{=html}
<!-- -->
```
-   To describe the safety profile after a single dose of Menactra

-   To compare the relative frequency of a solicited systemic reaction
    reported as severe among Menactra and Menomune^®^ recipients

####### Design

The study was a randomized, modified double blind, multi-center,
active-controlled trial. Participants were enrolled at thirty-two study
centers in the United States. Enrollment was stratified by two age
groups (11-14 years, 15-18 years) to ensure adequate representation of
participants in each age group. Participants were randomized in a 2.5: 1
(Menactra: Menomune^®^) ratio.

**[Primary Endpoint:]{.underline}**

The proportion of participants with a least one solicited systemic
reaction reported as severe during the 7-day period following
vaccination.

**Statistical plan**

**[Primary Hypothesis:]{.underline}**

**To demonstrate that Menactra is non-inferior to Menomune^®^ in the
proportion of participants with a least one solicited systemic reaction
reported as severe during the 7 day period following vaccination.**

This hypothesis would be supported by the data if the upper limit of the
two sided 90% CI of *p~Menactra~* / *p~Menomune®~* is less than 3, where
*p* represents the proportion of participants with at least one severe
solicited systemic reaction in the Menactra and Menomune^®^ groups,
respectively. The sample size provided 80% power to achieve the primary
hypothesis, assuming that the expected proportion of subjects with at
least one systemic reaction in the Menomune group is 1%. Primary
hypothesis testing was conducted at the 0.05 significance level. 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. The sponsor also
included primary safety analysis results according to current CBER
recommendations.

Although enrollment was stratified by two age groups (11-14 years, 15-18
years) to ensure adequate representation of participants in each age
group, the analyses were based upon the total study population,
regardless of stratified age group. In addition, all rashes occurring
during the first 7 days after vaccination were designated, for the
purpose of analysis, as a severe solicited systemic reaction.

####### Results 

A total of 3242 (Menactra n=2270, Menomune^®^ n= 972) adolescents were
enrolled, and 3211 (Menactra n= 2250, Menomune^®^ n=961) individuals
completed the study. The intent-to-treat population for safety included
3242 participants (Menactra n=2270, Menomune^®^ n= 972)**.**
Participants completing the safety assessment 6 months after vaccination
are summarized in [section 6.5]{.underline}.

##### Local Reactions

  ---------------- -------------- -------------- -------- ------- ------------ ----------------- -------- ----------
  **MTA-04: Local                                                                                         
  adverse                                                                                                 
  reactions (Days                                                                                         
  0-7)**                                                                                                  

                                  **Menactra**                                 **Menomune^®^**            

                                  N= 2264                                      N= 970                     

  **Reaction**     **Severity**   **n**\*        **%**†           **95% CI**   **n**\*           **%**†   **95% CI**

  **Redness**                                                                                              

                   **Any**        247            10.9             9.7, 12.3    55                5.7      4.3, 7.3

  \< 1 inch        **Mild**       197            8.7              7.6, 9.9     51                5.3      3.9, 6.7

  1 -- 2 inches    **Moderate**   37             1.6              1.2, 2.3     4                 0.4      0.1, 1.1

  \> 2 inches      **Severe**     13             0.6              0.3, 1.0     0                 0        0.0, 0.3

  **Swelling**                                                                                             

                   **Any**        245            10.8             9.6, 12.2    35                3.6      2.5, 5.0

  \< 1 inch        **Mild**       191            8.4              7.3, 9.7     32                3.3      2.3, 4.6

  1 -- 2 inches    **Moderate**   43             1.9              1.4, 2.6     3                 0.3      0.1, 0.9

  \> 2 inches      **Severe**     11             0.5              0.2, 0.9     0                 0        0.0, 0.3

  **Induration**                                                                                           

                   **Any**        355            15.7     14.2,                50                5.2      3.9, 6.7
                                                          17.2                                            

  \< 1 inch        **Mild**       292            12.9     11.5,                45                4.6      3.4, 6.2
                                                          14.4                                            

  1 -- 2 inches    **Moderate**   56             2.5      1.9,                 5                 0.5      0.2, 1.2
                                                          3.2                                             

  \> 2 inches      **Severe**     7              0.3      0.1,                 0                 0        0.0, 0.3
                                                          0.6                                             

  **Pain**                                                                                                 

                   **Any**        1340           59.2     57.1,                278               28.7     25.8, 31.6
                                                          61.2                                            

                   **Mild**       1045           46.2     44.1,                253               26.1     23.3, 29.0
                                                          48.2                                            

                   **Moderate**   289            12.8     11.4,                25                2.6      1.7, 3.8
                                                          14.2                                            

                   **Severe**     6              0.3      0.1,                 0                 0        0.0, 0.3
                                                          0.6                                             
  ---------------- -------------- -------------- -------- ------- ------------ ----------------- -------- ----------

\*n: number of participants reporting at least one event in this
category. Six Menactra and 2 Menomune participants did not provide any
data. Percentages are based on the total number of participants who did
submit safety information at each time point.

**†**%: n/N expressed as a percentage.

Pain: 0=none, 1= (mild) sx present, but arm movement not affected, 2=
(moderate) limits usual arm movement, 3= (severe) disabling

##### Systemic Reactions

  ------------------ -------------- -------------- -------- ------------- ----------------- -------- -----------
  **MTA-04: Systemic                                                                                 
  adverse reactions                                                                                  
  (Days 0-7)**                                                                                       

                                    **Menactra**                          **Menomune^®^**            

                                    N= 2265                               N= 970                     

  **Reaction**       **Severity**   **n**\*        **%**†   **95% CI**    **n**\*           **%**†   **95% CI**

  **Fever**                                                                                           

                     **Any**        115            5.1      4.2, 6.1      29                3.0      2.0, 4.3

  38.0ºC-38.9ºC      **Mild**       102            4.5      3.7, 5.4      25                2.6      1.7, 3.8

  39.0ºC-39.9ºC      **Moderate**   13             0.6      0.3, 1.0      3                 0.3      0.1, 0.9

  [\>]{.underline}   **Severe**     0              0.0      0.0, 0.1      1                 0.1      0.0, 0.6
  40.0ºC                                                                                             

  **Headache**                                                                                        

                     **Any**        807            35.6     33.7, 37.6    284               29.3     26.4, 32.3

                     **Mild**       566            25.0     23.2, 26.8    217               22.4     19.8, 25.1

                     **Moderate**   217            9.6      8.4, 10.9     63                6.5      5.0, 8.2

                     **Severe**     24             1.1      0.7, 1.6      4                 0.4      0.1, 1.1
  ------------------ -------------- -------------- -------- ------------- ----------------- -------- -----------

  ------------------- -------------- -------------- ------- ----------- ----------------- ------- ------ ---------- --
  **Cont. MTA-04:                                                                                                   
  Systemic adverse                                                                                                  
  reactions (Days                                                                                                   
  0-7)**                                                                                                            

                                     **Menactra**                       **Menomune^®^**                             

                                     N= 2265                            N= 970                                      

  **Reaction**        **Severity**   **n**\*        **%**   **95% CI**  **n**\*           **%**          **95% CI** 

  **Fatigue**                                                                                                       

                      **Any**        679            30.0    28.1, 31.9  243                       25.1   22.4, 27.9 

                      **Mild**       484            21.4    19.7, 23.1  181                       18.7   16.3, 21.3 

                      **Moderate**   169            7.5     6.4, 8.6    60                        6.2    4.8, 7.9   

                      **Severe**     26             1.1     0.8, 1.7    2                         0.2    0.0, 0.7   

  **Malaise**                                                                                                       

                      **Any**        496            21.9    20.2, 23.7  163                       16.8   14.5, 19.3 

                      **Mild**       340            15.0    13.6, 16.6  126                       13.0   10.9, 15.3 

                      **Moderate**   131            5.8     4.9, 6.8    33                        3.4    2.4, 4.7   

                      **Severe**     25             1.1     0.7, 1.6    4                         0.4    0.1, 1.1   

  **Arthralgia**      ** **                                                                                         

                      **Any**        394            17.4    15.9, 19.0  99                        10.2   8.4, 12.3  

                      **Mild**       304            13.4    12.0, 14.9  78                        8.0    6.4, 9.9   

                      **Moderate**   82             3.6     2.9, 4.5    20                        2.1    1.3, 3.2   

                      **Severe**     8              0.4     0.2, 0.7    1                         0.1    0.0, 0.6   

  **Chills**          ** **                                                                                         

                      **Any**        158            7.0     6.0, 8.1    34                        3.5    2.4, 4.9   

                      **Mild**       115            5.1     4.2, 6.1    29                        3.0    2.0, 4.3   

                      **Moderate**   38             1.7     1.2, 2.3    4                         0.4    0.1, 1.1   

                      **Severe**     5              0.2     0.1, 0.5    1                         0.1    0.0, 0.6   

  **Anorexia**                                                                                                      

                      **Any**        243            10.7    9.5, 12.1   75                        7.7    6.1, 9.6   

  Skips 1 meal        **Mild**       190            8.4     7.3, 9.6    62                        6.4    4.9, 8.1   

  Skips 2 meals       **Moderate**   46             2.0     1.5, 2.7    11                        1.1    0.6, 2.0   

  Skips               **Severe**     7              0.3     0.1, 0.6    2                         0.2    0.0, 0.7   
  [\>]{.underline} 3                                                                                                
  meals                                                                                                             

  **Vomiting**                                                                                                      

                      **Any**        44             1.9     1.4, 2.6    14                        1.4    0.8, 2.4   

  1 episode           **Mild**       29             1.3     0.9, 1.8    6                         0.6    0.2, 1.3   

  2 episodes          **Moderate**   9              0.4     0.2, 0.8    5                         0.5    0.2, 1.2   

  [\>]{.underline}3   **Severe**     6              0.3     0.1, 0.6    3                         0.3    0.1, 0.9   
  episodes                                                                                                          

  **Diarrhea**                                                                                                      

                      **Any**        271            12.0    10.7, 13.4  99                        10.2   8.4, 12.3  

  1-2 episodes        **Mild**       228            10.1    8.9, 11.4   86                        8.9    7.2, 10.8  

  3-4 episodes        **Moderate**   36             1.6     1.1, 2.2    13                        1.3    0.7, 2.3   

  [\>]{.underline} 5  **Severe**     7              0.3     0.1, 0.6    0                         0.0    0.0, 0.3   
  episodes                                                                                                          

  **Seizures** (Y/N)                                                                                                

  Yes                 **Days 0-3**   0              0.0     0.0, 0.1    0                         0.0    0.0, 0.3   

  Yes                 **Days 4-7**   0              0.0     0.0, 0.1    0                         0.0    0.0, 0.3   

  Yes                 **Days 0-7**   0              0.0     0.0, 0.1    0                         0.0    0.0, 0.3   

  **Rash**            ** **                                                                                         

  Any rash            **Days 0-3**   23             1.0     0.6, 1.5    10                        1.0    0.5, 1.9   

  Any rash            **Days 4-7**   23             1.0     0.6, 1.5    7                         0.7    0.3, 1.5   

  Any rash            **Days 0-7**   37             1.6     1.2, 2.2    14                        1.4    0.8, 2.4   
  ------------------- -------------- -------------- ------- ----------- ----------------- ------- ------ ---------- --

\*n: number of participants reporting at least one event in this
category. Five Menactra and 2 Menomune**^®^** participants did not
provide any data. Percentages are based on the total number of
participants who did submit safety information at each time point.

Headache, chills, arthralgia, fatigue, malaise: 0= none, 1= aware,
easily tolerated, 2= interferes with usual activities, 3= disabling

> *Reviewer comment:* Excluding rashes, 108 severe systemic reactions
> occurred in 61 Menactra participants, and 18 severe reactions in 12
> Menomune^®^ participants. Twenty-four of 61 (39%) Menactra
> participants reported two or more severe systemic reactions. In the
> Menomune group, 3 of 12 (25%) participants reported two or more severe
> systemic reactions.

Eleven Menactra and three Menomune^®^ participants, respectively,
reported localized rash either at or near the injection site. Lesions
appeared mainly within the first two days post-vaccination (range 0-5
days), and were described as red or pink, macular or papular, and
primarily non-itchy. The mean duration of the rash was 27 hours (range:
1hr-72hr). For the remaining participants with localized rash, rashes
described were non-specific, located more often on the extremities than
on the trunk, neck or face, and lasted a median of 2 days (range: 40
minutes to 2 months). Three participants reported generalized rash. One
participant in each group described the rash as itchy, blanching; one
participant required benedryl. The third participant \[Menactra\]
reported a generalized, non-blanching, red, raised rash that occurred
two days post-vaccination, and lasted 4 days

####### 

####### [Primary Hypothesis Testing]{.underline}

The proportion of Menactra participants with at least one severe
systemic reaction during Days 0-7 was 0.043 (4.3%) and 0.041 (4.1%) in
the Menomune^®^ group. The upper limit of the two-sided 90% CI, and 95%
CI, for the difference in two proportions was 0.020 (2.0%), and 0.024
(2.4%), respectively.

  -------------- -------------------- ----------------- --------------------- -------------------- -------------- ----------------
  **MTA-04:                                                                                                       
  Number and                                                                                                      
  Proportion of                                                                                                   
  Participants                                                                                                    
  11-18 Years                                                                                                     
  Old With At                                                                                                     
  Least One                                                                                                       
  Severe                                                                                                          
  Solicited                                                                                                       
  Systemic                                                                                                        
  Reaction**                                                                                                      

  **Menactra**                        **Menomune^®^**                         ** **                **Upper Limit  **Upper Limit
                                                                                                   of**           of**

  N= 2265                             N= 970                                  ** **                **the 2-sided  **the 2-sided
                                                                                                   90% CI‡**      95% CI‡**

  **n\***        ***p*~Menactra~**†   **n\***           ***p*~Menomune®~**†   **Ratio              **of the       **of the Ratio**
                                                                              *p*~Menactra~ /      Ratio**        
                                                                              *p*~Menomune®\ ~**                  

  97             0.043                25                0.026                 1.7                  2.4            2.6
  -------------- -------------------- ----------------- --------------------- -------------------- -------------- ----------------

\*Number of participants with at least 1 severe systemic reaction or
rash. N= Total number of participants for whom safety information is
available.

†*p*~Menactra~ and *p*~Menomune®~ : proportion of participants with at
least one severe systemic reaction or rash in the Menactra and
Menomune^®^ groups, respectively.

**‡**CI: Confidence interval

[Note:]{.underline} For analysis purposes, all rashes were counted as
severe solicited systemic reactions. Also, for each reaction, each
participant is counted no more than once.

> *Reviewer comment:* Aside from rash, 24 of 61 (34%) Menactra
> participants reported more than one severe systemic adverse event
> (AEs), as follows: 5 severe AEs (two participants), 4 AEs (three
> participants), 3 AEs (nine participants), and 2 AEs (nine
> participants). For 3 Menactra participants, severe systemic reactions
> consisted of fatigue and malaise. In the Menomune group, 3 of 12 (25%)
> participants reported two or more severe systemic reactions. One
> participant reported 4, 3, and 2 severe AEs, respectively.

1.  **[Study MTA-02]{.underline}**

**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.**

####### 

####### (Please see section 5.1 for synopsis of study design. The primary objective pertained to immunogenicity)

####### Safety Objectives 

####### [Secondary objective:]{.underline} 

####### To describe and compare the safety profile for Menactra and Menomune^®^ recipients.

####### [Other objectives:]{.underline}

> To describe any relationship between post-vaccination reactogenicity
> and elevated pre-vaccination SBA-BR titers to each serogroup among
> recipients receiving either Menactra or Menomune^^.

### Secondary Endpoint

The proportion of participants with a least one solicited systemic
reaction reported as severe during the 7-day period following
vaccination.

####### 

####### Statistical Plan

**[Secondary Hypothesis:]{.underline}**

To demonstrate that the relative frequency of severe systemic reactions
in Menactra recipients is non-inferior to the relative frequency of
severe systemic reactions among Menomune^^ recipients.

This hypothesis would be supported by the data if the upper bound of the
two-sided 90% CI of *p*~Menomune®~ -- *p*~Menactra~ is less than 0.10,
where *p* represents the proportion of participants with at least one
severe systemic reaction during Days 0-7. Hypothesis testing was
conducted at the 0.05 significance level. The definition of
non-inferiority to Menomune^®^ used for statistical hypothesis testing
varied from the primary safety hypothesis in studies MTA-04 and MTA-09,
and reflected ongoing discussions, between CBER and the sponsor, during
the course of clinical development. The sponsor also included an
additional analysis of the secondary endpoint, with two-sided 95%
confidence intervals, which is the current CBER recommendation for
non-inferiority hypothesis testing. All rashes occurring during the
first 7 days after vaccination were designated, for the purpose of
analysis, as a severe solicited systemic reaction.

####### Results

The proportion of Menactra participants with at least one severe
systemic reaction during Days 0-7 was 0.039 \[17/439\] and 0.041
\[18/441\] in the Menomune^®^ group. The upper limit of the two-sided
90% CI, and 95% CI, for the difference in two proportions was 0.020
(2.0%), and 0.024 (2.4%), respectively.

Participants completing the safety assessment 6 months after vaccination
are summarized in [section 6.5]{.underline}.

2.  **[Study MTA-09]{.underline}**

**Title:** **A Comparative Trial of the Safety and Immunogenicity of an
Experimental Tetravalent Meningococcal (A, C, Y, and W-135) Diphtheria
Conjugate Vaccine Compared with Menomune^®^ A/C/Y/W-135 in Healthy
Adults in the U.S.**

(Please see section 5.2 for synopsis of study design. This study
contained both safety and immunogenicity primary objectives.)

**Safety Objectives**

-   [Primary objective:]{.underline}

```{=html}
<!-- -->
```
-   To compare the safety profile for Menactra and Menomune^®^
    recipients, as measured by the proportion of participants with at
    least one solicited systemic reaction reported as severe during the
    7-day period following vaccination.

```{=html}
<!-- -->
```
-   [Other objectives:]{.underline}

```{=html}
<!-- -->
```
-   To compare the safety profile for Menactra and Menomune^®^
    recipients after a single injection.

-   To describe any relationship between post-vaccination reactogenicity
    and elevated pre-vaccination SBA-BR titers to each serogroup among
    recipients receiving either Menactra or Menomune^^.

### Primary Safety Endpoint 

The proportion of participants with a least one solicited systemic
reaction reported as severe during the 7-day period following
vaccination.

**Statistical plan**

### Primary Safety Hypothesis

**To demonstrate that Menactra is non-inferior to Menomune^®^ in the
proportion of participants with a least one solicited systemic reaction
reported as severe during the 7 day period following vaccination.**

This hypothesis would be supported by the data if the upper limit of the
two-sided 90% CI (one-sided 95% CI) of *p~Menactra~* / *p~Menomune®~* is
less than 3, where *p* represents the proportion of participants with at
least one severe solicited systemic reaction in the Menactra and
Menomune^®^ groups, respectively. The sample size provided 80% power to
achieve the primary hypothesis, assuming that the expected proportion of
subjects with at least one systemic reaction in the Menomune group is
1%. All tests of the primary hypothesis were conducted at the 0.05
significance level. During the course of the trial, CBER requested that
the data supporting this hypothesis be based on the upper bound of a
two-sided 95% CI, due to changed criteria preferred by CBER for
one-sided equivalence trials. The requested safety endpoint was
described as an additional analysis. All rashes occurring during the
first 7 days after vaccination were designated, for the purpose of
analysis, as a severe solicited systemic reaction.

**Results**

The intent-to-treat population for safety included 2530 participants
(Menactra n=1371, Menomune^®^ n= 1159). Participants completing the
safety assessment 6 months after vaccination are summarized in [section
6.5]{.underline}.

[Local Reactions:]{.underline}

+--------+-------+-------+----+------+--------+----+------+--------+
| **M    |       |       |    |      |        |    |      |        |
| TA-09: |       |       |    |      |        |    |      |        |
| Local  |       |       |    |      |        |    |      |        |
| a      |       |       |    |      |        |    |      |        |
| dverse |       |       |    |      |        |    |      |        |
| rea    |       |       |    |      |        |    |      |        |
| ctions |       |       |    |      |        |    |      |        |
| (Days  |       |       |    |      |        |    |      |        |
| 0-3,   |       |       |    |      |        |    |      |        |
| 4-7,   |       |       |    |      |        |    |      |        |
| 0-7)** |       |       |    |      |        |    |      |        |
+--------+-------+-------+----+------+--------+----+------+--------+
|        |       |       | ** |      |        | *  |      |        |
|        |       |       | Me |      |        | *M |      |        |
|        |       |       | na |      |        | en |      |        |
|        |       |       | ct |      |        | om |      |        |
|        |       |       | ra |      |        | un |      |        |
|        |       |       | ** |      |        | e^ |      |        |
|        |       |       |    |      |        | ®^ |      |        |
|        |       |       |    |      |        | ** |      |        |
+--------+-------+-------+----+------+--------+----+------+--------+
|        |       |       | #  |      |        | ** |      |        |
|        |       |       | ## |      |        | N= |      |        |
|        |       |       | ## |      |        | 11 |      |        |
|        |       |       | ## |      |        | 59 |      |        |
|        |       |       | ## |      |        | ** |      |        |
|        |       |       |  N |      |        |    |      |        |
|        |       |       | =  |      |        |    |      |        |
|        |       |       | 13 |      |        |    |      |        |
|        |       |       | 71 |      |        |    |      |        |
+--------+-------+-------+----+------+--------+----+------+--------+
| **Reac | **    | ** ** | *  | **   | **95%  | *  | **   | **95%  |
| tion** | Sever |       | *n | %**† | CI**   | *n | %**† | CI**   |
|        | ity** |       | ** |      |        | ** |      |        |
|        |       |       | \* |      |        | \* |      |        |
+--------+-------+-------+----+------+--------+----+------+--------+
| **Red  |       |       |    |      |        |    |      |        |
| ness** |       |       |    |      |        |    |      |        |
+--------+-------+-------+----+------+--------+----+------+--------+
|        | **    | Days  | 1  | 14.3 | 12.5,  | 1  | 16.0 | 13.9,  |
|        | Any** | 0-3   | 96 |      | 16.3   | 85 |      | 18.2   |
+--------+-------+-------+----+------+--------+----+------+--------+
|        | ** ** | Days  | 47 | 3.4  | 2.5,   | 5  | 0.4  | 0.1,   |
|        |       | 4-7   |    |      | 4.5    |    |      | 1.0    |
+--------+-------+-------+----+------+--------+----+------+--------+
|        | ** ** | Days  | 1  | 14.4 | 12.6,  | 1  | 16.0 | 13.9,  |
|        |       | 0-7   | 98 |      | 16.4   | 85 |      | 18.2   |
+--------+-------+-------+----+------+--------+----+------+--------+
| \< 1   | **M   | Days  | 1  | 10.5 | 8.9,   | 1  | 14.0 | 12.0,  |
| inch   | ild** | 0-3   | 44 |      | 12.3   | 62 |      | 16.1   |
+--------+-------+-------+----+------+--------+----+------+--------+
|        | ** ** | Days  | 25 | 1.8  | 1.2,   | 4  | 0.3  | 0.1,   |
|        |       | 4-7   |    |      | 2.7    |    |      | 0.9    |
+--------+-------+-------+----+------+--------+----+------+--------+
|        | ** ** | Days  | 14 | 10.4 | 8.9,   | 1  | 14.0 | 12.0,  |
|        |       | 0-7   | 3‡ |      | 12.2   | 62 |      | 16.1   |
+--------+-------+-------+----+------+--------+----+------+--------+
| 1 -- 2 | **    | Days  | 37 | 2.7  | 1.9,   | 22 | 1.9  | 1.2,   |
| inches | Moder | 0-3   |    |      | 3.7    |    |      | 2.9    |
|        | ate** |       |    |      |        |    |      |        |
+--------+-------+-------+----+------+--------+----+------+--------+
|        | ** ** | Days  | 18 | 1.3  | 0.8,   | 1  | 0.1  | 0.0,   |
|        |       | 4-7   |    |      | 2.1    |    |      | 0.5    |
+--------+-------+-------+----+------+--------+----+------+--------+
|        | ** ** | Days  | 40 | 2.9  | 2.1,   | 22 | 1.9  | 1.2,   |
|        |       | 0-7   |    |      | 4.0    |    |      | 2.9    |
+--------+-------+-------+----+------+--------+----+------+--------+
| \> 2   | **Sev | Days  | 15 | 1.1  | 0.6,   | 1  | 0.1  | 0.0,   |
| inches | ere** | 0-3   |    |      | 1.8    |    |      | 0.5    |
+--------+-------+-------+----+------+--------+----+------+--------+
|        | ** ** | Days  | 4  | 0.3  | 0.1,   | 0  | 0.0  | 0.0,   |
|        |       | 4-7   |    |      | 0.8    |    |      | 0.3    |
+--------+-------+-------+----+------+--------+----+------+--------+
|        | ** ** | Days  | 15 | 1.1  | 0.6,   | 1  | 0.1  | 0.0,   |
|        |       | 0-7   |    |      | 1.8    |    |      | 0.5    |
+--------+-------+-------+----+------+--------+----+------+--------+

  ---------------- -------------- -------- -------------- -------- --------- ----------------- -------- ------- ---------
  **Cont. MTA-09:                                                                                               
  Local adverse                                                                                                 
  reactions (Days                                                                                               
  0-3, 4-7, 0-7)**                                                                                              

                                           **Menactra**                      **Menomune^®^**                    

                                           **N= 1371**                       **N= 1159**                        

  **Reaction**     **Severity**   ** **    **n**\*        **%†**   **95%     **n**\*           **%**†   **95%   
                                                                   CI**                                 CI**    

  **Swelling**                                                                                                  

                   **Any**        Days 0-3 171            12.5     10.8,     86                7.4      6.0,    
                                                                   14.3                                 9.1     

                   ** **          Days 4-7 36             2.6      1.9, 3.6  3                 0.3      0.1,    
                                                                                                        0.8     

                   ** **          Days 0-7 173            12.6     10.9,     88                7.6      6.1,    
                                                                   14.5                                 9.3     

  \< 1 inch        **Mild**       Days 0-3 127            9.3      7.8, 10.9 78                6.7      5.4,    
                                                                                                        8.3     

                   ** **          Days 4-7 24             1.8      1.1, 2.6  3                 0.3      0.1,    
                                                                                                        0.8     

                   ** **          Days 0-7 128            9.3      7.9, 11.0 80                6.9      5.5,    
                                                                                                        8.5     

  1 -- 2 inches    **Moderate**   Days 0-3 31             2.3      1.5, 3.2  8                 0.7      0.3,    
                                                                                                        1.4     

                   ** **          Days 4-7 9              0.7      0.3, 1.2  0                 0.0      0.0,    
                                                                                                        0.3     

                   ** **          Days 0-7 32             2.3      1.6, 3.3  8                 0.7      0.3,    
                                                                                                        1.4     

  \> 2 inches      **Severe**     Days 0-3 13             0.9      0.5, 1.6  0                 0.0      0.0,    
                                                                                                        0.3     

                   ** **          Days 4-7 3              0.2      0.1, 0.6  0                 0.0      0.0,    
                                                                                                        0.3     

                   ** **          Days 0-7 13             0.9      0.5, 1.6  0                 0.0      0.0,    
                                                                                                        0.3     

  **Induration**   ** **                                                                                        

                   **Any**        Days 0-3 233            17.0     15.0,     125               10.8     9.1,    
                                                                   19.1                                 12.7    

                   ** **          Days 4-7 49             3.6      2.7, 4.7  6                 0.5      0.2,    
                                                                                                        1.1     

                   ** **          Days 0-7 235            17.1     15.2,     127               11.0     9.2,    
                                                                   19.2                                 12.9    

  \< 1 inch        **Mild**       Days 0-3 180            13.1     11.4,     113               9.7      8.1,    
                                                                   15.0                                 11.6    

                   ** **          Days 4-7 33             2.4      1.7, 3.4  5                 0.4      0.1,    
                                                                                                        1.0     

                   ** **          Days 0-7 179‡           13.1     11.3,     115               9.9      8.3,    
                                                                   15.0                                 11.8    

  1 -- 2 inches    **Moderate**   Days 0-3 44             3.2      2.3, 4.3  12                1.0      0.5,    
                                                                                                        1.8     

                   ** **          Days 4-7 13             0.9      0.5, 1.6  1                 0.1      0.0,    
                                                                                                        0.5     

                   ** **          Days 0-7 47             3.4      2.5, 4.5  12                1.0      0.5,    
                                                                                                        1.8     

  \> 2 inches      **Severe**     Days 0-3 9              0.7      0.3, 1.2  0                 0.0      0.0,    
                                                                                                        0.3     

                   ** **          Days 4-7 3              0.2      0.1, 0.6  0                 0.0      0.0,    
                                                                                                        0.3     

                   ** **          Days 0-7 9              0.7      0.3, 1.2  0                 0.0      0.0,    
                                                                                                        0.3     

  **Pain**                                                                                                       

                   **Any**        Days 0-3 736            53.7     51.0,     556               48.0             45.1,
                                                                   56.4                                         50.9

                   ** **          Days 4-7 82             6.0      4.8, 7.4  7                 0.6              0.2, 1.2

                   ** **          Days 0-7 739            53.9     51.2,     558               48.1             45.2,
                                                                   56.6                                         51.1

                   **Mild**       Days 0-3 578            42.2     39.5,     518               44.7             41.8,
                                                                   44.8                                         47.6

                   ** **          Days 4-7 73             5.3      4.2, 6.7  6                 0.5              0.2, 1.1

                   ** **          Days 0-7 581            42.4     39.7,     519               44.8             41.9,
                                                                   45.0                                         47.7

                   **Moderate**   Days 0-3 155            11.3     9.7, 13.1 37                3.2              2.3, 4.4

                   ** **          Days 4-7 9              0.7      0.3, 1.2  1                 0.1              0.0, 0.5

                   ** **          Days 0-7 155            11.3     9.7, 13.1 38                3.3              2.3, 4.5

                   **Severe**     Days 0-3 3              0.2      0.1, 0.6  1                 0.1              0.0, 0.5

                   ** **          Days 4-7 0              0.0      0.0, 0.2  0                 0.0              0.0, 0.3

                                  Days 0-7 3              0.2      0.1, 0.6  1                 0.1              0.0, 0.5
  ---------------- -------------- -------- -------------- -------- --------- ----------------- -------- ------- ---------

\*n: number of participants reporting at least one event in this
category. Thirteen Menactra and 11 Menomune participants did not provide
any information. Percentages were based on the total number of
participants who did provide safety information at each time point.

**†**%: n/N expressed as a percentage.

Pain: 0=none, 1= (mild) sx present, but arm movement not affected, 2=
(moderate) limits usual arm movement, 3= (severe) disabling

  -------------- -------------- -------------- -------------- --------------- --------------
  **MTA-09:                                                                   
  Injection Site                                                              
  Pain,                                                                       
  Participants                                                                
  18-25 & 22-55                                                               
  years old,                                                                  
  Days 0-7**                                                                  

                                **Menactra**                  **Menomune®**   

  **Local Pain** **Severity**   **%**          **95% CI**     **%**           **95% CI**

  **Age 18-25    **Any**        61.1           57.5, 64.5     51.8            47.9, 55.6
  years**                                                                     

                 **Mild**       45.8           42.3, 49.4     47.9            44.1, 51.8

                 **Moderate**   15.2           12.9, 18.0     3.7             2.5, 5.5

                 **Severe**     0.0            0.0, 0.0       0.2             0.0, 0.9

  **Age 26-55    **Any**        45.1           41.2, 49.1     43.6            39.4, 47.9
  years**                                                                     

                 **Mild**       38.2           34.4, 42.1     40.9            36.7, 45.2

                 **Moderate**   6.5            4.8, 8.7       2.7             1.6, 4.5

                 **Severe**     0.5            0.8, 1.4       0.0             0.0, 0.8
  -------------- -------------- -------------- -------------- --------------- --------------

\*n: number of participants reporting at least one event in this
category. N= Total number of participants for whom safety information is
available for this time point.

**†**%: n/N expressed as a percentage.

Pain: 0=none, 1= (mild) sx present, but arm movement not affected, 2=
(moderate) limits usual arm movement, 3= (severe) disabling

Systemic Reactions:

  ------------------ -------------- -------------- -------- ----------- ----------------- -------- -----------
  **MTA-09: Systemic                                                                               
  adverse reactions                                                                                
  (Days 0-7)**                                                                                     

                                    **Menactra**                        **Menomune^®^**            

                                    **N= 1371**                         **N= 1159**                

  **Reaction**       **Severity**   **n**\*        **%**†   **95% CI**  **n**\*           **%**†   **95% CI**

  **Fever**                                                                                         

                     **Any**        21             1.5      1.0, 2.3    6                 0.5      0.2, 1.1

  38.0ºC-38.9ºC      **Mild**       17             1.2      0.7, 2.0    5                 0.4      0.1, 1.0

  39.0ºC-39.9ºC      **Moderate**   4              0.3      0.1, 0.8    1                 0.1      0.0, 0.5

  [\>]{.underline}   **Severe**     0              0        0.0, 0.2    0                 0        0.0, 0.3
  40.0ºC                                                                                           

  **Headache**                                                                                      

                     **Any**        568            41.4     38.8, 44.1  484               41.8     38.9, 44.7

                     Mild           414            30.2     27.8, 32.7  370               31.9     29.3, 34.7

                     **Moderate**   138            10.1     8.5, 11.8   103               8.9      7.3, 10.7

                     **Severe**     16             1.2      0.7, 1.9    11                0.9      0.5, 1.7

  **Fatigue**        ** **                                                                          

                     **Any**        476            34.7     32.2, 37.3  374               32.3     29.6, 35.1

                     **Mild**       350            25.5     23.2, 27.9  293               25.3     22.8, 27.9

                     **Moderate**   114            8.3      6.9, 9.9    76                6.6      5.2, 8.1

                     **Severe**     12             0.9      0.5, 1.5    5                 0.4      0.1, 1.0

  **Malaise**                                                                                       

                     **Any**        324            23.6     21.4, 26.0  259               22.3     20.0, 24.9

                     **Mild**       219            16       14.1, 18.0  195               16.8     14.7, 19.1

                     **Moderate**   90             6.6      5.3, 8.0    54                4.7      3.2, 6.0

                     **Severe**     15             1.1      0.6, 1.8    10                0.9      0.4, 1.6

  **Chills**         ** **                                                                          

                     **Any**        133            9.7      8.2, 11.4   65                5.6      4.4, 7.1

                     **Mild**       96             7.0      5.7, 8.5    53                4.6      3.4, 5.9

                     **Moderate**   29             2.1      1.4, 3.0    12                1        0.5, 1.8

                     **Severe**     8              0.6      0.3, 1.2    0                 0        0.0, 0.3

  **Arthralgia**     ** **                                                                          

                     **Any**        272            19.8     17.8, 22.1  185               16       13.9, 18.2

                     **Mild**       204            14.9     13.0, 16.9  154               13.3     11.4, 15.4

                     **Moderate**   64             4.7      3.6, 5.9    30                2.6      1.8, 3.7

                     **Severe**     4              0.3      0.1, 0.8    1                 0.1      0.0, 0.5
  ------------------ -------------- -------------- -------- ----------- ----------------- -------- -----------

  ------------------- -------------- -------------- -------- ----------- ----------------- -------- -----------
  **Cont. MTA-09:                                                                                   
  Systemic adverse                                                                                  
  reactions (Days                                                                                   
  0-7)**                                                                                            

                                     **Menactra**                        **Menomune^®^**            

                                     **N= 1371**                         **N= 1159**                

  **Reaction**        **Severity**   **n**\*        **%**†   **95% CI**  **n**\*           **%**†   **95% CI**

  **Anorexia**                                                                                       

                      **Any**        162            11.8     10.2, 13.6  115               9.9      8.3, 11.8

  Skips 1 meal        **Mild**       125            9.1      7.7, 10.8   91                7.9      6.4, 9.6

  Skips 2 meals       **Moderate**   32             2.3      1.6, 3.3    19                1.6      1.0, 2.6

  Skips               **Severe**     5              0.4      0.1, 0.9    5                 0.4      0.1, 1.0
  [\>]{.underline} 3                                                                                
  meals                                                                                             

  **Vomiting**                                                                                       

                      **Any**        32             2.3      1.6, 3.3    17                1.5      0.9, 2.3

  1 episode           **Mild**       24             1.8      1.1, 2.6    10                0.9      0.4, 1.6

  2 episodes          **Moderate**   5              0.4      0.1, 0.9    2                 0.2      0.0, 0.6

  [\>]{.underline}3   **Severe**     3              0.2      0.1, 0.6    5                 0.4      0.1, 1.0
  episodes                                                                                          

  **Diarrhea**                                                                                       

                      **Any**        219            16       14.8, 18.0  162               14       12.0, 16.1

  1-2 episodes        **Mild**       178            13       11.3, 14.9  124               10.7     9.0, 12.6

  3-4 episodes        **Moderate**   36             2.6      1.9, 3.6    34                2.9      2.0, 4.1

  [\>]{.underline} 5  **Severe**     5              0.4      0.1, 0.9    4                 0.3      0.1, 0.9
  episodes                                                                                          

  **Seizures** (Y/N)                                                                                 

  Yes                 **Days 0-3**   0              0        0.0, 0.2    0                 0        0.0, 0.3

  Yes                 **Days 4-7**   0              0        0.0, 0.2    0                 0        0.0, 0.3

  Yes                 **Days 0-7**   0              0        0.0, 0.2    0                 0        0.0, 0.3

  **Rash**            ** **                                                                          

  Any rash            **Days 0-3**   15             1.1      0.6, 1.8    7                 0.6      0.2, 1.2

  Any rash            **Days 4-7**   10             0.7      0.4, 1.3    3                 0.3      0.1, 0.8

  Any rash            **Days 0-7**   19             1.4      0.8, 2.2    9                 0.8      0.4, 1.5
  ------------------- -------------- -------------- -------- ----------- ----------------- -------- -----------

\*n: number of participants reporting at least one event in this
category. Thirteen Menactra and 11 Menomune participants did not provide
any information. Percentages were based on the total number of
participants who did provide safety information at each time point.

**†**%: n/N expressed as a percentage.

Headache, chills, arthralgia, fatigue, malaise: 0= none, 1= aware,
easily tolerated, 2= interferes with usual activities, 3= disabling

##### Primary Hypothesis Testing

The proportion of Menactra participants with at least one severe
systemic reaction during Days 0-7 was 0.038 (3.8%) and 0.026 (2.6%) in
the Menomune^®^ group. The upper limit of the two-sided 90% CI, and 95%
CI, for the difference in two proportions was 0.021 (2.1%), and 0.023
(2.3%), respectively.

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+---+----------+---+--------+------------+----------------+-------------+
| # |          | * |        | ** **      | **Upper Limit  | **Upper     |
| # |          | * |        |            | of**           | Limit of**  |
| # |          | M |        |            |                |             |
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+---+----------+---+--------+------------+----------------+-------------+
| N |          | N |        | ** **      | **the 2-sided  | **the       |
| = |          | = |        |            | 90% CI‡**      | 2-sided 95% |
| 1 |          | 1 |        |            |                | CI‡**       |
| 3 |          | 1 |        |            |                |             |
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+---+----------+---+--------+------------+----------------+-------------+
| * | **       | * | *      | **Ratio    | **of the       | **of the    |
| * | *P*~Mena | * | **p*~M | *p*        | Ratio**        | Ratio**     |
| n | ctra†~** | n | enomun | ~Menactra~ |                |             |
| \ |          | ^ | e®†~** | /          |                |             |
| * |          | \ |        | *p*~Meno   |                |             |
| * |          | * |        | mune®\ ~** |                |             |
| * |          | ^ |        |            |                |             |
|   |          | * |        |            |                |             |
|   |          | * |        |            |                |             |
+---+----------+---+--------+------------+----------------+-------------+
| 5 | 0.038    | 3 | 0.026  | 1.5        | 2.1            | 2.3         |
| 2 |          | 0 |        |            |                |             |
+---+----------+---+--------+------------+----------------+-------------+

\*n: Number of participants with at least 1 severe systemic reaction or
rash. N= Total number of participants for whom safety information is
available.

†*p*~Menactra~ and *p*~Menomune®~ : proportion of participants with at
least one severe systemic reaction or rash in the Menactra and
Menomune^®^ groups, respectively.

**‡**CI: Confidence interval

[Note:]{.underline} For analysis purposes, all rashes were counted as
severe solicited systemic reactions. Also, for each reaction, each
participant is counted no more than once.

> *Reviewer comment:* Aside from rash, 15 of 35 (43%) Menactra
> participants reported more than one severe systemic adverse event
> (AEs), as follows: 7 severe AEs (one participant), 5 AEs (one
> participant), 4 AEs (two participants), 3 AEs (seven participants),
> and 2 AEs (four participants). For 2 Menactra participants, severe
> systemic reactions consisted of fatigue and malaise. In the Menomune
> group, 8 of 23 (36%) participants reported two or more severe systemic
> reactions, as follows: 5 severe AEs (one participant), 4 AEs (two
> participants), 3 AEs (three participants), and 2 AEs (two
> participants).

1.  **[Study MTA-14]{.underline}**

**Title: A Trial of the Lot Consistency of an Experimental Tetravalent
(A, C, Y, and W-135) Meningococcal Diphtheria Toxoid Conjugate Vaccine
Among Healthy U.S. Adults**

**Safety Objectives** (The primary objective pertained to
immunogenicity)

-   [Secondary objectives:]{.underline}

```{=html}
<!-- -->
```
-   To compare the safety profile of each Menactra vaccine lot

-   To compare the safety profile for Menactra (3 lots combined) and
    Menomune^®^ participants 26-55 years old

```{=html}
<!-- -->
```
-   [Other objectives:]{.underline}

```{=html}
<!-- -->
```
-   To describe the safety profile of each Menactra vaccine lot

-   To describe any relationship between post-vaccination reactogenicity
    and elevated pre-vaccination SBA-BR titer in all participants who
    receive Menactra

**Design:** The study was a randomized (1:1:1 for each Menactra lot),
modified double blind, multi-center trial. An active control group was
also included to enable safety comparisons in the 26-55 year old group,
and enrollment was stratified by age to ensure adequate representation
of participants for the safety assessment. Participants 18-25 years old
were randomized to receive one of three Menactra vaccine, and
participants 26-55 years old were randomized to receive either Menactra
(lots 1, 2, or 3) or Menomune^®^. The study was conducted at twenty-four
study centers in the United States.

**Secondary Endpoints:**

-   The proportion of participants who experience at least one systemic
    reaction reported as severe during the 7-day period following
    vaccination is similar among the three vaccine lots.

-   The proportion of participants 26-55 years old (3 Menactra lots
    combined) who experience at least one systemic reaction reported as
    severe during the 7-day period following vaccination.

**Statistical plan** (The primary hypothesis and secondary hypothesis #2
pertained to immunogenicity)

**Secondary Hypotheses:**

*[Secondary Hypothesis #1:]{.underline}*

To demonstrate that the proportion of participants who experience at
least one systemic reaction reported as severe during the 7 day period
following vaccination is similar among the three vaccine lots.

This hypothesis would be supported by the data if the upper limit of the
2-sided 95% CI of p~max~ -- p~min~ \<0.1, where p~max~ and p~min~ are
the maximum and minimum proportion of participants with safety responses
following vaccination with one of three Menactra vaccine lots.

*[Secondary Hypothesis #3:]{.underline}*

To demonstrate that the safety response among 26-55 year old
participants in the three Menactra groups is non-inferior to
Menomune^®^, as measured by the proportion of participants who
experience at least one systemic reaction reported as severe during the
7 day period following vaccination.

This hypothesis would be supported by the data if the upper limit of the
2-sided 95% CI of the difference in two proportions is less than 0.1.
For this analysis, safety data from all Menactra participants 26-55
years old (lots #1-3) were combined and compared to data from
age-matched Menomune^®^ recipients.

**Results**

A total of 2040 (Menactra lot 1 n= 527, Menactra lot 2 n= 528, Menactra
lot 3 n= 527, Menomune^®^ n= 458) adults were enrolled, and 1886
(Menactra lot 1 n= 491, Menactra lot 2 n= 480, Menactra lot 3 n= 490,
Menomune^®^ n= 425) individuals completed the study. The intent-to-treat
population for safety, for the Menactra lot consistency comparisons,
included 1582 participants (Menactra lot 1 n= 527, lot 2 n= 528, lot 3
n= 527). Participants completing the safety assessment 6 months after
vaccination are summarized in [section 6.5]{.underline}.

##### Secondary Hypothesis #1

The proportion of Menactra vaccine lot #1, #2, and #3. with at least one
severe systemic reaction during Days 0-7 was 0.035 \[18/521\], 0.033
\[17/521\] and 0.027 \[14/522\], respectively. The upper limit of the
two-sided 95% CI for the difference in maximum and minimum proportions
was 0.03 (3.0%).

##### Secondary Hypothesis #3

The proportion of Menactra participants 26-55 years old with at least
one severe systemic reaction during Days 0-7 was 0.022 \[15/685\] and
0.055 \[25/455\] in the Menomune^®^ group. The upper limit of the
two-sided 95% CI, for the difference in two proportions was -0.01
(-1.0%).

1.  **SAEs and safety assessment 6 months post-vaccination**

The number of subjects completing the safety assessment 6 months
post-vaccination for studies MTA-02, -04, -09, and --14 is summarized in
the following table:

> ![](media/image9.wmf)
>
> *Reviewer comment*: No apparent increase in the frequency of newly
> diagnosed asthma, diabetes mellitus, or autoimmune disease was
> observed based on the data available.

**Serious Adverse Events**

Two deaths unrelated to vaccination occurred in study MTA-14. A 25-year
old woman, who received Menactra lot #3, died in a motor vehicle
accident 109 days after vaccination. The second participant, a 35-year
old man, developed cardiopulmonary arrest approximately two hours after
drug ingestion, and died at home on the same day. The emergency medical
service had not been contacted, and details regarding the type of drug
and how the body was discovered were not provided. The event occurred 72
days after Menomune^®^ vaccination.

One SAE was reported by the investigator as possibly related to
vaccination. A 17- year old Menactra participant, in study MTA-04,
developed severe esophagitis and was hospitalized six days following
immunization. A plausible cause for the event included a history of a
sports-related back injury, four weeks prior to enrollment, and extended
NSAID use thereafter. The event was thus considered by the CBER clinical
reviewer as unlikely related to vaccination.

6.  **Concurrent Immunizations**

Concurrent immunizations with two vaccines, Typhim Vi^®^ and Td, was
assessed in two separate studies.

1.  **[Study MTA-11]{.underline}**

**Title: Immunogenicity and Safety of Typhoid Vi**^®^ **Vaccine When
Administered Concomitantly with an Experimental Tetravalent (A, C, Y,
and W-135) Meningococcal Diphtheria Toxoid Conjugate Vaccine in Adults
in the U.S.**

**Objectives**

-   [Primary objectives:]{.underline}

    1.  To compare the post-vaccination antibody level to typhoid Vi
        polysaccharide antigen (anti-Vi PS), when Typhim Vi^®^ vaccine
        is co-administered with a saline placebo or with Menactra.

    2.  To compare the bactericidal antibody response to serogroups A,
        C, Y, W135, using baby rabbit complement (SBA-BR), when Menactra
        is co-administered with Typhim Vi^®^, to the corresponding
        antibody response when Menactra is given 28 days after Typhim
        Vi^®^.

-   [Secondary objectives]{.underline}:

1.  To compare the post-vaccination antibody level to Typhoid Vi
    antigen, when Typhim Vi^®^ vaccine is co-administered with a saline
    placebo or with Menactra.

2.  To compare the bactericidal antibody titer to serogroups A, C, Y,
    W135, using baby rabbit complement (SBA-BR), when Menactra is
    co-administered with Typhim Vi^®^, to the corresponding antibody
    response when Menactra is given 28 days after Typhim Vi^®^

-   [Other objectives:]{.underline}

```{=html}
<!-- -->
```
-   To describe the SBA-BR titer to each serogroup, pre- and 28 days
    post-vaccination, in each vaccine group

-   To describe the anti-Vi PS antibody level, pre- and 28 days
    post-vaccination, in each vaccine group

-   To describe the distribution of participants with at least a 4-fold
    increase in anti-Vi PS antibody level, when Typhim Vi^®^ vaccine is
    co-administered with a saline placebo or with Menactra.

**Design**

The study was a randomized, double blind, multi-center, controlled
trial. Participants were randomized in a 1: 1 ratio (Menactra + Vi: Vi,
then Menactra). Participants were enrolled at twelve study centers in
the United States.

**Vaccine administration**

Each group received two injections 28 days apart. Group A received
Typhim Vi^®^ + Menactra, then a saline placebo. Group B received Typhim
Vi^®^ + saline placebo, followed by Menactra. Participants received all
injections intramuscularly.

The [typhoid Vi polysaccharide vaccine]{.underline}, Typhim Vi^®^, is
commercially available in the United States. Each 0.5ml dose contains 25
µg of purified Vi polysaccharide, isotonic phosphate buffered saline,
and 0.25% phenol, which is added as a preservative. The vaccine also
contains residual polydimethylsiloxane or fatty acid ester based
antifoam. The vaccine is formulated as a clear colorless solution, and
packaged in a unit dose syringe.

[Buffered Sterile Normal Saline]{.underline} (0.9% NaCl) was utilized as
the placebo.

**Primary Endpoints:**

-   The proportion of participants who achieve a protective level of
    anti-Vi polysaccharide antibody when Typhim Vi^®^ vaccine is given
    together with a saline placebo, followed by Menactra 28 days later.

-   The proportion of participants with at least a 4-fold rise in SBA-BR
    antibody titer to serogroups A, C, Y, and W-135 in the Typhim Vi^®^+
    Menactra group is non-inferior to the proportion in the group
    receiving Typhim Vi^®^ + placebo, followed by Menactra 28 days
    later.

**Secondary endpoints:**

-   Anti-Vi PS antibody titer among these recipients is non-inferior to
    the same parameter among the group given Typhim Vi^®^ + placebo,
    followed by Menactra 28 days later.

-   SBA-BR antibody titer for serogroups A, C, Y, and W135 in the group
    receiving a staggered dosing regimen of Menactra and Typhoid Vi^®^
    vaccines is non-inferior to the same parameter in the group
    receiving the two vaccines concomitantly.

####### Surveillance

[Monitored parameters:]{.underline}

[Safety:]{.underline} Study participants were monitored for immediate
reactions 30 minutes after vaccination, and for local and systemic
reactogenicity during the 7 days following vaccination. Pre-specified
adverse events included localized reactions (erythema, swelling,
induration, pain) and systemic symptoms (fever measured by oral
temperature, headache, fatigue, chills, arthralgia, anorexia, vomiting,
diarrhea, seizures, malaise and rash), which were assessed after each
vaccination. These events were recorded daily on a diary card, and also
collected by study personnel through telephone interview eight days
after each vaccination. If rash was reported, the investigator was
prompted to record additional details on a separate case report form.
Other non-serious, unexpected adverse events were obtained by telephone
interview eight and twenty-eight days after each vaccination. Serious
adverse events were reported and recorded during the entire study
duration.

[Efficacy (Immunogenicity):]{.underline}

Serum samples were obtained pre- and 28 days after each vaccination.

[Anti-Meningococcal Antibody]{.underline}

Functional antibody activity to each serogroup was determined using a
serum bactericidal assay. The lower limit of detection for this assay,
using baby rabbit complement, is an antibody titer of 8.

[Anti-Vi Polysaccharide Antibody]{.underline}

Anti-Vi polysaccharide antibody was measured by a radioimmunoassay
(RIA), according to a "Farr" type radioimmunologic method. Antibodies
present in the blood sample bind to an Iodine 125 labeled Vi antigen,
and form an immunological complex, which is then precipitated by an
ammonium sulfate solution. The radioactivity measured in the precipitate
is proportional to the quantity of Vi antibodies present in the sample.

**Statistical plan**

**Primary Hypotheses:**

*[Primary Hypothesis #1:]{.underline}*

To demonstrate that 28 days following concomitant vaccination with
Typhim Vi^®^ vaccine (Vi) and Menactra, the proportion of participants
who achieve a protective level of anti-Vi polysaccharide (Vi PS)
antibody is non-inferior to the proportion of participants who achieve a
protective level of anti-Vi polysaccharide antibody when Typhim Vi^®^
vaccine is given together with a saline placebo, followed by Menactra 28
days later.

This hypothesis would be supported by the data if the upper bound of the
two-sided 95% CI of the difference *p* ~Vi\ +\ placebo~ -- *p*
~Vi\ +\ Menactra~ \< 0.1, where *p* is the proportion of participants,
in the \[Vi + placebo, then Menactra\] and \[Vi + Menactra\] groups,
respectively, who achieve an anti-Vi antibody level [\>]{.underline}1
μg/mL. The sample size provided 99.9% power to achieve the primary
hypothesis. Testing of the primary hypothesis was conducted at the 0.025
significance level.

*[Primary Hypothesis #2:]{.underline}*

To demonstrate that 28 days post-vaccination with Menactra, the
proportion of participants with at least a 4-fold rise in SBA-BR
antibody titer to serogroups A, C, Y, and W-135 in the Typhim Vi^®^+
Menactra group is non-inferior to the proportion in the group receiving
Typhim Vi^®^ + placebo, followed by Menactra 28 days later.

This hypothesis would be supported by the data if the upper bound of the
two-sided 95% CI of *p* ~Menactra~ -- *p* ~Vi\ +\ Menactra~ \< 0.1,
where *~P~* is the proportions of participants with at least a 4-fold
rise in SBA-BR antibody to meningococcal serogroups A, C, Y, and W-135,
in the \[Vi + placebo, then Menactra\] and \[Vi +Menactra\] groups,
respectively. The sample size provided at least 94% power to achieve the
primary hypothesis for each serogroup. All tests of the primary
hypothesis were conducted at the 0.025 significance level.

The primary analyses were based on data generated from the per-protocol
population.

**Secondary Hypotheses:**

*[Secondary Hypothesis #1:]{.underline}*

To demonstrate that 28 days following concomitant vaccination with
Typhim Vi^®^ vaccine and Menactra, the anti-Vi PS antibody titer among
these recipients is non-inferior to the same parameter among the group
given Typhim Vi^®^ + placebo, followed by Menactra 28 days later.

This hypothesis would be supported by the data if the upper bound of the
two-sided 95% CI of the ratio of GMT~Vi\ +\ placebo~ /
GMT~Vi\ +\ Menactra~ \< 2.

*[Secondary Hypothesis #2:]{.underline}*

To demonstrate that 28 days after vaccination with Menactra, the SBA-BR
antibody titer for serogroups A, C, Y, and W135 in the group receiving a
staggered dosing regimen of Menactra and Typhoid Vi^®^ vaccines is
non-inferior to the same parameter in the group receiving the two
vaccines concomitantly.

This hypothesis would be supported by the data if the upper bound of the
two-sided 95% CI of the ratio of GMT ~Menactra~ / GMT ~Vi\ +\ Menactra~
\< 2, where GMT ~Menactra~ and GMT ~Vi\ +\ Menactra~ are the proportion
of participants with at least a 4-fold rise in SBA-BR antibody to
meningococcal serogroups A, C, Y, and W-135, in the Vi + placebo and
Vi + Menactra groups, respectively. The statistical methods include an
analysis of covariance with the baseline outcome as a covariate. The
post-vaccination SBA-BR GMTs are calculated as a log~2~ titer.

**Per-protocol population for immunogenicity:**

The per-protocol population included all eligible participants who
received the assigned vaccine at visits 1 & 2, who complied with
scheduled visits for blood specimens, and for whom a sufficient quantity
of paired sera was available for analysis.

**Intent-to-treat population for safety:**

The intent-to-treat population consisted of all participants who
received one dose of vaccine and for whom safety information was
available. Analyses were performed according to the vaccine received.

All rashes occurring during the first 7 days after vaccination were
designated, for the purpose of analysis, as a severe solicited systemic
reaction.

**Results**

The group given Typhim Vi^®^ (Vi) co-administered with Menactra, is
designated Group A. The group receiving a staggered vaccination schedule
\[Vi + saline placebo, then Menactra 28 days later\] is designated Group
B. A total of 945 (Group A n= 469, Group B n= 476) adults were enrolled,
and 871 (Group A n= 432, Group B n= 439) individuals completed the
study.

[Safety population:]{.underline}

The intent-to-treat population for safety included all enrolled
participants (n= 945).

[Immunogenicity population:]{.underline}

The per-protocol population included 839 participants (Group A n=419,
Group B n=420).

*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
(73.2%), but also included African American (10.6%), Hispanic (11.4%),
Asian populations (3.1%) and individuals with mixed racial background
(1.7%).

**Immunogenicity**

[Antibody response to Vi Polysaccharide (Vi PS):]{.underline}

  --------------------- ------------ -------------------------- ------------ --------------------------- ----------------------- ---------------
  **MTA-11: Number and                                                                                                           
  Proportion of                                                                                                                  
  Participants 18-55                                                                                                             
  Years Old With                                                                                                                 
  Anti-Vi PS Antibody                                                                                                            
  Level                                                                                                                          
  [\>]{.underline} 1.0                                                                                                           
  ug/ml                                                                                                                          
  Post-vaccination**                                                                                                             

                        **Vi +                                  **Vi +                                   ** **                    
                        Placebo,**                              Menactra**                                                       

                        **Then                                  **Then                                   **Difference**          **Upper Limit
                        Menactra**                              Placebo**                                                        of the**

                        N=418                                   N=418                                    (*p*~Vi\ +\ Placebo~ -  **2-sided 95%
                                                                                                                                 CI**

                        **n\***      ***p*~Vi\ +\ Placebo†~**   **n\***      ***p*~Vi\ +\ Menactra‡~**   *p*~Vi\ +\ Menactra~)   **for the
                                                                                                                                 Difference§**

  Vi PS antibody                                                                                                                  

  [\>]{.underline}1.0   331          0.792                      342          0.818                       -0.026                  0.027
  µg/mL                                                                                                                          
  --------------------- ------------ -------------------------- ------------ --------------------------- ----------------------- ---------------

\* n: number of participants with anti-Vi PS antibody titer
[\>]{.underline} 1.0 µg/mL. N: total number of participants with valid
serology results on Day 28.

† *p*~Vi\ +\ Placebo**:\ **~proportion of participants with anti-Vi PS
antibody titer [\>]{.underline} 1.0 µg/mL in the group given Typhim
Vi^®^ vaccine together with a saline placebo, and then Menactra 28 days
later.

‡ *p~Vi\ +\ ~*~Menactra~: proportion of participants with anti-Vi PS
antibody titer [\>]{.underline} 1.0 µg/mL in the group given Typhim
Vi^®^ concomitantly with Menactra.

§ CI: Confidence interval.

[Proportions with four-fold or greater increases in SBA-BR
titer:]{.underline}

+--------+-----+-------+----+---------+-------------+----------------+
| ####   |     |       |    |         |             |                |
| #### M |     |       |    |         |             |                |
| TA-11: |     |       |    |         |             |                |
|  Numbe |     |       |    |         |             |                |
| r and  |     |       |    |         |             |                |
| Propor |     |       |    |         |             |                |
| tion o |     |       |    |         |             |                |
| f Part |     |       |    |         |             |                |
| icipan |     |       |    |         |             |                |
| ts 18- |     |       |    |         |             |                |
| 55 Yea |     |       |    |         |             |                |
| rs Old |     |       |    |         |             |                |
|  with  |     |       |    |         |             |                |
| a ≥ 4- |     |       |    |         |             |                |
| Fold I |     |       |    |         |             |                |
| ncreas |     |       |    |         |             |                |
| e in S |     |       |    |         |             |                |
| BA-BR  |     |       |    |         |             |                |
| Antibo |     |       |    |         |             |                |
| dy Tit |     |       |    |         |             |                |
| ers on |     |       |    |         |             |                |
|  Day 2 |     |       |    |         |             |                |
| 8, com |     |       |    |         |             |                |
| pared  |     |       |    |         |             |                |
| to Bas |     |       |    |         |             |                |
| eline  |     |       |    |         |             |                |
+--------+-----+-------+----+---------+-------------+----------------+
|        | **V |       | ** |         |             |                |
|        | i + |       | Vi |         |             |                |
|        | P   |       |  + |         |             |                |
|        | lac |       | Me |         |             |                |
|        | ebo |       | na |         |             |                |
|        | ,** |       | ct |         |             |                |
|        |     |       | ra |         |             |                |
|        |     |       | ** |         |             |                |
+--------+-----+-------+----+---------+-------------+----------------+
| ** **  | **T |       | *  |         | **Di        | **Upper Limit  |
|        | hen |       | *  |         | fference ** | of the**       |
|        | M   |       | Th |         |             |                |
|        | ena |       | en |         |             |                |
|        | ctr |       | P  |         |             |                |
|        | a** |       | la |         |             |                |
|        |     |       | ce |         |             |                |
|        |     |       | bo |         |             |                |
|        |     |       | ** |         |             |                |
+--------+-----+-------+----+---------+-------------+----------------+
| *      | N=  |       | N  |         | (*p         | **2-sided 95%  |
| *Serog | 419 |       | =4 |         | *~Menactra~ | CI**           |
| roup** |     |       | 18 |         | -           |                |
+--------+-----+-------+----+---------+-------------+----------------+
|        | **n | ***   | *  | ***p    | *p*~Vi\ +\  | **for the      |
|        | ^\* | p*~Me | *n | *~Vi\ + |  Menactra~) | Difference**   |
|        | ^** | nactr | \* | \ Menac |             |                |
|        |     | a†~** | ** | tra‡~** |             |                |
+--------+-----+-------+----+---------+-------------+----------------+
| >      | 315 | 0.752 | 3  | 0.797   | -0.045      | 0.012          |
|  **A** |     |       | 33 |         |             |                |
+--------+-----+-------+----+---------+-------------+----------------+
| >      | 370 | 0.883 | 3  | 0.895   | -0.012      | 0.031          |
|  **C** |     |       | 74 |         |             |                |
+--------+-----+-------+----+---------+-------------+----------------+
| >      | 273 | 0.657 | 3  | 0.744   | -0.093      | -0.031         |
|  **Y** |     |       | 11 |         |             |                |
+--------+-----+-------+----+---------+-------------+----------------+
| > **W  | 351 | 0.838 | 3  | 0.852   | -0.014      | 0.035          |
| -135** |     |       | 56 |         |             |                |
+--------+-----+-------+----+---------+-------------+----------------+

\* n: number of participants with a [\>]{.underline} 4-fold increase in
SBA-BR titer compared with baseline. N: total number of participants
with valid serology results on Day 28.

† %: proportion of participants with a ≥ 4-fold rise from baseline SBA
titer in the group given a staggered vaccine or concomitant vaccine
regimen, respectively.

*[Vi PS GMT:]{.underline}*

  --------------- ------------ ---------- ------------ ---------- -------------------------- --------------
  **MTA-11:                                                                                  
  Comparison of                                                                              
  Vi PS GMT,                                                                                 
  measured on Day                                                                            
  28 Following                                                                               
  Typhim Vi^®^                                                                               
  Vaccination**                                                                              

  ** **           **Vi +                  **Vi +                  ** **                      ** **
                  Placebo,**              Menactra**                                         

                  **Then                  ** Then                 ** **                      **Upper Limit
                  Menactra**              Placebo**                                          of the**

                  N=418                   N=418                   **Ratio of**               **2-sided 95%
                                                                                             CI**

                  **GMT**      **95% CI** **GMT**      **95% CI** GMT**~Vi\ +\ Placebo~ /**  **for the GMT
                                                                  GMT**~Vi\ +\ Menactra~**   Ratio**

  Vi PS GMT       2.07         1.86, 2.32 2.4          2.15, 2.69 0.86                       1.0
  --------------- ------------ ---------- ------------ ---------- -------------------------- --------------

[SBA-BR GMT:]{.underline} At baseline, the proportion of control group
recipients with a SBA-BR titer [\>]{.underline}1:8 to serogroups A, C, Y
and W-135 was 87% \[365/419\], 69% \[289/419\], 79% \[329/419\], and 54%
\[227/419\], respectively. The respective proportions in the concomitant
vaccine group were 79% \[330/418\], 64% \[267/418\], 71% \[298/418\],
and 50% \[208/418\].

+-------------------+----------+------------+-----------+------------+
| **MTA-11: SBA-BR  |          |            |           |            |
| GMT 28 days after |          |            |           |            |
| Menactra          |          |            |           |            |
| vaccination**     |          |            |           |            |
+-------------------+----------+------------+-----------+------------+
|                   | **Group  |            | **Group   |            |
|                   | B**      |            | A**       |            |
+-------------------+----------+------------+-----------+------------+
|                   | **Vi +   |            | **Vi +    |            |
|                   | Pl       |            | M         |            |
|                   | acebo,** |            | enactra** |            |
+-------------------+----------+------------+-----------+------------+
|                   | **then   |            | **then    |            |
|                   | Me       |            | placebo** |            |
|                   | nactra** |            |           |            |
+-------------------+----------+------------+-----------+------------+
|                   | N= 420   |            | N= 419    |            |
+-------------------+----------+------------+-----------+------------+
|                   | **GMT**  | **95% CI** | **GMT**   | **95% CI** |
+-------------------+----------+------------+-----------+------------+
| **Serogroup A**   |          |            |           |            |
+-------------------+----------+------------+-----------+------------+
| > SBA-BR GMT Day  | 336.9    | 274.2,     | 174.2     | 137.1,     |
| > 0               |          | 414.0      |           | 221.5      |
+-------------------+----------+------------+-----------+------------+
| > SBA-BR GMT (28d | 5109.8   | 4523.3,    | 5137.9    | 4490.4,    |
| > post-)          |          | 5772.4     |           | 5878.9     |
+-------------------+----------+------------+-----------+------------+
| **Serogroup C**   |          |            |           |            |
+-------------------+----------+------------+-----------+------------+
| > SBA-BR GMT Day  | 47.6     | 38.2, 59.4 | 34.8      | 28.2, 42.9 |
| > 0               |          |            |           |            |
+-------------------+----------+------------+-----------+------------+
| > SBA-BR GMT (28d | 3145.4   | 2635.1,    | 3061.3    | 2525.2,    |
| > post-)          |          | 3754.6     |           | 3711.4     |
+-------------------+----------+------------+-----------+------------+
| **Serogroup Y**   |          |            |           |            |
+-------------------+----------+------------+-----------+------------+
| > SBA-BR GMT Day  | 159.0    | 127.5,     | 97.7      | 78.1,      |
| > 0               |          | 198.2      |           | 122.2      |
+-------------------+----------+------------+-----------+------------+
| > SBA-BR GMT (28d | 1742.2   | 1455.4,    | 1821      | 1534.4,    |
| > post-)          |          | 2085.5     |           | 2161.2     |
+-------------------+----------+------------+-----------+------------+
| **Serogroup       |          |            |           |            |
| W135**            |          |            |           |            |
+-------------------+----------+------------+-----------+------------+
| > SBA-BR GMT Day  | 20.0     | 16.6, 24.1 | 18.7      | 15.4, 22.6 |
| > 0               |          |            |           |            |
+-------------------+----------+------------+-----------+------------+
| > SBA-BR GMT (28d | 929      | 750.3,     | 1002      | 81.4, 88.3 |
| > post-)          |          | 1150.3     |           |            |
+-------------------+----------+------------+-----------+------------+

N: total number of participants with valid serology results on Day 28.

*[Comparison of Log~2~ SBA-BR Titer, using baseline titer as a
covariate]{.underline}*

+-----------+-----------+--------------+---------------+--------------+
| ########  |           |              |               |              |
| MTA-11: C |           |              |               |              |
| omparison |           |              |               |              |
|  of Log~2 |           |              |               |              |
| ~ SBA-BR  |           |              |               |              |
| Titer, me |           |              |               |              |
| asured on |           |              |               |              |
|  Day 28 F |           |              |               |              |
| ollowing  |           |              |               |              |
| Menactra  |           |              |               |              |
| Vaccinati |           |              |               |              |
| on, using |           |              |               |              |
|  the Log~ |           |              |               |              |
| 2~ Baseli |           |              |               |              |
| ne SBA Ti |           |              |               |              |
| ter as a  |           |              |               |              |
| Covariate |           |              |               |              |
+-----------+-----------+--------------+---------------+--------------+
|           | **Vi +    | **Vi +       |               |              |
|           | P         | Menactra**   |               |              |
|           | lacebo,** |              |               |              |
+-----------+-----------+--------------+---------------+--------------+
| ** **     | **Then    | ** Then      | *             | **Upper      |
|           | M         | Placebo**    | *Difference** | Limit of     |
|           | enactra** |              |               | the**        |
+-----------+-----------+--------------+---------------+--------------+
| **Se      |           |              | (Log~2~       | **2-sided    |
| rogroup** |           |              | SBA~Menactra~ | 95% CI**     |
|           |           |              | -             |              |
+-----------+-----------+--------------+---------------+--------------+
|           | **Log~2~  | **Log~2~ SBA | Log~2~ SBA    | **for the    |
|           | SBA~Men   | ~Vi\ +\      | ~Vi\          | Difference** |
|           | actra†~** | Menactra‡~** | +\ Menactra~) |              |
+-----------+-----------+--------------+---------------+--------------+
| **A**     | 4.336     | 4.465        | -0.129        | 0.13         |
+-----------+-----------+--------------+---------------+--------------+
| #         | 6.210     | 6.292        | -0.082        | 0.28         |
| ####### C |           |              |               |              |
+-----------+-----------+--------------+---------------+--------------+
| **Y**     | 3.704     | 3.969        | -0.265        | 0.07         |
+-----------+-----------+--------------+---------------+--------------+
| **W-135** | 5.563     | 5.710        | -0.147        | 0.25         |
+-----------+-----------+--------------+---------------+--------------+

† Log~2~ SBA~Menactra**:\ **~proportion of participants, with at least a
4-fold rise in SBA-BR antibody to meningococcal serogroups A, C, Y, and
W-135, in the group given Typhim Vi^®^ vaccine together with a saline
placebo, and then Menactra 28 days later.

‡ Log~2~ SBA ~Vi\ +\ Menactra~: proportion of participants, with at
least a 4-fold rise in SBA-BR antibody to meningococcal serogroups A, C,
Y, and W-135, in the group given Typhim Vi^®^ concomitantly with
Menactra.

Note: If the upper 95% CI of the difference is less than log2 (2) = 1,
the inferiority assumption is rejected.

**Safety**

[Local reactions following first vaccination:]{.underline}

The following table presents local adverse reactions, at the Menactra
and Vi injection sites, in the same participant:

+-----------+----------+----+-----+---------+-----+-----+----------+
| **MTA-11: |          |    |     |         |     |     |          |
| Local     |          |    |     |         |     |     |          |
| adverse   |          |    |     |         |     |     |          |
| reactions |          |    |     |         |     |     |          |
| after the |          |    |     |         |     |     |          |
| 1st       |          |    |     |         |     |     |          |
| Va        |          |    |     |         |     |     |          |
| ccination |          |    |     |         |     |     |          |
| (Days     |          |    |     |         |     |     |          |
| 0-7):**   |          |    |     |         |     |     |          |
|           |          |    |     |         |     |     |          |
| Menactra  |          |    |     |         |     |     |          |
| (Group A) |          |    |     |         |     |     |          |
| and Vi    |          |    |     |         |     |     |          |
| (Group A) |          |    |     |         |     |     |          |
| injection |          |    |     |         |     |     |          |
| sites     |          |    |     |         |     |     |          |
+-----------+----------+----+-----+---------+-----+-----+----------+
|           |          | *  |     |         | *   |     |          |
|           |          | *G |     |         | *Gr |     |          |
|           |          | ro |     |         | oup |     |          |
|           |          | up |     |         | A;  |     |          |
|           |          | A; |     |         | N   |     |          |
|           |          | N  |     |         | =45 |     |          |
|           |          | =4 |     |         | 6** |     |          |
|           |          | 56 |     |         |     |     |          |
|           |          | ** |     |         |     |     |          |
+-----------+----------+----+-----+---------+-----+-----+----------+
|           |          | Vi |     |         | **  |     |          |
|           |          |  + |     |         | Vi* |     |          |
|           |          | *  |     |         | * + |     |          |
|           |          | *M |     |         | Men |     |          |
|           |          | en |     |         | act |     |          |
|           |          | ac |     |         | ra, |     |          |
|           |          | tr |     |         |     |     |          |
|           |          | a, |     |         |     |     |          |
|           |          | ** |     |         |     |     |          |
+-----------+----------+----+-----+---------+-----+-----+----------+
|           |          | Th |     |         | T   |     |          |
|           |          | en |     |         | hen |     |          |
|           |          | P  |     |         | P   |     |          |
|           |          | la |     |         | lac |     |          |
|           |          | ce |     |         | ebo |     |          |
|           |          | bo |     |         |     |     |          |
+-----------+----------+----+-----+---------+-----+-----+----------+
|           |          | *  |     |         | **( |     |          |
|           |          | *( |     |         | Typ |     |          |
|           |          | Me |     |         | him |     |          |
|           |          | na |     |         | Vi  |     |          |
|           |          | ct |     |         | Inj |     |          |
|           |          | ra |     |         | ect |     |          |
|           |          | I  |     |         | ion |     |          |
|           |          | nj |     |         | s   |     |          |
|           |          | ec |     |         | ite |     |          |
|           |          | ti |     |         | )** |     |          |
|           |          | on |     |         |     |     |          |
|           |          | s  |     |         |     |     |          |
|           |          | it |     |         |     |     |          |
|           |          | e) |     |         |     |     |          |
|           |          | ** |     |         |     |     |          |
+-----------+----------+----+-----+---------+-----+-----+----------+
| **R       | **Se     | *  | **  | **95%   | **  | **  | **95%    |
| eaction** | verity** | *n | %** | CI**    | n** | %** | CI**     |
|           |          | ** |     |         |     |     |          |
+-----------+----------+----+-----+---------+-----+-----+----------+
| **        |          |    |     |         |     |     |          |
| Redness** |          |    |     |         |     |     |          |
+-----------+----------+----+-----+---------+-----+-----+----------+
|           | **Any**  | 52 | 1   | 8.6,    | 64  | 1   | 1        |
|           |          |    | 1.4 | 14.7    |     | 4.0 | 1.0,17.6 |
+-----------+----------+----+-----+---------+-----+-----+----------+
| \< 1 inch | **Mild** | 32 | 7.0 | 4.8,    | 52  | 1   | 8.6,14.7 |
|           |          |    |     | 9.8     |     | 1.4 |          |
+-----------+----------+----+-----+---------+-----+-----+----------+
| 1 -- 2    | **Mo     | 16 | 3.5 | 2.0,    | 12  | 2.6 | 1.4,4.6  |
| inches    | derate** |    |     | 5.6     |     |     |          |
+-----------+----------+----+-----+---------+-----+-----+----------+
| \> 2      | **       | 4  | 0.9 | 0.2,    | 0   | 0.0 | 0.0,0.8  |
| inches    | Severe** |    |     | 2.2     |     |     |          |
+-----------+----------+----+-----+---------+-----+-----+----------+
| **S       |          |    |     |         |     |     |          |
| welling** |          |    |     |         |     |     |          |
+-----------+----------+----+-----+---------+-----+-----+----------+
|           | **Any**  | 61 | 1   | 10.4,   | 68  | 1   | 1        |
|           |          |    | 3.4 | 16.8    |     | 4.9 | 1.8,18.5 |
+-----------+----------+----+-----+---------+-----+-----+----------+
| \< 1 inch | **Mild** | 44 | 9.6 | 7.1,    | 60  | 1   | 1        |
|           |          |    |     | 12.7    |     | 3.2 | 0.2,16.6 |
+-----------+----------+----+-----+---------+-----+-----+----------+
| 1 -- 2    | **Mo     | 14 | 3.1 | 1.7,    | 7   | 1.5 | 0.6,3.1  |
| inches    | derate** |    |     | 5.1     |     |     |          |
+-----------+----------+----+-----+---------+-----+-----+----------+
| \> 2      | **       | 3  | 0.7 | 0.1,    | 1   | 0.2 | 0.0,1.2  |
| inches    | Severe** |    |     | 1.9     |     |     |          |
+-----------+----------+----+-----+---------+-----+-----+----------+
| **Ind     |          |    |     |         |     |     |          |
| uration** |          |    |     |         |     |     |          |
+-----------+----------+----+-----+---------+-----+-----+----------+
|           | **Any**  | 78 | 1   | 13.8,   | 91  | 2   | 1        |
|           |          |    | 7.1 | 20.9    |     | 0.0 | 6.4,23.9 |
+-----------+----------+----+-----+---------+-----+-----+----------+
| \< 1 inch | **Mild** | 57 | 1   | 9.6,    | 75  | 1   | 1        |
|           |          |    | 2.5 | 15.9    |     | 6.4 | 3.2,20.2 |
+-----------+----------+----+-----+---------+-----+-----+----------+
| 1 -- 2    | **Mo     | 18 | 3.9 | 2.4,    | 15  | 3.3 | 1.9,5.4  |
| inches    | derate** |    |     | 6.2     |     |     |          |
+-----------+----------+----+-----+---------+-----+-----+----------+
| \> 2      | **       | 3  | 0.7 | 0.1,    | 1   | 0.2 | 0.0,1.2  |
| inches    | Severe** |    |     | 1.9     |     |     |          |
+-----------+----------+----+-----+---------+-----+-----+----------+
| **Pain**  |          |    |     |         |     |     |          |
+-----------+----------+----+-----+---------+-----+-----+----------+
|           | **Any**  | 2  | 4   | 41.8,   | 343 | 7   | 7        |
|           |          | 12 | 6.5 | 51.2    |     | 5.2 | 1.0,79.1 |
+-----------+----------+----+-----+---------+-----+-----+----------+
|           | **Mild** | 17 | 3   | 34.1,   | 261 | 5   | 5        |
|           |          | 6§ | 8.6 | 43.2    |     | 7.2 | 2.6,61.8 |
+-----------+----------+----+-----+---------+-----+-----+----------+
|           | **Mo     | 33 | 7.2 | 5.0,    | 80  | 1   | 1        |
|           | derate** |    |     | 10.0    |     | 7.5 | 4.2,21.4 |
+-----------+----------+----+-----+---------+-----+-----+----------+
|           | **       | 3  | 0.7 | 0.1,    | 2   | 0.4 | 0.1,1.6  |
|           | Severe** |    |     | 1.9     |     |     |          |
+-----------+----------+----+-----+---------+-----+-----+----------+

§ Some participants reported a mild or moderate pain reaction during
Days 0-3, but subsequently reported the reaction as moderate or severe
during Days 4-7, respectively. Since each participant is counted only
once according to the highest severity score reported, the number of
participants with mild reactions during Days 0-7 may be lower than the
number of participants in the Days 0-3 subcategory.

*[Menactra injection site]{.underline}*: Visits 1 (1^st^ vaccination)
and 2 (2^nd^ vaccination)

MTA-11 Table 9 summarizes local adverse events at the Menactra injection
site when Menactra given with Vi (Group A, visit 1), or after Vi (Group
B, visit 2).

  ---------------- -------------- --------------- -------- ---------- -------------- -------- ----------
  **MTA-11:                                                                                   
  Menactra Local                                                                              
  adverse                                                                                     
  reactions (Days                                                                             
  0-7)**                                                                                      

                                  **Group A**                         **Group B**             

                                  Vi +                                Vi + Placebo,           
                                  **Menactra,**                                               

                                  Then Placebo                        Then                    
                                                                      **Menactra**            

                                  **(Menactra                         **(Menactra             
                                  Injection                           Injection               
                                  site)**                             site)**                 

  **Reaction**     **Severity**   **n\*/N**       **%**†   **95% CI** **n\*/N**      **%**†   **95% CI**

  **Redness**                                                                                  

                   **Any**        52/456          11.4     8.6, 14.7  62/439         14.1     11.0, 17.7

  \< 1 inch        **Mild**       32/456          7.0      4.8, 9.8   43/439         9.8      7.2, 13.0

  1 -- 2 inches    **Moderate**   16/456          3.5      2.0, 5.6   16/439         3.6      2.1, 5.9

  \> 2 inches      **Severe**     4/456           0.9      0.2, 2.2   3/439          0.7      0.1, 2.0

  **Swelling**                                                                                 

                   **Any**        61/456          13.4     10.4, 16.8 50/439         11.4     8.6, 14.7

  \< 1 inch        **Mild**       44/456          9.6      7.1, 12.7  31/439         7.1      4.8, 9.9

  1 -- 2 inches    **Moderate**   14/456          3.1      1.7, 5.1   15/439         3.4      1.9, 5.6

  \> 2 inches      **Severe**     3/456           0.7      0.1, 1.9   4/439          0.9      0.2, 2.3

  **Induration**                                                                               

                   **Any**        78/456          17.1     13.8, 20.9 67/439         15.3     12.0, 19.0

  \< 1 inch        **Mild**       57/456          12.5     9.6, 15.9  46/439         10.5     7.8, 13.7

  1 -- 2 inches    **Moderate**   18/456          3.9      2.4, 6.2   18/439         4.1      2.4, 6.4

  \> 2 inches      **Severe**     3/456           0.7      0.1, 1.9   3/439          0.7      0.1, 2.0

  **Pain**                                                                                     

                   **Any**        212/456         46.5     41.8, 51.2 192/439        43.7     39.0, 48.5

                   **Mild**       176/456§        38.6     34.1, 43.2 140/439        31.9     27.6, 36.5

                   **Moderate**   33/456          7.2      5.0, 10.0  44/439         10.0     7.4, 13.2

                   **Severe**     3/456           0.7      0.1, 1.9   8/439          1.8      0.8, 3.6
  ---------------- -------------- --------------- -------- ---------- -------------- -------- ----------

\*n: Number of participants reporting at least one event in this
category.

**†**%: n/N expressed as a percentage.

Pain: 0=none, 1= (mild) sx present, but arm movement not affected, 2=
(moderate) limits usual arm movement, 3= (severe) disabling

[Systemic reactions:]{.underline}

  ------------------ -------------- ------------- -------- ----------- ------------ -------- ----------
  **MTA-11 Table 11:                                                                         
  Systemic adverse                                                                           
  reactions after                                                                            
  Menactra                                                                                   
  vaccination (Days                                                                          
  0-7)**                                                                                     

                                    **Group A**                        **Group B**           

                                    **Vi +                             Vi +                  
                                    Menactra,**                        Placebo,              

                                    Then Placebo                       **Then                
                                                                       Menactra**            

  **Reaction**       **Severity**   **n\*/N**     **%**†   **95% CI**  **n\*/N**    **%**†   **95% CI**

  **Fever**                                                                                   

                     **Any**        4/448         0.9      0.2, 2.3    5/434        1.2      0.4, 2.7

  38.0ºC-38.9ºC      **Mild**       3/448         0.7      0.1, 1.9    5/434        1.2      0.4, 2.7

  39.0ºC-39.9ºC      **Moderate**   1/448         0.2      0.0, 1.2    0/434        0.0      0.0, 0.8

  [\>]{.underline}   **Severe**     0/448         0.0      0.0, 0.8    0/434        0.0      0.0, 0.8
  40.0ºC                                                                                     
  ------------------ -------------- ------------- -------- ----------- ------------ -------- ----------

  ------------------- -------------- -------------- --------- ------------- -------- ------ ------- ----------- --------- ------------ -------- ------ ----------
  **Cont. MTA-11                                                                                                                                       
  Table 11: Systemic                                                                                                                                   
  adverse reactions                                                                                                                                    
  after Menactra                                                                                                                                       
  vaccination (Days                                                                                                                                    
  0-7)**                                                                                                                                               

                                                              **Group A**                                                 **Group B**                  

                                                              **Vi +                                                      Vi +                         
                                                              Menactra,**                                                 Placebo,                     

                                                              Then Placebo                                                **Then                       
                                                                                                                          Menactra**                   

  **Reaction**                       **Severity**             **n\*/N**     **%**†          **95%                         **n\*/N**    **%**†          **95% CI**
                                                                                            CI**                                                       

  **Headache**                                                                                                                                          

                                     **Any**                  185/456       40.6            36.0,                         143/439      32.6            28.2, 37.2
                                                                                            45.2                                                       

                                     **Mild**                 127/456       27.9            23.8,                         104/439      23.7            19.8, 28.0
                                                                                            32.2                                                       

                                     **Moderate**             52/456        11.4            8.6,                          37/439       8.4             6.0, 11.4
                                                                                            14.7                                                       

                                     **Severe**               6/456         1.3             0.5,                          2/439        0.5             0.1, 1.6
                                                                                            2.8                                                        

  **Fatigue**                                                                                                                                           

                      **Any**                       172/456                          37.7           33.3, 42.3  119/439                         27.1   23.0, 31.5

                      **Mild**                      123/456                          27.0           23.0, 31.3  81/439                          18.5   14.9, 22.4

                      **Moderate**                  41/456                           9.0            6.5, 12.0   34/439                          7.7    5.4, 10.7

                      **Severe**                    8/456                            1.8            0.8, 3.4    4/439                           0.9    0.2, 2.3

  **Arthralgia**      ** **                                                                                                                             

                      **Any**                       84/455                           18.5           15.0, 22.3  51/439                          11.6   8.8, 15.0

                      **Mild**                      61/455                           13.4           10.4, 16.9  33/439                          7.5    5.2, 10.4

                      **Moderate**                  20/455                           4.4            2.7, 6.7    16/439                          3.6    2.1, 5.9

                      **Severe**                    3/455                            0.7            0.1, 1.9    2/439                           0.5    0.1, 1.6

  **Chills**          ** **                                                                                                                             

                      **Any**                       30/455                           6.6            4.5, 9.3    14/427                          3.3    1.8, 5.4

                      **Mild**                      22/455                           4.8            3.1, 7.2    13/427                          3.0    1.6, 5.1

                      **Moderate**                  6/455                            1.3            0.5, 2.8    1/427                           0.2    0.0, 1.3

                      **Severe**                    2/455                            0.4            0.1, 1.6    0/427                           0.0    0.0, 0.9

  **Anorexia**                                                                                                                                          

                      **Any**                       50/456                           11.0           8.2, 14.2   38/439                          8.7    6.2, 11.7

  Skips 1 meal        **Mild**                      37/456                           8.1            5.8, 11.0   32/439                          7.3    5.0, 10.1

  Skips 2 meals       **Moderate**                  10/456                           2.2            1.1, 4.0    4/439                           0.9    0.2, 2.3

  Skips               **Severe**                    3/456                            0.7            0.1, 1.9    2/439                           0.5    0.1, 1.6
  [\>]{.underline} 3                                                                                                                                   
  meals                                                                                                                                                

  **Vomiting**                                                                                                                                          

                      **Any**                       10/456                           2.2            1.1, 4.0    8/439                           1.8    0.8, 3.6

  1 episode           **Mild**                      5/456                            1.1            0.4, 2.5    7/439                           1.6    0.6, 3.3

  2 episodes          **Moderate**                  3/456                            0.7            0.1, 1.9    0/439                           0.0    0.0, 0.8

  [\>]{.underline}3   **Severe**                    2/456                            0.4            0.1, 1.6    1/439                           0.2    0.0, 1.3
  episodes                                                                                                                                             

  **Diarrhea**        ** **                                                                                                                             

                      **Any**                       54/455                           11.9           9.0, 15.2   32/439                          7.3    5.0, 10.1

  1-2 episodes        **Mild**                      40/455                           8.8            6.4, 11.8   25/439                          5.7    3.7, 8.3

  3-4 episodes        **Moderate**                  13/455                           2.9            1.5, 4.8    7/439                           1.6    0.6, 3.3

  \> 5 episodes       **Severe**                    1/455                            0.2            0.0, 1.2    0/439                           0.0    0.0, 0.8

  **Seizures (Y/N)**  ** **                                                                                                                             

  Yes                 **Days 0-3**                  0/455                            0.0            0.0, 0.8    0/439                           0.0    0.0, 0.8

  Yes                 **Days 4-7**                  0/455                            0.0            0.0, 0.8    0/439                           0.0    0.0, 0.8

  Yes                 **Days 0-7**                  0/455                            0.0            0.0, 0.8    0/439                           0.0    0.0, 0.8

  **Rash**            ** **                                                                                                                             

  Any rash            **Days 0-3**                  8/455                            1.8            0.8, 3.4    2/439                           0.5    0.1, 1.6

  Any rash            **Days 4-7**                  7/455                            1.5            0.6, 3.1    1/439                           0.2    0.0, 1.3

  Any rash            **Days 0-7**                  11/455                           2.4            1.2, 4.3    2/439                           0.5    0.1, 1.6
  ------------------- -------------- -------------- --------- ------------- -------- ------ ------- ----------- --------- ------------ -------- ------ ----------

\*n: Number of participants reporting at least one event in this
category.

**†**%: n/N expressed as a percentage.

Headache, chills, arthralgia, fatigue, malaise: 0= none, 1= aware,
easily tolerated, 2= interferes with usual activities, 3= disabling

1.  **[Study MTA-12]{.underline}**

**Title:** **Immunogenicity and Safety of Tetanus/diphtheria (Td)
Vaccine When Administered Concomitantly with an Experimental Tetravalent
(A, C, Y, and W-135) Meningococcal Diphtheria Toxoid Conjugate Vaccine
in Adolescents in the U.S.**

**Objectives**

-   [Primary objectives:]{.underline}

1.  To compare the tetanus and diphtheria toxoid booster response, when
    Td vaccine is co-administered with a saline placebo or with
    Menactra.

2.  To compare the bactericidal antibody response to serogroups A, C, Y,
    W135, using baby rabbit complement (SBA-BR), when Menactra is
    co-administered with Td, to the corresponding antibody response when
    Menactra is given 28 days after Td vaccination.

-   [Secondary objectives]{.underline}:

1.  To compare the proportion of participants with antibody levels
    [\>]{.underline}1.0 IU/mL to tetanus and diphtheria toxoids, when Td
    vaccine is co-administered with a saline placebo or Menactra.

2.  To compare the geometric mean antibody concentrations to tetanus and
    diphtheria toxoids, when Td vaccine is co-administered with a saline
    placebo or Menactra.

3.  To compare the bactericidal antibody titer to serogroups A, C, Y,
    W135, using baby rabbit complement (SBA-BR), when Menactra is
    co-administered with Td, to the corresponding antibody response when
    Menactra is given 28 days after Td vaccination.

-   [Other objectives:]{.underline}

```{=html}
<!-- -->
```
-   To describe the safety profile for participants in each vaccine
    group.

-   To compare the post-vaccination SBA-BR geometric mean titer for
    serogroups A, C, Y and W135, in both vaccine groups of the proposed
    study, to the corresponding antibody response in Menactra
    participants in study MTA-02.

**Design**: The study was a randomized, double blind, multi-center,
controlled trial. Participants were randomized in a 1: 1 ratio
(Menactra + Td: Td, then Menactra), and were enrolled at eight study
centers in the United States.

**Vaccine administration**

Each group received two injections 28 days apart. Group A received Td +
Menactra, then a saline placebo. Group B received Td + saline placebo,
followed by Menactra. Participants received all injections
intramuscularly.

[Tetanus and Diphtheria Toxoids Adsorbed for Adult Use^®^]{.underline}
is a commercially available in the United States. Each 0.5mL dose
contains 5Lf of tetanus toxoid, 2Lf of diphtheria toxoid and not more
than 0.28mg of aluminum by assay. Tetanus and diphtheria toxoids induce
at least 2 units and 0.5 units of antitoxin per mL, respectively, in the
guinea pig potency test. The vaccine is formulated as liquid, and after
shaking, appears as a turbid, whitish gray suspension. Td vaccine was
supplied in single dose vials.

[Buffered Sterile Normal Saline]{.underline} (0.9% NaCl) was utilized as
the placebo.

**Primary Endpoints:**

-   The proportion of participants who have a booster response to
    tetanus and diphtheria antigens

-   The proportion of participants with at least a 4-fold increase in
    SBA-BR antibody titer to each serogroup

**Secondary endpoints:**

-   The proportion of participants with anti-diphtheria and anti-tetanus
    antibody levels [\>]{.underline} 1.0 IU/ml

-   Anti-diphtheria and anti-tetanus geometric mean antibody
    concentrations among these recipients

-   SBA-BR geometric mean antibody titer to each meningococcal serogroup

**Surveillance**

[Monitored parameters:]{.underline}

[Safety:]{.underline} Study participants were monitored for immediate
reactions 30 minutes after vaccination, and for local and systemic
reactogenicity during the 7 days following vaccination. Pre-specified
adverse events included localized reactions (erythema, swelling,
induration, pain) and systemic symptoms (fever measured by oral
temperature, headache, fatigue, chills, arthralgia, anorexia, vomiting,
diarrhea, seizures, malaise and rash), which were assessed after each
vaccination. These events were recorded daily on a diary card, and also
collected by study personnel through telephone interview eight days
after each vaccination. If rash was reported, the investigator was
prompted to record additional details on a separate case report form.
Other non-serious, unexpected adverse events were obtained by telephone
interview eight and twenty-eight days after each vaccination. Serious
adverse events were reported and recorded during the entire duration of
the study.

[Efficacy (Immunogenicity):]{.underline}

Serum samples were obtained pre- and 28 days after each vaccination.

[Anti-Meningococcal Antibody]{.underline}

Functional antibody activity to each serogroup was determined using a
serum bactericidal assay. The lower limit of detection for this assay,
using baby rabbit complement, is an antibody titer of 8.

[Anti-diphtheria Antibody]{.underline}

Anti-diphtheria antibody response, reported in International Units/mL
(IU/mL), was measured by the ability of the test sera to
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
The assay is calibrated using a WHO reference serum and to determine the
limits of detection. The minimum detectable antitoxin level of the
reference serum, and the starting dilution of the test sera, is
\-\-\-\-\-\-\--IU/mL.

[Anti-tetanus Antibody]{.underline}

Anti-tetanus IgG antibody levels were measured by an \-\-\-\-\-\-\-\-\--
Enzyme Linked Immunosorbent Assay (ELISA). The antibody concentration
was calculated by comparison to an international human reference (WHO
Lot TE-3) with assigned unitage by a
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--method.
Results are reported as International Units per milliliter (IU/mL). The
minimum level of quantitation for this assay is \-\-\-\-\-- IU/mL.

**Statistical plan**

**Primary Hypotheses:**

*[Primary Hypothesis #1:]{.underline}*

To demonstrate that 28 days following concomitant vaccination with Td
and Menactra, the proportion of participants who have a booster response
to tetanus and diphtheria antigens is non-inferior to the same parameter
in the group given Td together with a saline placebo, followed by
Menactra 28 days later.

The definition of a post-vaccination booster response to tetanus and
diphtheria antigens is based on the baseline pre-vaccination level. For
participants with a baseline anti-diphtheria antibody level ≤ 1.28 IU/mL
and/or an anti-tetanus antibody level ≤ 5.3 IU/mL, a booster response is
at least a 4-fold increase in baseline level to each respective antigen.
For participants with a baseline anti-diphtheria antibody level \>1.28
IU/mL and/or an anti-tetanus antibody level \>5.3 IU/mL, at least a
2-fold increase in antibody level to each respective antigen is needed.

This hypothesis would be supported by the data if the upper bound of the
two-sided 95% CI of *p* ~Td\ +\ placebo~ --*p* ~Td\ +\ Menactra~ \< 0.1,
where *p* is the proportion of participants with acceptable increases in
antibody level to diphtheria and tetanus, as stated in the preceding
paragraph, in the group given a staggered and concomitant dosing regimen
of Td and Menactra, respectively. The sample size provided 99.6% and
99.9% power to achieve the primary hypothesis for tetanus and
diphtheria, respectively. Testing of the primary hypothesis was
conducted at the one-sided 0.025 significance level.

*[Primary Hypothesis #2:]{.underline}*

To demonstrate that 28 days post Menactra vaccination, the proportion of
participants with at least a 4-fold increase in SBA-BR antibody titer to
serogroups A, C, Y, and W-135 in the Td + Menactra group is non-inferior
to the same parameter in the group given Td together with a saline
placebo, followed by Menactra 28 days later.

This hypothesis would be supported by the data if the upper limit of the
two-sided 95% confidence limit *P*Menactra - *P*Td+Menactra \< 0.1,
where *p* is the proportions of participants with at least a 4-fold rise
in SBA-BR antibody to meningococcal serogroups A, C, Y, and W-135, in
the Td + placebo and Td + Menactra groups, respectively. The sample size
provided 88.7% power, overall, to achieve the primary hypothesis for
each serogroup. Testing of the primary hypothesis was conducted at the
one-sided 0.025 significance level. The primary analyses were based on
data generated from the per-protocol population.

**Secondary Hypotheses:**

*[Secondary Hypothesis #1:]{.underline}*

To demonstrate that 28 days following concomitant vaccination with Td
vaccine and Menactra, the proportion of participants with
anti-diphtheria and anti-tetanus antibody levels [\>]{.underline} 1.0
IU/ml is non-inferior to the same parameter in the group given Td
together with a saline placebo, followed by Menactra 28 days later.

This hypothesis would be supported by the data if the upper bound of the
two-sided 95% CI of *p* ~Td\ +\ placebo~ --*p* ~Td\ +\ Menactra~ \< 0.1
for both antigens, where *p* is the proportion of participants with
antibody titer [\>]{.underline} 1.0 IU/ml to diphtheria and tetanus in
the groups given \[Td + placebo, then Menactra\] and \[Td + Menactra\],
respectively.

*[Secondary Hypothesis #2:]{.underline}*

To demonstrate that 28 days following concomitant vaccination with Td
vaccine and Menactra, the anti-diphtheria and anti-tetanus geometric
mean antibody concentrations among these recipients is non-inferior to
the same parameter in the group given Td together with a saline placebo,
followed by Menactra 28 days later.

This hypothesis would be supported by the data if the upper bound of the
two-sided 95% CI of the ratio GMT ~Td\ +\ Placebo~ / GMT
~Td\ +\ Menactra~ \< 2.

*[Secondary Hypothesis #3:]{.underline}*

To demonstrate that 28 days following vaccination with Menactra, the
SBA-BR geometric mean antibody titer for serogroups A, C, Y, and W-135
in the group receiving a staggered dosing regimen of Menactra and Td
vaccines is non-inferior to the same parameter in the group receiving
the two vaccines concomitantly.

This hypothesis would be supported by the data if the upper bound of the
two-sided 95% CI of the ratio

GMT ~Menactra~ / GMT ~Td\ +\ Menactra~ \< 2, where GMT ~Menactra~ and
GMT ~Td\ +\ Menactra~ are the proportion of participants with at least a
4-fold rise in SBA-BR antibody to meningococcal serogroups A, C, Y, and
W-135, in the \[Td + placebo\] and \[Td + Menactra\] groups,
respectively. Analyses of the secondary points were performed on both
per-protocol and intent-to-treat populations.

**Per-protocol population for immunogenicity:**

The per-protocol population included all eligible participants who
received the assigned vaccine at visits 1 & 2, who complied with
scheduled visits for blood specimens, and for whom a sufficient quantity
of paired sera was available for analysis.

**Intent-to-treat population for safety:**

The intent-to-treat population consisted of all participants who
received one dose of vaccine and for whom safety information was
available. Analyses were performed according to the vaccine received.

All rashes occurring during the first 7 days after vaccination were
designated, for the purpose of analysis, as a severe solicited systemic
reaction. Since the nature and severity of a rash were difficult to
categorize, initial designation of each rash as severe emphasized to the
investigator that additional descriptive information regarding the
occurrence and description of the rash was needed.

**Results**

The group given Td co-administered with Menactra, is designated Group A.
The group receiving a staggered vaccination schedule \[Td + saline
placebo, then Menactra 28 days later\] is designated Group B. A total of
1021 (Group A n=509, Group B n= 512) adults were enrolled, and 990
(Group A n=492, Group B n= 498) individuals completed the study. The
intent-to-treat population for safety included all enrolled participants
(n= 1021). The per protocol population for immunogenicity included 469
Group A and 478 Group B 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
(89.8%), but also included African American (4.8%), Hispanic (2.6%),
Asian populations (0.5%) and individuals with mixed racial background
(2.3%).

**Immunogenicity**

[Four-fold or greater increases in SBA-BR titer 28 days after Menactra
vaccination:]{.underline}

**The proportion (expressed as a percentage) of participants who
received Td prior to Menactra, and achieved a [\>]{.underline}four-fold
increase in SBA-BR titer post-vaccination was 90.6% for serogroup A,
82.4% for serogroup C, 65.1% for serogroup Y and 87.7% for serogroup
W135.** In the same order, the proportion of participants in the
concomitant vaccine group who achieved the stated criteria was 90.1%,
91.9%, 85.8% and 96.3%, respectively.

  ------------------ ------------ ------------------- ------------ -------------------------- ----------------------- ---------------
  **MTA-12: Number                                                                                                    
  and Proportion of                                                                                                   
  Participants 11-17                                                                                                  
  Years Old with                                                                                                      
  [\>]{.underline}                                                                                                    
  4-fold Increase in                                                                                                  
  SBA-BR Antibody                                                                                                     
  Titer on Day 28,                                                                                                    
  compared to                                                                                                         
  Baseline**                                                                                                          

  ** **              **Td+                            **Td +                                  ** **                    
                     Placebo,**                       Menactra**                                                      

  **Serogroup**      **Then                           **Then                                  **Difference**          **Upper Limit
                     Menactra**                       Placebo**                                                       of the**

                     N=465                            N=478                                   (*p*~Td\ +\ placebo~ -  **2-sided 95%
                                                                                                                      CI**

                     **n\***      ***p*~Menactra~**   **n\***      ***p*~Td\ +\ Menactra~**   *p*~Td\ +\ Menactra~)   **for the
                                                                                                                      Difference**§

  **A**              433          0.906               419          0.901                      0.005                   0.043

  **C**              394          0.824               424          0.912                      -0.088                  -0.045

  **Y**              **311**      **0.651**           **399**      **0.858**                  **-0.207**              **-0.154**

  **W-135**          419          0.877               448          0.963                      -0.087                  -0.053
  ------------------ ------------ ------------------- ------------ -------------------------- ----------------------- ---------------

\* n: number of participants with a booster response on 28 days
post-vaccination. N: total number of participants with valid serology
results on Day 28.

§ CI: Confidence interval.

*[Proportions with diphtheria and tetanus antibody levels \>1.0IU/ml or
greater:]{.underline}*

[Diphtheria:]{.underline} The upper limit of the 2-sided 95% CI for the
difference in two proportions was 0.001 (0.10%).

[Tetanus:]{.underline} The upper limit of the 2-sided 95% CI for the
difference in two proportions was 0.008 (0.80%).

  --------------------- ------------ ------------------------- ------------ -------------------------- ----------------------- ---------------
  **MTA-12: Number and                                                                                                         
  Proportion of                                                                                                                
  Participants 11-17                                                                                                           
  Years Old with                                                                                                               
  Diphtheria and                                                                                                               
  Tetanus Antibody                                                                                                             
  Levels                                                                                                                       
  [\>]{.underline}1.0                                                                                                          
  IU/ml                                                                                                                        
  Post-vaccination**                                                                                                           

                        **Td +                                 **Td +                                  **Difference**          **Upper Limit
                        Placebo,**                             Menactra**                                                      of the**

                        **Then                                 **Then                                  (*p*~Td\ +\ placebo~ -  **2-sided 95%
                        Menactra**                             Placebo**                                                       CI**

                        **n/N\***    ***p*~Td\ +\ Placebo~**   **n/N\***    ***p*~Td\ +\ Menactra~**   *p*~Td\ +\ Menactra~)   **for the
                                                                                                                               Difference**§

  Diphtheria            470/473      0.994                     465/465      1.0                        -0.006                  0.001

  Tetanus               470/477      0.985                     460/464      0.991                      -0.006                  0.008
  --------------------- ------------ ------------------------- ------------ -------------------------- ----------------------- ---------------

\* n: number of participants with a booster response on 28 days
post-vaccination. N: total number of participants with valid serology
results on Day 28.

§ CI: Confidence interval.

*[Diphtheria and Tetanus GMT:]{.underline}*

The diphtheria GMT prior to vaccination was 0.4 IU/ml in each group.
Twenty-eight days following Td vaccination, the GMT increased to 8.35
IU/ml in the group given a staggered vaccine regimen, and 120.88 IU/ml
in the group given the vaccines concomitantly (MTA-12 Table 4).

  -------------------- ------------ --------- --------- ------------ --------- ---------- -------------------------- ------------
  **MTA-12: Comparison                                                                                               
  of Diphtheria and                                                                                                  
  Tetanus GMT (IU/ml)                                                                                                
  Post-vaccination**                                                                                                 

                       **Td+                            **Td +                            ** **                      **Upper
                       Placebo,**                       Menactra**                                                   Limit of
                                                                                                                     the**

                       **Then                           **Then                            **Ratio of**               **2-sided
                       Menactra**                       Placebo**                                                    95% CI**§

                       **N**        **GMT**   **95%     **N**        **GMT**   **95% CI** GMT**~Td\ +\ Placebo~ /**  **for the
                                              CI**                                        GMT**~Td\ +\ Menactra~**   GMT Ratio**

  Diphtheria           473          8.4       7.6, 9.2  465          120.9     104.6,     0.07                       0.08
                                                                               139.8                                 

  Tetanus              477          13.6      12.7,     464          11.5      10.8, 12.2 1.18                       1.29
                                              14.4                                                                   
  -------------------- ------------ --------- --------- ------------ --------- ---------- -------------------------- ------------

§ CI: Confidence interval.

*[Baseline SBA-BR GMT:]{.underline}*

At baseline, the proportion of control group recipients with a SBA-BR
titer [\>]{.underline}1:8 to serogroups A, C, Y and W-135 was 89%
\[425/478\], 68% \[325/478\], 81% \[385/478\], and 55% \[265/478\],
respectively. Similar distributions of pre-vaccination SBA-BR titer were
observed in the concomitant vaccine group. The distribution of baseline
bactericidal antibody titer.

*[SBA-BR GMT 28 days after Menactra vaccination:]{.underline}*

  -------------------- --------------- -------------- -------------------------- ----------------
  **MTA-12: Comparison                                                           
  of SBA-BR GMT to                                                               
  Meningococcal                                                                  
  Serogroups A, C, Y,                                                            
  W135                                                                           
  Post-vaccination**                                                             

                       **Td+           **Td +                                     
                       Placebo,**      Menactra**                                

  ** **                **Then          **Then         ** **                      **Limits of
                       Menactra**      Placebo**                                 the**

  **Serogroup**        N=466           N=478          **Ratio of**               **2-sided 95%
                                                                                 CI**

                       **GMT**         **GMT**        GMT**~Menactra~ /**        **for the GMT
                                                      GMT**~Td\ +\ Menactra~**   Ratio**

  **A**                10391.4         11312.8        0.92                       0.8, 1.1

  **C**                2136.0          5059.3         0.42                       0.3, 0.5

  **Y**                1331.3          3390.9         0.39                       0.3, 0.5

  **W-135**            1339.1          4194.7         0.32                       0.3, 0.4
  -------------------- --------------- -------------- -------------------------- ----------------

§ CI: Confidence interval.

*[Seroconversion]{.underline}*

The 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 after vaccination. Recipients in both groups, with SBA-BR
antibody titer less than 1:8 pre-vaccination, achieved this criterion
for serogroup A. For serogroup C, seroconversion was observed in 96.7%
\[148/153\] and 99.3% \[149/150\] of Group B and A recipients,
respectively. For the remaining serogroups, of those participants who
received a staggered vaccine regimen (Group B), 92.5% \[86/93\] and
96.7% \[206/213\] responded with a [\>]{.underline}4-fold antibody rise
to serogroups Y and W135, respectively, compared with 97.0% \[97/100\]
and 99.5% \[203/204\] of individuals who received the vaccines
concomitantly.

**Safety**

[Local reactions following first vaccination:]{.underline}

The following table presents local adverse reactions, at the Menactra
and Vi injection sites, in the same participant:

+---------+--------+--------+-----+---------+------+-----+---------+
| **      |        |        |     |         |      |     |         |
| MTA-12: |        |        |     |         |      |     |         |
| Local   |        |        |     |         |      |     |         |
| adverse |        |        |     |         |      |     |         |
| re      |        |        |     |         |      |     |         |
| actions |        |        |     |         |      |     |         |
| after   |        |        |     |         |      |     |         |
| the     |        |        |     |         |      |     |         |
| First   |        |        |     |         |      |     |         |
| Vacc    |        |        |     |         |      |     |         |
| ination |        |        |     |         |      |     |         |
| (Days   |        |        |     |         |      |     |         |
| 0-7):** |        |        |     |         |      |     |         |
|         |        |        |     |         |      |     |         |
| Td      |        |        |     |         |      |     |         |
| (Group  |        |        |     |         |      |     |         |
| A),     |        |        |     |         |      |     |         |
| M       |        |        |     |         |      |     |         |
| enactra |        |        |     |         |      |     |         |
| (Group  |        |        |     |         |      |     |         |
| A)      |        |        |     |         |      |     |         |
| In      |        |        |     |         |      |     |         |
| jection |        |        |     |         |      |     |         |
| sites   |        |        |     |         |      |     |         |
+---------+--------+--------+-----+---------+------+-----+---------+
|         |        | *      |     |         | **G  |     |         |
|         |        | *Group |     |         | roup |     |         |
|         |        | A**    |     |         | A**  |     |         |
+---------+--------+--------+-----+---------+------+-----+---------+
|         |        | Td +   |     |         | **Td |     |         |
|         |        | *      |     |         | ** + |     |         |
|         |        | *Menac |     |         | M    |     |         |
|         |        | tra,** |     |         | enac |     |         |
|         |        |        |     |         | tra, |     |         |
+---------+--------+--------+-----+---------+------+-----+---------+
|         |        | Then   |     |         | Then |     |         |
|         |        | P      |     |         | Pla  |     |         |
|         |        | lacebo |     |         | cebo |     |         |
+---------+--------+--------+-----+---------+------+-----+---------+
|         |        | **(Me  |     |         | *    |     |         |
|         |        | nactra |     |         | *(Td |     |         |
|         |        | Inj    |     |         | I    |     |         |
|         |        | ection |     |         | njec |     |         |
|         |        | s      |     |         | tion |     |         |
|         |        | ite)** |     |         | sit  |     |         |
|         |        |        |     |         | e)** |     |         |
+---------+--------+--------+-----+---------+------+-----+---------+
| **Rea   | **Seve | **n    | **% | **95%   | *    | **% | **95%   |
| ction** | rity** | \*/N** | **† | CI**    | *n\* | **† | CI**    |
|         |        |        |     |         | /N** |     |         |
+---------+--------+--------+-----+---------+------+-----+---------+
| **Re    |        |        |     |         |      |     |         |
| dness** |        |        |     |         |      |     |         |
+---------+--------+--------+-----+---------+------+-----+---------+
|         | *      | 61/505 | 1   | 9.4,    | 73   | 1   | 11.5,   |
|         | *Any** |        | 2.1 | 15.2    | /505 | 4.5 | 17.8    |
+---------+--------+--------+-----+---------+------+-----+---------+
| \< 1    | **     | 52/505 | 1   | 7.8,    | 58   | 1   | 8.8,    |
| inch    | Mild** |        | 0.3 | 13.3    | /505 | 1.5 | 14.6    |
+---------+--------+--------+-----+---------+------+-----+---------+
| 1 -- 2  | **Mode | 3/505  | 0.6 | 0.1,    | 12   | 2.4 | 1.2,    |
| inches  | rate** |        |     | 1.7     | /505 |     | 4.1     |
+---------+--------+--------+-----+---------+------+-----+---------+
| \> 2    | **Se   | 6/505  | 1.2 | 0.4,    | 3    | 0.6 | 0.1,    |
| inches  | vere** |        |     | 2.6     | /505 |     | 1.7     |
+---------+--------+--------+-----+---------+------+-----+---------+
| **Swe   |        |        |     |         |      |     |         |
| lling** |        |        |     |         |      |     |         |
+---------+--------+--------+-----+---------+------+-----+---------+
|         | *      | 59/505 | 1   | 9.0,    | 83   | 1   | 13.3,   |
|         | *Any** |        | 1.7 | 14.8    | /505 | 6.4 | 20.0    |
+---------+--------+--------+-----+---------+------+-----+---------+
| \< 1    | **     | 47/505 | 9.3 | 6.9,    | 63   | 1   | 9.7,    |
| inch    | Mild** |        |     | 12.2    | /505 | 2.5 | 15.7    |
+---------+--------+--------+-----+---------+------+-----+---------+
| 1 -- 2  | **Mode | 9/505  | 1.8 | 0.8,    | 19   | 3.8 | 2.3,    |
| inches  | rate** |        |     | 3.4     | /505 |     | 5.8     |
+---------+--------+--------+-----+---------+------+-----+---------+
| \> 2    | **Se   | 3/505  | 0.6 | 0.1,    | 1    | 0.2 | 0.0,    |
| inches  | vere** |        |     | 1.7     | /505 |     | 1.1     |
+---------+--------+--------+-----+---------+------+-----+---------+
| **Indur |        |        |     |         |      |     |         |
| ation** |        |        |     |         |      |     |         |
+---------+--------+--------+-----+---------+------+-----+---------+
|         | *      | 86/505 | 1   | 13.9,   | 105  | 2   | 17.3,   |
|         | *Any** |        | 7.0 | 20.6    | /505 | 0.8 | 24.6    |
+---------+--------+--------+-----+---------+------+-----+---------+
| \< 1    | **     | 68/505 | 1   | 10.6,   | 75   | 1   | 11.9,   |
| inch    | Mild** |        | 3.5 | 16.8    | /505 | 4.9 | 18.3    |
+---------+--------+--------+-----+---------+------+-----+---------+
| 1 -- 2  | **Mode | 13/505 | 2.6 | 1.4,    | 27   | 5.3 | 3.6,    |
| inches  | rate** |        |     | 4.4     | /505 |     | 7.7     |
+---------+--------+--------+-----+---------+------+-----+---------+
| \> 2    | **Se   | 5/505  | 1.0 | 0.3,    | 3    | 0.6 | 0.1,    |
| inches  | vere** |        |     | 2.3     | /505 |     | 1.7     |
+---------+--------+--------+-----+---------+------+-----+---------+
| *       |        |        |     |         |      |     |         |
| *Pain** |        |        |     |         |      |     |         |
+---------+--------+--------+-----+---------+------+-----+---------+
|         | *      | 2      | 5   | 48.4,   | 358  | 7   | 66.7,   |
|         | *Any** | 67/505 | 2.9 | 57.3    | /505 | 0.9 | 74.8    |
+---------+--------+--------+-----+---------+------+-----+---------+
|         | **     | §2     | 4   | 37.8,   | 244  | 4   | 43.9,   |
|         | Mild** | 13/505 | 2.2 | 46.6    | /505 | 8.3 | 52.8    |
+---------+--------+--------+-----+---------+------+-----+---------+
|         | **Mode | 54/505 | 1   | 8.1,    | 113  | 2   | 18.8,   |
|         | rate** |        | 0.7 | 13.7    | /505 | 2.4 | 26.3    |
+---------+--------+--------+-----+---------+------+-----+---------+
|         | **Se   | 0/505  | 0.0 | 0.0,    | 1    | 0.2 | 0.0,    |
|         | vere** |        |     | 0.7     | /505 |     | 1.1     |
+---------+--------+--------+-----+---------+------+-----+---------+

\*n: Number of participants reporting at least one event in this
category.

**†**%: n/N expressed as a percentage.

§ Some participants reported a mild or moderate pain reaction during
Days 0-3, but subsequently reported the reaction as moderate or severe
during Days 4-7, respectively. Since each participant is counted only
once according to the highest severity score reported, the number of
participants with mild reactions during Days 0-7 may be lower than the
number of participants in the Days 0-3 subcategory.

Pain: 0=none, 1= (mild) sx present, but arm movement not affected, 2=
(moderate) limits usual arm movement, 3= (severe) disabling

*[Menactra injection site]{.underline}*: Visits 1 (1^st^ vaccination)
and 2 (2^nd^ vaccination)

<table>
<colgroup>
<col style="width: 13%" />
<col style="width: 11%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 11%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 11%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 12%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="11"><strong>MTA-12: Menactra local adverse reactions (Days
0-7)</strong></td>
</tr>
<tr class="even">
<td> </td>
<td></td>
<td colspan="3"><strong>Group A (N= 505)</strong></td>
<td colspan="3"><strong>Group B (N= 505)</strong></td>
<td colspan="3"><strong>MTA-04</strong></td>
</tr>
<tr class="odd">
<td> </td>
<td></td>
<td colspan="3">Td + <strong>Menactra,</strong></td>
<td colspan="3">Td + Placebo,</td>
<td colspan="3"><strong>Menactra</strong></td>
</tr>
<tr class="even">
<td> </td>
<td></td>
<td colspan="3">Then Placebo</td>
<td colspan="3">Then <strong>Menactra</strong></td>
<td colspan="3"><strong>N= 2264</strong></td>
</tr>
<tr class="odd">
<td> </td>
<td></td>
<td colspan="3"><strong>Menactra Injection site</strong></td>
<td colspan="3"><strong>Menactra Injection site</strong></td>
<td colspan="3"><p><strong>Menactra Injection</strong></p>
<p><strong>site</strong></p></td>
</tr>
<tr class="even">
<td><strong>Reaction</strong></td>
<td><strong>Severity</strong></td>
<td><strong>n</strong></td>
<td><strong>%</strong>†</td>
<td><strong>95% CI</strong></td>
<td><strong>n</strong></td>
<td><strong>%</strong>†</td>
<td><strong>95% CI</strong></td>
<td><strong>n</strong>*</td>
<td><strong>%</strong>†</td>
<td><strong>95% CI</strong></td>
</tr>
<tr class="odd">
<td><strong>Redness</strong></td>
<td> </td>
<td></td>
<td></td>
<td></td>
<td> </td>
<td> </td>
<td> </td>
<td> </td>
<td> </td>
<td> </td>
</tr>
<tr class="even">
<td> </td>
<td><strong>Any</strong></td>
<td>61</td>
<td>12.1</td>
<td>9.4, 15.2</td>
<td>56</td>
<td>11.1</td>
<td>8.5, 14.2</td>
<td>247</td>
<td>10.9</td>
<td>9.65, 12.27</td>
</tr>
<tr class="odd">
<td>&lt; 1 inch</td>
<td><strong>Mild</strong></td>
<td>52</td>
<td>10.3</td>
<td>7.8, 13.3</td>
<td>40</td>
<td>7.9</td>
<td>5.7, 10.6</td>
<td>197</td>
<td>8.7</td>
<td>7.57, 9.94</td>
</tr>
<tr class="even">
<td>1 – 2 inches</td>
<td><strong>Moderate</strong></td>
<td>3</td>
<td>0.6</td>
<td>0.1, 1.7</td>
<td>11</td>
<td>2.2</td>
<td>1.1, 3.9</td>
<td>37</td>
<td>1.6</td>
<td>1.15, 2.25</td>
</tr>
<tr class="odd">
<td>&gt; 2 inches</td>
<td><strong>Severe</strong></td>
<td>6</td>
<td>1.2</td>
<td>0.4, 2.6</td>
<td>5</td>
<td>1.0</td>
<td>0.3, 2.3</td>
<td>13</td>
<td>0.6</td>
<td>0.31, 0.98</td>
</tr>
<tr class="even">
<td><strong>Swelling</strong></td>
<td> </td>
<td></td>
<td></td>
<td></td>
<td> </td>
<td></td>
<td> </td>
<td> </td>
<td> </td>
<td> </td>
</tr>
<tr class="odd">
<td> </td>
<td><strong>Any</strong></td>
<td>59</td>
<td>11.7</td>
<td>9.0, 14.8</td>
<td>66</td>
<td>13.1</td>
<td>10.3, 16.3</td>
<td>245</td>
<td>10.8</td>
<td>9.57, 12.17</td>
</tr>
<tr class="even">
<td>&lt; 1 inch</td>
<td><strong>Mild</strong></td>
<td>47</td>
<td>9.3</td>
<td>6.9, 12.2</td>
<td>44</td>
<td>8.7</td>
<td>6.4, 11.5</td>
<td>191</td>
<td>8.4</td>
<td>7.32, 9.66</td>
</tr>
<tr class="odd">
<td>1 – 2 inches</td>
<td><strong>Moderate</strong></td>
<td>9</td>
<td>1.8</td>
<td>0.8, 3.4</td>
<td>15</td>
<td>3.0</td>
<td>1.7, 4.9</td>
<td>43</td>
<td>1.9</td>
<td>1.38, 2.55</td>
</tr>
<tr class="even">
<td>&gt; 2 inches</td>
<td><strong>Severe</strong></td>
<td>3</td>
<td>0.6</td>
<td>0.1, 1.7</td>
<td>7</td>
<td>1.4</td>
<td>0.6, 2.8</td>
<td>11</td>
<td>0.5</td>
<td>0.24, 0.87</td>
</tr>
<tr class="odd">
<td><strong>Induration</strong></td>
<td> </td>
<td></td>
<td></td>
<td></td>
<td> </td>
<td></td>
<td> </td>
<td> </td>
<td> </td>
<td> </td>
</tr>
<tr class="even">
<td> </td>
<td><strong>Any</strong></td>
<td>86</td>
<td>17.0</td>
<td>13.9, 20.6</td>
<td>78</td>
<td>15.4</td>
<td>12.4, 18.9</td>
<td>355</td>
<td>15.7</td>
<td>14.21, 17.24</td>
</tr>
<tr class="odd">
<td>&lt; 1 inch</td>
<td><strong>Mild</strong></td>
<td>68</td>
<td>13.5</td>
<td>10.6, 16.8</td>
<td>61</td>
<td>12.1</td>
<td>9.4, 15.2</td>
<td>292</td>
<td>12.9</td>
<td>11.54, 14.35</td>
</tr>
<tr class="even">
<td>1 – 2 inches</td>
<td><strong>Moderate</strong></td>
<td>13</td>
<td>2.6</td>
<td>1.4, 4.4</td>
<td>12</td>
<td>2.4</td>
<td>1.2, 4.1</td>
<td>56</td>
<td>2.5</td>
<td>1.87, 3.20</td>
</tr>
<tr class="odd">
<td>&gt; 2 inches</td>
<td><strong>Severe</strong></td>
<td>5</td>
<td>1.0</td>
<td>0.3, 2.3</td>
<td>5</td>
<td>1.0</td>
<td>0.3, 2.3</td>
<td>7</td>
<td>0.3</td>
<td>0.12, 0.64</td>
</tr>
<tr class="even">
<td><strong>Pain</strong></td>
<td> </td>
<td></td>
<td></td>
<td></td>
<td> </td>
<td></td>
<td> </td>
<td> </td>
<td> </td>
<td> </td>
</tr>
<tr class="odd">
<td> </td>
<td><strong>Any</strong></td>
<td>267</td>
<td>52.9</td>
<td>48.4, 57.3</td>
<td>270</td>
<td>53.5</td>
<td>49.0, 57.9</td>
<td>1340</td>
<td>59.2</td>
<td>57.13, 61.22</td>
</tr>
<tr class="even">
<td> </td>
<td><strong>Mild</strong></td>
<td>213</td>
<td>42.2</td>
<td>37.8, 46.6</td>
<td>198</td>
<td>39.2</td>
<td>34.9, 43.6</td>
<td>1045</td>
<td>46.2</td>
<td>44.09, 48.24</td>
</tr>
<tr class="odd">
<td> </td>
<td><strong>Moderate</strong></td>
<td>54</td>
<td>10.7</td>
<td>8.1, 13.7</td>
<td>68</td>
<td>13.5</td>
<td>10.6, 16.8</td>
<td>289</td>
<td>12.8</td>
<td>11.42, 14.21</td>
</tr>
<tr class="even">
<td> </td>
<td><strong>Severe</strong></td>
<td>0</td>
<td>0.0</td>
<td>0.0, 0.7</td>
<td>4</td>
<td>0.8</td>
<td>0.2, 2.0</td>
<td>6</td>
<td>0.3</td>
<td>0.10, 0.58</td>
</tr>
</tbody>
</table>

\*n: Number of participants reporting at least one event in this
category.

**†**%: n/N expressed as a percentage.

Pain: 0=none, 1= (mild) sx present, but arm movement not affected, 2=
(moderate) limits usual arm movement, 3= (severe) disabling

Study MTA-04 enrolled participants 11-18 years old.

[Systemic reactions:]{.underline}

  ------------------ -------------- -------------- ------------- -------- ------- ---------- -------------- -------- ------- ---------
  **MTA-12: Systemic                                                                                                         
  adverse reactions                                                                                                          
  (Days 0-7)**                                                                                                               

                                                   **Group A**                               **Group B**                     

                                                   **Td +                                    Td + Placebo,                   
                                                   Menactra,**                                                               

                                                   Then Placebo                              Then                            
                                                                                             **Menactra**                    

  **Reaction**                      **Severity**   **n\*/N**     **%**†           **95% CI** **n\*/N**      **%**†           **95%
                                                                                                                             CI**

  **Fever**                                                                                                                   

                                    **Any**        25/503        5.0              3.2, 7.2   11/505         2.2              1.1, 3.9

  38.0ºC-38.9ºC                     **Mild**       19/503        3.8              2.3, 5.8   10/505         2.0              1.0, 3.6

  39.0ºC-39.9ºC                     **Moderate**   5/503         1.0              0.3, 2.3   1/505          0.2              0.0, 1.1

  [\>]{.underline}                  **Severe**     1/503         0.2              0.0, 1.1   0/505          0.0              0.0, 0.7
  40.0ºC                                                                                                                     

  **Headache**       ** **                         ** **                  ** **   ** **      ** **          ** **    ** **   

                     **Any**                       180/505                35.6    31.5, 40.0 110/505        21.8     18.3,   
                                                                                                                     25.6    

                     **Mild**                      116/505                23.0    19.4, 26.9 79/505         15.6     12.6,   
                                                                                                                     19.1    

                     **Moderate**                  54/505                 10.7    8.1, 13.7  28/505         5.5      3.7,    
                                                                                                                     7.9     

                     **Severe**                    10/505                 2.0     1.0, 3.6   3/505          0.6      0.1,    
                                                                                                                     1.7     
  ------------------ -------------- -------------- ------------- -------- ------- ---------- -------------- -------- ------- ---------

  ------------------- -------------- ------------- -------- -------- --------- -------------- -------- ------ ---------
  **Cont. MTA-12:                                                                                             
  Systemic adverse                                                                                            
  reactions (Days                                                                                             
  0-7)**                                                                                                      

                                     **Group A**                               **Group B**                    

                                     **Td +                                    Td + Placebo,                  
                                     Menactra,**                                                              

                                     Then Placebo                              Then                           
                                                                               **Menactra**                   

  **Reaction**        **Severity**   **n\*/N**              **%**†   **95%     **n\*/N**      **%**†          **95%
                                                                     CI**                                     CI**

  **Malaise**                                                                                                  

                      **Any**        119/505                23.6     19.9,     61/505         12.1            9.4, 15.2
                                                                     27.5                                     

                      **Mild**       72/505                 14.3     11.3,     35/505         6.9             4.9, 9.5
                                                                     17.6                                     

                      **Moderate**   36/505                 7.1      5.0, 9.7  21/505         4.2             2.6, 6.3

                      **Severe**     11/505                 2.2      1.1, 3.9  5/505          1.0             0.3, 2.3

  **Arthralgia**      ** **                                                                                    

                      **Any**        127/505                25.1     21.4,     61/505         12.1            9.4, 15.2
                                                                     29.2                                     

                      **Mild**       94/505                 18.6     15.3,     45/505         8.9             6.6, 11.7
                                                                     22.3                                     

                      **Moderate**   29/505                 5.7      3.9, 8.1  15/505         3.0             1.7, 4.9

                      **Severe**     4/505                  0.8      0.2, 2.0  1/505          0.2             0.0, 1.1

  **Chills**          ** **                                                                                    

                      **Any**        56/505                 11.1     8.5, 14.2 18/505         3.6             2.1, 5.6

                      **Mild**       35/505                 6.9      4.9, 9.5  16/505         3.2             1.8, 5.1

                      **Moderate**   18/505                 3.6      2.1, 5.6  2/505          0.4             0.0, 1.4

                      **Severe**     3/505                  0.6      0.1, 1.7  0/505          0.0             0.0, 0.7

  **Anorexia**                                                                                                 

                      **Any**        64/505                 12.7     9.9, 15.9 22/505         4.4             2.7, 6.5

  Skips 1 meal        **Mild**       43/505                 8.5      6.2, 11.3 15/505         3.0             1.7, 4.9

  Skips 2 meals       **Moderate**   16/505                 3.2      1.8, 5.1  5/505          1.0             0.3, 2.3

  Skips               **Severe**     5/505                  1.0      0.3, 2.3  2/505          0.4             0.0, 1.4
  [\>]{.underline} 3                                                                                          
  meals                                                                                                       

  **Vomiting**                                                                                                 

                      **Any**        23/505                 4.6      2.9, 6.8  7/505          1.4             0.6, 2.8

  1 episode           **Mild**       17/505                 3.4      2.0, 5.3  5/505          1.0             0.3, 2.3

  2 episodes          **Moderate**   6/505                  1.2      0.4, 2.6  1/505          0.2             0.0, 1.1

  [\>]{.underline}3   **Severe**     0/505                  0.0      0.0, 0.7  1/505          0.2             0.0, 1.1
  episodes                                                                                                    

  **Diarrhea**                                                                                                 

                      **Any**        45/505                 8.9      6.6, 11.7 19/505         3.8             2.3, 5.8

  1-2 episodes        **Mild**       39/505                 7.7      5.5, 10.4 15/505         3.0             1.7, 4.9

  3-4 episodes        **Moderate**   5/505                  1.0      0.3, 2.3  4/505          0.8             0.2, 2.0

  [\>]{.underline} 5  **Severe**     1/505                  0.2      0.0, 1.1  0/505          0.0             0.0, 0.7
  episodes                                                                                                    

  **Seizures** (Y/N)                                                                                          

  Yes                 **Days 0-3**                 0/505    0.0      0.0, 0.7  0/505          0.0      0.0,   
                                                                                                       0.7    

  Yes                 **Days 4-7**                 0/505    0.0      0.0, 0.7  0/505          0.0      0.0,   
                                                                                                       0.7    

  Yes                 **Days 0-7**                 0/505    0.0      0.0, 0.7  0/505          0.0      0.0,   
                                                                                                       0.7    

  **Rash**            ** **                                                                                   

  Any rash            **Days 0-3**                 4/505    0.8      0.2, 2.0  4/505          0.8      0.2,   
                                                                                                       2.0    

  Any rash            **Days 4-7**                 7/505    1.4      0.6, 2.8  4/505          0.8      0.2,   
                                                                                                       2.0    

  Any rash            **Days 0-7**                 9/505    1.8      0.8, 3.4  7/505          1.4      0.6,   
                                                                                                       2.8    
  ------------------- -------------- ------------- -------- -------- --------- -------------- -------- ------ ---------

\*n: Number of participants reporting at least one event in this
category.

**†**%: n/N expressed as a percentage.

Headache, chills, arthralgia, fatigue, malaise: 0= none, 1= aware,
easily tolerated, 2= interferes with usual activities, 3= disabling

7.  **Lot Consistency**

**Title: A Trial of the Lot Consistency of an Experimental Tetravalent
(A, C, Y, and W-135) Meningococcal Diphtheria Toxoid Conjugate Vaccine
Among Healthy U.S. Adults**

(Please see section 6.4 for synopsis of study design. This study
contained both safety and immunogenicity primary objectives.)

**Objectives**

-   [Primary objective:]{.underline}

> To assess the consistency of the immune response from three
> manufactured lots of Menactra, as measured by the bactericidal
> antibody response to serogroups A, C, Y, W135, using baby rabbit
> complement (SBA-BR) in the assay.

-   [Other objectives:]{.underline}

```{=html}
<!-- -->
```
-   To describe and compare the SBA-BR response to each serogroup pre-
    and 28 days post-vaccination for all participants who receive
    Menactra.

-   To describe and compare the proportion of participants who achieve
    seroconversion 28 days following vaccination with any of the three
    Menactra vaccine lots.

**[Primary Endpoint:]{.underline}**

-   The immune responses to the three consistency lots of Menactra, as
    measured by the SBA-BR geometric mean titer (GMT)

**[Surveillance (Immunogenicity):]{.underline}** 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. The lower limit of detection for this assay,
using baby rabbit complement, is an antibody titer of 8.

**Statistical plan**

**[Primary Hypothesis:]{.underline}**

To demonstrate that 28 days after vaccination, the immune responses to
the three consistency lots of Menactra, as measured by the SBA-BR
geometric mean titer (GMT), are equivalent for each of the four
serogroups.

This hypothesis will be supported by the data if the upper limit of the
two-sided 90% confidence interval of the difference between the maximum
and the minimum treatment effect among the three lot responses is \<
log~2~ (1.5) for each of the four serogroups. Planned enrollment of 1599
participants for the lot consistency evaluation, with resultant 1400
evaluable study subjects, provided 99.9% power, overall, to achieve the
primary hypothesis for serogroups A, C, Y and W135. The per-protocol
population for immunogenicity was used for the primary analysis.

Results

  -------------------- --------------- -------------- ----------- -------------- ----------- -------------- ------------
  **MTA-14: SBA-BR                                                                                          
  Geometric Mean Titer                                                                                      
  Pre- and 28 days                                                                                          
  Post-vaccination**                                                                                        

  ** **                ** **           **Menactra**               **Menactra**               **Menactra**   

  ** **                ** **           **Lot 1**                  **Lot 2**                  **Lot 3**      

  ** **                ** **           N= 496 (pre)/              N= 486                     N= 499         
                                       495 (post)                                                           

                                       **SBA-BR**     ** **       **SBA-BR**     ** **       **SBA-BR**     ** **

  **Serogroup**        **Timepoint**   **GMT**        **95% CI**  **GMT**        **95% CI**  **GMT**        **95% CI**

  **A**                Day 0           239.1          191.1,      271.4          217.9,      248.6          198.7, 311.2
                                                      299.0                      338.1                      

                       Day 28          8169.1         7363.5,     8215.4         7388.3,     6679.0         5976.3,
                                                      9062.8                     9135.1                     7464.3

  **C**                Day 0           72.6           58.6, 89.9  57.3           46.5, 70.7  79.3           63.7, 98.6

                       Day 28          3867.5         3299.4,     4154.8         3621.4,     3216.6         2743.1,
                                                      4533.4                     4766.9                     3771.7

  **Y**                Day 0           243.8          201.6,      184.7          151.1,      208.4          171.0, 254.1
                                                      294.9                      225.7                      

                       Day 28          2898.3         2541.2,     2477.2         2150.2,     3805.3         3331.6,
                                                      3305.7                     2842.6                     4346.3

  **W-135**            Day 0           47.4           38.8, 57.8  48.5           39.8, 59.1  44.5           36.7, 53.9

                       Day 28          2030.9         1742.8,     2573.0         2199.1,     2456.7         2136.1,
                                                      2366.5                     3010.5                     2825.4
  -------------------- --------------- -------------- ----------- -------------- ----------- -------------- ------------

  ------------------ -------------- -------------------- --------- -------------- -------------------- --------- -------------- -------------------- ----------
  **MTA-14: Number                                                                                                                                   
  and Percentage of                                                                                                                                  
  Participants 18-55                                                                                                                                 
  Years Old                                                                                                                                          
  Achieving a                                                                                                                                        
  [\>]{.underline}                                                                                                                                   
  Four-fold Increase                                                                                                                                 
  in SBA-BR Antibody                                                                                                                                 
  Titer, with                                                                                                                                        
  95%CI**                                                                                                                                            

                     **Menactra**                                  **Menactra**                                  **Menactra**                        

                     **Lot 1**                                     **Lot 2**                                     **Lot 3**                           

  **Serogroup**      N= 495                                        N= 486                                        N= 499                              

                     **n**\*        ***P*~Menactra~**†   **95%     **n**\*        ***P*~Menactra~**†   **95%     **n**\*        ***P*~Menactra~**†   **95% CI**
                                                         CI**                                          CI**                                          

  **A**              421            85.1%                81.6,     415            85.4%                81.9,     407            81.6%                77.9, 84.9
                                                         88.1                                          88.4                                          

  **C**              425            85.9%                82.5,     435            89.5%                86.4,     415            83.2%                79.6, 86.3
                                                         88.8                                          92.1                                          

  **Y**              371            74.9%                70.9,     348            71.6%                67.4,     402            80.6%                76.8, 83.9
                                                         78.7                                          75.6                                          

  **W-135**          426            86.1%                82.7,     428            88.1%                84.9,     458            91.8%                89.0, 94.0
                                                         89.0                                          90.8                                          
  ------------------ -------------- -------------------- --------- -------------- -------------------- --------- -------------- -------------------- ----------

\*n: number of participants with ≥ 4-fold rise SBA-BR titer from
baseline. N: total number of participants with valid serology data.

† *p*~Menomune®~: percentage of Menomune^®^ participants with a ≥4-fold
rise in SBA-BR titer post-vaccination, compared with baseline.

‡ *p*~Menactra:~ percentage of Menactra participants with a ≥ 4-fold
rise in SBA-BR titer post-vaccination compared with baseline.

§ CI: Confidence interval.

[Seroconversion]{.underline} 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 after vaccination. All Menactra recipients with
SBA-BR antibody titer less than 1:8 pre-vaccination achieved this
criterion for serogroup A. The minimum proportion of Menactra
participants who achieve seroconversion for serogroups C, Y and W135 was
95.7% \[133/139, lot 1\], 92.9% \[79/85, lot 2\] and 94.6% \[158/167,
lot 2\]. The maximum proportion of Menactra participants who achieve
seroconversion, in the same order, was 100.0% \[144/144, lot 2\], 96.6%
\[85/88, lot 3\] and 97.6% \[165/169, lot 3\].

**[References]{.underline}**

## 1. Center for Disease Control. Prevention and control of meningococcal disease and meningococcal disease in college students: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2000; 49(RR-7): 1-22

## 

2.  Rosenstein NE, Perkins BA, Stephens DS et al. The changing
    epidemiology of meningococcal disease in the United States,
    1992-1996. J Infect Dis 1999; 180:1894-1901.

3.  Jackson LA, Schuchat A, Reeves MW, Wenger JD. Serogroup C
    meningococcal outbreaks in the United States. An emerging threat.
    JAMA 1995; 273: 383-389.

4.  Center for Disease Control. Serogroup W-135 Meningococcal Disease
    Among Travelers Returning From Saudi Arabia --- United States, 2000.
    MMWR- Morbidity & Mortality Weekly Report 2000; 49(16): 345-346.

5.  Fellick JM, Sills JA, Marzouk O et al. Neurodevelopmental outcome in
    meningococcal disease: a case-control study. Arch Dis Child 2001;
    85: 6-11.

6.  Erikson L, De Wals P. Complications and sequelae of meningococcal
    disease in Quebec, Canada, 1990-1994. Clin Infect Dis 1998; 26:
    1159-1164.

7.  Erikson LJ, De Wals P, McMahon J et al. Complications of
    meningococcal disease in college students. Clin Infect Dis 2001; 33:
    737-739.

8.  Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the
    meningococcus. II. Development of natural immunity. J Exp Med 1969;
    129: 1327-1348.

9.  Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the
    meningococcus. I. The role of humoral antibodies. J Exp Med 1969;
    129: 1307-1326.

10. http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3544t2a.pdf

11. Jodar L, Cartwright K, Feavers IM. Standardisation and validation of
    serological assays for the evaluation of immune responses to
    Neisseria meningitidis serogroup A and C vaccines. Biologicals.
    2000; 28:193-197.

12. Jodar L, Stephens D, Feavers IM. Assay parameters and methods of
    data analysis for the comparison of complement sources in the
    Neisseria meningitidis serogroup C serum bactericidal assay.
    Biologicals. 2002; 30:323-329.