Immunogenicity and Safety of an Investigational Quadrivalent Meningococcal Conjugate Vaccine Administered as a Booster Dose in Children Vaccinated 3 Years Earlier as Toddlers
Phase: PHASE3
Conditions: Meningococcal Infections
Sponsor: Sanofi Pasteur, a Sanofi Company

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Immunogenicity and Safety of an Investigational 
Quadrivalent Meningococcal Conjugate Vaccine Administered 
as a Booster Dose in Children Vaccinated 3 Years Earlier as 
Toddlers 
A Phase III, open-label, multi-center study to describe the immune persistence of the priming 
dose and describe the immunogenicity and safety of a booster dose of MenACYW conjugate 
vaccine in children in Finland who had been vaccinated 3 years earlier as toddlers with either 
MenACYW conjugate vaccine or Nimenrix® as part of the MET54 study. 
Clinical Study Protocol, Amendment 1 
Health Authority File Number: 
EudraCT #: 
2017-001993-40 
WHO Universal Trial Number 
(UTN): 
U1111-1183-5988 
Study Code: 
MET62 
Development Phase: 
Phase III 
Sponsor: 
Sanofi Pasteur Inc. 
Discovery Drive, Swiftwater, PA 18370-0187, USA 
Investigational Product: 
MenACYW conjugate vaccine: Meningococcal Polysaccharide (Serogroups 
A, C, Y, and W) Tetanus Toxoid Conjugate Vaccine 
Form / Route: 
Liquid solution / Intramuscular (IM) 
Indication For This Study: 
Meningococcal conjugate vaccine as a booster dose in children vaccinated 
3 years earlier as toddlers 
Manufacturer: 
Same as Sponsor 
Coordinating Investigator 
 
 
Sponsor’s Responsible Medical 
Officer: 
 
 Sanofi Pasteur Inc. 
Tel:  
 
E-mail: 
 
Pharmacovigilance Global Safety 
Expert: 
 
 Sanofi Pasteur Inc. 
Tel:  
 
E-mail: 
 
Clinical Trial Manager: 
 
  
 
Tel:  
 
E-mail: 
 
Version and Date of the Protocol: 
Version 2.0 dated 15 March 2018 
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NCT Number:NCT03476135

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Information contained in this publication is the property of Sanofi Pasteur and is confidential. This information may not be 
disclosed to third parties without written authorization from Sanofi Pasteur. This document may not be reproduced, stored in a 
retrieval system, or transmitted in any form or by any means–electronic, mechanical recording, or otherwise–without prior 
authorization from Sanofi Pasteur. This document must be returned to Sanofi Pasteur upon request. 
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History of Protocol Versions 
Table 1: Previous versions of the protocol 
Version* 
Date 
Comments 
1.0 
24 August 2017 
Original study protocol (first version used in the study) 
* Versions in bold font have been approved by the Independent Ethics Committee(s) (IEC[s]) / Institutional Review 
Board(s) (IRB[s]) and used in the study. 
 
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Table of Contents 
History of Protocol Versions........................................................................................................... 3 
List of Tables .................................................................................................................................... 8 
Synopsis ............................................................................................................................................ 9 
Table of Study Procedures ............................................................................................................ 15 
List of Abbreviations ..................................................................................................................... 16 
1 
Introduction ..................................................................................................................... 18 
1.1 
Background ..................................................................................................................... 18 
1.2 
Background of the Investigational Product ..................................................................... 19 
1.2.1 
Clinical ......................................................................................................................... 19 
1.2.1.1 
Study MET39 (Phase II) ............................................................................................ 19 
1.2.1.2 
Study MET54 (Phase II) ............................................................................................ 20 
1.3 
Potential Benefits and Risks ........................................................................................... 21 
1.3.1 
Potential Benefits to Subjects ....................................................................................... 21 
1.3.2 
Potential Risks to Subjects ........................................................................................... 22 
1.4 
Rationale for the Study ................................................................................................... 23 
2 
Study Objectives .............................................................................................................. 23 
3 
Investigators and Study Organization ........................................................................... 24 
4 
Independent Ethics Committee / Institutional Review Board .................................... 24 
5 
Investigational Plan ......................................................................................................... 25 
5.1 
Description of the Overall Study Design and Plan ......................................................... 25 
5.1.1 
Study Design ................................................................................................................ 25 
5.1.2 
Justification of the Study Design .................................................................................. 25 
5.1.3 
Study Plan ..................................................................................................................... 26 
5.1.4 
Visit Procedures ............................................................................................................ 26 
5.1.5 
Planned Study Calendar ............................................................................................... 28 
5.2 
Enrollment and Retention of Study Population .............................................................. 29 
5.2.1 
Recruitment Procedures ................................................................................................ 29 
5.2.2 
Informed Consent Procedures ...................................................................................... 29 
5.2.3 
Screening Criteria ......................................................................................................... 30 
5.2.4 
Inclusion Criteria .......................................................................................................... 30 
5.2.5 
Exclusion Criteria ......................................................................................................... 30 
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5.2.6 
Medical History ............................................................................................................ 32 
5.2.7 
Contraindications for Subsequent Vaccinations ........................................................... 32 
5.2.8 
Contraindications for Subsequent Blood Draw ............................................................ 32 
5.2.9 
Conditions for Withdrawal ........................................................................................... 32 
5.2.10 
Lost to Follow-up Procedures....................................................................................... 33 
5.2.11 
Classification of Subjects Who Discontinue the Study ................................................ 33 
5.2.12 
Follow-up of Discontinuations ..................................................................................... 34 
5.3 
Safety Emergency Call ................................................................................................... 34 
5.4 
Modification of the Study and Protocol .......................................................................... 35 
5.5 
Interruption of the Study ................................................................................................. 35 
6 
Vaccines Administered ................................................................................................... 35 
6.1 
Identity of the Investigational Product ............................................................................ 35 
6.1.1 
Identity of Study Product .............................................................................................. 35 
6.1.1.1 
Composition ............................................................................................................... 36 
6.1.1.2 
Preparation and Administration ................................................................................. 36 
6.1.1.3 
Dose Selection and Timing ........................................................................................ 36 
6.1.2 
Identity of Control Product ........................................................................................... 37 
6.2 
Identity of Other Products ............................................................................................... 37 
6.3 
Product Logistics ............................................................................................................ 37 
6.3.1 
Labeling and Packaging ............................................................................................... 37 
6.3.2 
Product Shipment, Storage, and Accountability ........................................................... 37 
6.3.2.1 
Product Shipment ....................................................................................................... 37 
6.3.2.2 
Product Storage .......................................................................................................... 37 
6.3.2.3 
Product Accountability ............................................................................................... 37 
6.3.3 
Replacement Doses....................................................................................................... 38 
6.3.4 
Disposal of Unused Products ........................................................................................ 38 
6.3.5 
Recall of Products ......................................................................................................... 38 
6.4 
Blinding and Code-breaking Procedures ........................................................................ 38 
6.5 
Randomization and Allocation Procedures ..................................................................... 38 
6.6 
Treatment Compliance .................................................................................................... 39 
6.7 
Concomitant Medications and Other Therapies ............................................................. 39 
7 
Management of Samples ................................................................................................. 41 
7.1 
Sample Collection ........................................................................................................... 41 
7.2 
Sample Preparation ......................................................................................................... 41 
7.3 
Sample Storage and Shipment ........................................................................................ 41 
7.4 
Future Use of Stored Serum Samples for Research ........................................................ 42 
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8 
Clinical Supplies .............................................................................................................. 42 
9 
Endpoints and Assessment Methods ............................................................................. 43 
9.1 
Immunogenicity .............................................................................................................. 43 
9.1.1 
Immunogenicity Endpoints .......................................................................................... 43 
9.1.2 
Immunogenicity Assessment Methods ......................................................................... 43 
9.2 
Safety .............................................................................................................................. 44 
9.2.1 
Safety Definitions ......................................................................................................... 44 
9.2.2 
Safety Endpoints ........................................................................................................... 47 
9.2.3 
Safety Assessment Methods ......................................................................................... 47 
9.2.3.1 
Immediate Post-vaccination Observation Period ....................................................... 47 
9.2.3.2 
Reactogenicity (Solicited Reactions From Day 0 to Day 07 After Vaccination) ...... 48 
9.2.3.3 
Unsolicited Adverse Events ....................................................................................... 52 
9.2.3.4 
Adverse Events of Special Interest ............................................................................ 53 
9.2.3.5 
Assessment of Causality ............................................................................................ 54 
9.3 
Efficacy ........................................................................................................................... 54 
10 
Reporting of Serious Adverse Events ............................................................................ 54 
10.1 
Initial Reporting by the Investigator ............................................................................... 54 
10.2 
Follow-up Reporting by the Investigator ........................................................................ 55 
10.3 
Reporting of SAEs Occurring After a Subject Has Completed the Study ...................... 55 
10.4 
Assessment of Causality ................................................................................................. 56 
10.5 
Reporting SAEs to Health Authorities and IECs / IRBs................................................. 56 
11 
Data Collection and Management ................................................................................. 56 
11.1 
Data Collection and CRB Completion ............................................................................ 56 
11.2 
Data Management ........................................................................................................... 57 
11.3 
Data Review .................................................................................................................... 58 
12 
Statistical Methods and Determination of Sample Size ............................................... 58 
12.1 
Statistical Methods .......................................................................................................... 58 
12.1.1 
Hypotheses and Statistical Methods for the Objective ................................................. 58 
12.1.1.1 
Hypotheses ................................................................................................................. 58 
12.1.1.2 
Statistical Methods ..................................................................................................... 58 
12.2 
Analysis Sets ................................................................................................................... 60 
12.2.1 
Full Analysis Set ........................................................................................................... 60 
12.2.2 
Safety Analysis Set ....................................................................................................... 60 
12.2.3 
Per-Protocol Analysis Set ............................................................................................. 60 
12.2.4 
Populations Used in Analyses ...................................................................................... 61 
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12.3 
Handling of Missing Data and Outliers .......................................................................... 61 
12.3.1 
Safety ............................................................................................................................ 61 
12.3.2 
Immunogenicity ............................................................................................................ 61 
12.4 
Interim / Preliminary Analysis ........................................................................................ 62 
12.5 
Determination of Sample Size and Power Calculation ................................................... 62 
13 
Ethical and Legal Issues and Investigator / Sponsor Responsibilities........................ 62 
13.1 
Ethical Conduct of the Study / Good Clinical Practice ................................................... 62 
13.2 
Source Data and Source Documents ............................................................................... 62 
13.3 
Confidentiality of Data and Access to Subject Records ................................................. 63 
13.4 
Monitoring, Auditing, and Archiving ............................................................................. 63 
13.4.1 
Monitoring .................................................................................................................... 63 
13.4.2 
Audits and Inspections ................................................................................................. 64 
13.4.3 
Archiving ...................................................................................................................... 64 
13.5 
Financial Contract and Insurance Coverage ................................................................... 64 
13.6 
Stipends for Participation ................................................................................................ 65 
13.7 
Publication Policy ........................................................................................................... 65 
14 
Reference List .................................................................................................................. 66 
15 
Signature Page ................................................................................................................. 70 
 
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List of Tables 
Table 1: Previous versions of the protocol ........................................................................................3 
Table 9.1: Solicited injection site reactions: terminology, definitions, and intensity scales ...........49 
Table 9.2: Solicited systemic reactions: terminology, definitions, and intensity scales .................50 
 
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Synopsis 
Company: 
Sanofi Pasteur 
Investigational Product: 
MenACYW conjugate vaccine 
Active Substances: 
Capsular polysaccharide from meningococcal serogroups A, C, Y, and W 
conjugated to tetanus toxoid 
Title of the Trial: 
Immunogenicity and Safety of an Investigational Quadrivalent 
Meningococcal Conjugate Vaccine Administered as a Booster Dose in 
Children Vaccinated 3 Years Earlier as Toddlers 
Development Phase: 
Phase III 
Coordinating Investigator: 
 
 
Trial Centers: 
This will be a multi-center trial conducted at approximately 8 sites in 
Finland. 
Investigators and sites are listed in the “List of Investigators and Centers 
Involved in the Trial” document. 
Planned Trial Period: 
1Q 2018 to 4Q 2018 
Trial Design and Methodology: 
A Phase III, open-label, multi-center study to describe the immune 
persistence of the priming dose and describe the immunogenicity and safety 
of a booster dose of MenACYW conjugate vaccine in children in Finland 
who had been vaccinated 3 years earlier as toddlers with either MenACYW 
conjugate vaccine or Nimenrix® as part of the MET54 study. 
Subjects who were vaccinated 3 years (± 45 days) earlier at 12 to 23 months 
of age in study MET54 will be eligible for enrollment in study MET62. 
All subjects will receive a single dose of MenACYW conjugate vaccine on 
Day (D) 0. 
All subjects will provide blood samples for immunogenicity assessment at 
baseline (pre-vaccination) and at 30 to 44 days after vaccination.  
Solicited adverse event (AE) information will be collected for 7 days after 
vaccination; unsolicited AE information will be collected from Visit 1 (D0) 
to Visit 2 (D30 [+14 days]), and serious adverse event (SAE) information 
(including adverse events of special interest [AESIs]) will be collected 
throughout the study period. 
Objectives: 
Immunogenicity 
1) 
To describe the antibody persistence of meningococcal serogroups A, 
C, Y, and W before a booster dose in children who received either 
MenACYW conjugate vaccine or Nimenrix® 3 years earlier as toddlers 
2) 
To describe the antibody responses to meningococcal serogroups A, C, 
Y, and W 30 days after a booster dose of MenACYW conjugate 
vaccine in children who received either MenACYW conjugate vaccine 
or Nimenrix® 3 years earlier as toddlers 
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3) 
To describe the antibody responses against tetanus toxoid 30 days after 
a booster dose of MenACYW conjugate vaccine in children who 
received either MenACYW conjugate vaccine or Nimenrix® 3 years 
earlier as toddlers 
Safety 
To describe the safety profile of a booster dose of MenACYW conjugate 
vaccine in children who received either MenACYW conjugate vaccine or 
Nimenrix® 3 years earlier as toddlers 
Endpoints: 
Immunogenicity 
1) 
Antibody titers against meningococcal serogroups A, C, Y, and W 
measured by hSBA and rSBA: 
a) At D0 (baseline) and D30 in toddlers after having received a single 
dose of either MenACYW conjugate vaccine or Nimenrix®, as part 
of study MET54 
b) At D0 (baseline) in children before receiving a booster dose of 
MenACYW conjugate vaccine as part of study MET62 (3 years after 
having received a single dose of either MenACYW conjugate 
vaccine or Nimenrix®) 
2) 
Antibody titers against meningococcal serogroups A, C, Y, and W 
measured by hSBA and rSBA at D0 (baseline) and D30 after the 
administration of a booster dose of MenACYW conjugate vaccine in 
children who received either MenACYW conjugate vaccine or 
Nimenrix® 3 years earlier as toddlers 
Tetanus toxoid is contained as a carrier protein in both the investigational 
vaccine and the control vaccine that was used in study MET54. Therefore, 
blood samples will also be tested to assess: 
3) 
Antibody concentrations against tetanus toxoid at D0 (baseline) and 
D30 after the administration of a booster dose of MenACYW 
conjugate vaccine in children who received either MenACYW 
conjugate vaccine or Nimenrix® 3 years earlier as toddlers 
 
Safety 
• 
Occurrence, nature (Medical Dictionary for Regulatory Activities 
[MedDRA] preferred term [PT]), duration, intensity, and relationship to 
vaccination of any unsolicited systemic AEs reported in the 30 minutes 
after vaccination 
• 
Occurrence, time of onset, number of days of occurrence, intensity, 
action taken, and whether the reaction led to early termination from the 
study, of solicited (prelisted in the subject’s diary card [booklet or 
electronic device (e-diary)] and electronic case report book [CRB]) 
injection site reactions occurring up to 7 days after vaccination 
Note: The diary card may be either a booklet or an electronic device 
that contains an application to enter the information (e-diary). 
 
• 
Occurrence, time of onset, number of days of occurrence, intensity, 
action taken, and whether the reaction led to early termination from the 
study, of solicited (prelisted in the subject’s diary card [booklet or e-
diary] and CRB) systemic reactions occurring up to 7 days after 
vaccination 
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• 
Occurrence, nature (MedDRA PT), time of onset, duration, intensity, 
action taken, relationship to vaccination (for systemic AEs only), and 
whether the event led to early termination from the study, of unsolicited 
AEs up to Visit 2 after vaccination 
 
• 
Occurrence, nature (MedDRA PT), time of onset, duration, seriousness 
criteria, relationship to vaccination, outcome, and whether the SAE led 
to early termination from the study, of SAEs, including AESIs, 
throughout the trial 
Planned Sample Size: 
A total of 188 subjects who participated in the MET54 study are planned to 
be enrolled. 
Schedule of Study Procedures: 
Vaccination 
All subjects will receive a single dose of MenACYW conjugate vaccine at 
Visit 1 (D0). 
Blood sampling 
All subjects will provide a pre-vaccination blood sample on D0 and a post-
vaccination sample at Visit 2 (30 to 44 days after the vaccination at Visit 1). 
Collection of safety data 
• 
All subjects will be observed for 30 minutes after vaccination and any 
unsolicited systemic AEs occurring during that time will be recorded as 
immediate unsolicited systemic AEs in the CRB. 
• 
The subject’s parent / legally acceptable representative will record 
information in a diary card (booklet or e-diary) about solicited reactions 
from D0 to D07 after vaccination and unsolicited AEs from D0 to 
Visit 2. SAEs will be reported throughout the duration of the trial. 
• 
In addition, the subject’s parent / legally acceptable representative will 
be asked to notify the site immediately about potential SAEs at any time 
during the trial. 
• 
Alerts will be sent to the e-diary (if applicable) and staff will contact the 
subject’s parent / legally acceptable representative by telephone on D08 
(+2 days) to identify the occurrence of any SAE not yet reported, and to 
remind them to complete the diary card (booklet or e-diary) up to 
Visit 2 and to bring it back at Visit 2.  
• 
The completed diary card (booklet or e-diary) will be reviewed with the 
subject’s parent / legally acceptable representative at Visit 2. 
Duration of Participation in the 
Trial: 
The duration of each subject’s participation in the study will be 30 to 
44 days. 
Investigational Product: 
MenACYW conjugate vaccine: Meningococcal Polysaccharide 
(Serogroups A, C, Y, and W) Tetanus Toxoid Conjugate Vaccine (Sanofi 
Pasteur Inc., Swiftwater, PA, USA) 
 Form: 
Liquid solution 
 Composition: 
Each 0.5 milliliter (mL) dose of MenACYW conjugate vaccine is 
formulated in sodium acetate buffered saline solution to contain the 
following ingredients: 
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Meningococcal capsular polysaccharides: 
Serogroup A .............................................................. 10 micrograms (µg) 
Serogroup C ..................................................................................... 10 µg 
Serogroup Y ..................................................................................... 10 µg 
Serogroup W .................................................................................... 10 µg 
Tetanus toxoid protein carrier ....................................... approximately 55 µg* 
* Tetanus toxoid protein quantity is approximate and dependent on the 
polysaccharide-to-protein ratio for the conjugates used in each formulation.  
 Route: 
IM 
 Batch Number: 
To be determined 
Inclusion Criteria: 
An individual must fulfill all of the following criteria in order to be eligible 
for trial enrollment: 
1) Participated in and completed (attended Visit 2) study MET54 
2) Informed consent form has been signed and dated by the parent(s) or 
another legally acceptable representative (and by an independent 
witness, if required by local regulations) 
3) Subject and parent/legally acceptable representative are able to attend 
all scheduled visits and to comply with all trial procedures 
4) Covered by health insurance where applicable 
Exclusion Criteria: 
An individual fulfilling any of the following criteria is to be excluded from 
trial enrollment: 
1) Participation in the 4 weeks preceding the trial vaccination or planned 
participation during the present trial period in another clinical trial 
investigating a vaccine, drug, medical device, or medical procedure  
2) Receipt of any vaccine in the 4 weeks (28 days) preceding the trial 
vaccination or planned receipt of any vaccine prior to Visit 2 except for 
influenza vaccination, which may be received at a gap of at least 
2 weeks before or after the study vaccines. This exception includes 
monovalent pandemic influenza vaccines and multivalent influenza 
vaccines. If the subject is due to receive vaccination(s) recommended 
for his / her age by the national immunization schedule at the time of 
the study, the subject will be recommended to complete his/her 
immunization schedule after Visit 2. 
3) Previous vaccination against meningococcal disease with either the trial 
vaccine or another vaccine (i.e., mono- or polyvalent, polysaccharide, or 
conjugate meningococcal vaccine containing serogroups A, C, Y, or W; 
or meningococcal B vaccine) with the exception of the single dose of 
meningococcal vaccine administered as part of study MET54 
 
4) Receipt of immune globulins, blood or blood-derived products in the 
past 3 months 
 
5) Known or suspected congenital or acquired immunodeficiency; or 
receipt of immunosuppressive therapy, such as anti-cancer 
chemotherapy or radiation therapy, within the preceding 6 months; or 
long-term systemic corticosteroid therapy (prednisone or equivalent for 
more than 2 consecutive weeks within the past 3 months) 
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6) History of meningococcal infection, confirmed either clinically, 
serologically, or microbiologically 
7) At high risk for meningococcal infection during the trial (specifically, 
but not limited to, subjects with persistent complement deficiency, with 
anatomic or functional asplenia, or subjects traveling to countries with 
high endemic or epidemic disease) 
 
8) Known systemic hypersensitivity to any of the vaccine components, or 
history of a life-threatening reaction to the vaccine used in the trial or to 
a vaccine containing any of the same substances 
9) Verbal report of thrombocytopenia, contraindicating intramuscular 
vaccination in the Investigator’s opinion 
 
10) Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding 
inclusion, contraindicating intramuscular vaccination  
 
11) Personal history of Guillain-Barré syndrome (GBS) 
12) Personal history of an Arthus-like reaction after vaccination with a 
tetanus toxoid-containing vaccine 
13) Chronic illness that, in the opinion of the Investigator, is at a stage 
where it might interfere with trial conduct or completion 
14) Moderate or severe acute illness/infection (according to Investigator 
judgment) on the day of vaccination or febrile illness (temperature 
≥ 38.0°C). A prospective subject should not be included in the study 
until the condition has resolved or the febrile event has subsided 
15) Receipt of oral or injectable antibiotic therapy within 72 hours prior to 
the first blood draw.   
16) Identified as a natural or adopted child of the Investigator or employee 
with direct involvement in the proposed study 
Statistical Methods: 
All immunogenicity analyses will be performed on the Per-Protocol 
Analysis Set (PPAS). Additional immunogenicity analyses will be 
performed for exploratory purposes on the Full Analysis Set (FAS). All 
safety analyses will be performed on the Safety Analysis Set (SafAS). All 
analyses will be based on the overall study population as well as the type of 
meningococcal vaccine received in MET54 (subjects who received 
MenACYW conjugate vaccine and subjects who received Nimenrix® 3 years 
earlier as toddlers).  
Immunogenicity 
All analyses will be descriptive; no hypotheses will be tested. Descriptive 
statistics will be provided for the hSBA and rSBA antibody titers against 
meningococcal serogroups (A, C, Y, and W) and for antibody concentrations 
against tetanus toxoid contained in MenACYW conjugate vaccine.  
 
In general, categorical variables will be summarized and presented by 
frequency counts, proportion percentages, and confidence intervals (CIs). 
The 95% CIs of point estimates will be calculated using the normal 
approximation for quantitative data and the exact binomial distribution 
(Clopper-Pearson method) for percentages. For geometric mean titers 
(GMTs), 95% CIs of point estimates will be calculated using normal 
approximation assuming they are log-normally distributed.  
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Reverse cumulative distribution curve (RCDC) figures will be provided for 
the antibody titers against meningococcal serogroups and the antibody 
concentrations against tetanus toxoid contained in MenACYW conjugate 
vaccine. 
 
In summary, descriptive analyses on A, C, Y, and W serogroups will include 
but not be limited to: 
• 
hSBA and rSBA GMTs and 95% CI 
• 
hSBA and rSBA titer distribution and RCDC 
• 
Percentage of subjects with hSBA titer ≥ 1:4 and ≥ 1:8 and 95% CI 
• 
Percentage of subjects with rSBA titer ≥ 1:8 and ≥ 1:128 and 95% CI 
Percentage of subjects with hSBA and rSBA titer ≥4-fold rise from pre-
vaccination to post-vaccination, and 95% CI 
 
• 
Percentage of subjects with hSBA and rSBA vaccine seroresponse* rate 
and 95% CI 
*hSBA vaccine seroresponse (definition proposed by the Center for 
Biologics Evaluation and Research [CBER] in 2016) for serogroups A, C, Y, 
and W is defined as: 
• For a subject with a pre-vaccination titer < 1:8, the post-vaccination titer 
must be ≥ 1:16. 
• For a subject with a pre-vaccination titer ≥ 1:8, the post-vaccination titer 
must be at least 4-fold greater than the pre-vaccination titer. 
 hSBA vaccine seroresponse (definition used in study MET54) for 
serogroups A, C, Y, and W is defined as: 
• For a subject with a pre-vaccination titer < 1:8, the post-vaccination titer 
must be ≥ 1:8. 
• For a subject with a pre-vaccination titer ≥ 1:8, the post-vaccination titer 
must be at least 4-fold greater than the pre-vaccination titer 
 rSBA vaccine seroresponse is defined as: 
• a post-vaccination rSBA titer ≥ 1:32 for subjects with pre-vaccination rSBA 
titer < 1:8, 
   or  
• a post-vaccination titer ≥ 4 times the pre-vaccination titer for subjects with 
pre-vaccination rSBA titer ≥ 1:8. 
In summary, descriptive analyses on anti-tetanus antibody concentrations 
will include but not be limited to: 
• 
Geometric mean concentrations (GMCs) and 95% CI 
• 
The percentage of subjects with antibody concentrations to tetanus 
toxoid ≥ 0.01 international units (IU)/mL and ≥ 0.1 IU/mL and 95% CI 
Data from MET54 and MET62 will also be combined and paired to evaluate 
antibody persistence and overall trends over 3 years. 
Safety 
Safety results will be described for subjects in the study. The main 
parameters for the safety endpoints will be described by 95% CIs (based on 
the Clopper-Pearson method). 
 
Calculation of Sample Size: 
This is an exploratory study with no hypothesis-driven primary objectives. 
All available subjects who participated in and completed the MET54 study 
and received either MenACYW conjugate vaccine or Nimenrix® vaccine, as 
a part of the study, will be enrolled. 
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Table of Study Procedures 
Phase III Study, 2 Visits, 1 Vaccination, 2 Blood Samples, 1 Telephone Call,  
30 Days Duration per Subject 
Visit/Contact 
Visit 1 
Telephone  
Call 1 
Visit 2 
Trial timelines (days) 
D0 
D08 
D30 
Time windows (days) 
-- 
+2 days 
+14 days 
Informed consent  
X 
 
 
Inclusion/exclusion criteria 
X 
 
 
Collection of demographic data 
X 
 
 
Medical history 
X 
 
 
Physical examination* 
X 
 
 
Review of temporary contraindications for blood sampling† 
 
 
X 
Allocation of subject number 
X 
 
 
Blood sampling (BL), 5 mL‡ 
BL1 
 
BL2 
Vaccination§ 
X 
 
 
Immediate surveillance (30 minutes) 
X 
 
 
Diary card (booklet or e-diary) provided 
X 
 
 
Telephone call 
 
X** 
 
Recording of solicited injection site & systemic reactions 
D0 to D07 
 
 
Recording of unsolicited AEs 
D0 to Visit 2 
Reporting of SAEs (including AESIs)†† 
To be reported throughout the study period 
Diary card (booklet or e-diary) reviewed and collected 
 
 
X 
Collection of reportable concomitant medications 
X 
 
X 
Trial termination record 
 
 
X 
*Temperature needs to be measured and recorded in source documents. 
† Should a subject receive oral or injectable antibiotic therapy within 3 days prior to the second blood draw, the Investigator will 
postpone that blood draw until it has been 3 days since the subject last received oral or injectable antibiotic therapy. 
Postponement must still be within the timeframe for blood draw (30 to 44 days after vaccination at D0). If postponement 
would result in the sample collection falling outside of the 30 to 44 day timeframe, the blood sample should be collected 
without postponement and it should be documented that the sample was taken less than 3 days after stopping antibiotic 
treatment.  
‡ Blood sample at Visit 1 will be drawn before administration of vaccine 
§ Subjects will receive 1 dose of MenACYW conjugate vaccine 
** This call is made 8 to 10 days after the vaccination at Visit 1. If D08 (+2 days) falls on a weekend or holiday, the telephone call 
may be made on the following business day. During this telephone call, the staff will find out whether the subject experienced 
any SAE, including AESIs, not yet reported, and will remind the subject’s parent / legally acceptable representative to continue 
using the diary card (booklet or e-diary) up to Visit 2, to bring the diary card (booklet or e-diary) to the study center at Visit 2, 
and confirm the date and time of Visit 2. Additionally, an alert may be sent to the e-diary (as applicable) to remind the subject's 
parent / legally acceptable representative to report any SAEs, including AESIs, not yet reported and to continue to use the e-
diary up to Visit 2, to bring the e-diary to the study center at Visit 2, and confirm the date and time of Visit 2. 
†† AESIs will be collected throughout the trial as SAEs to ensure that the events are communicated to the Sponsor in an expedited 
manner and followed up until the end of the follow-up period or resolution, as per the assigned causality. 
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List of Abbreviations 
µg 
microgram(s) 
AE 
adverse event 
AESI 
adverse event of special interest 
AR 
adverse reaction 
BL 
blood sampling/sample 
CBER 
Center for Biologics Evaluation and Research 
CDM 
Clinical Data Management 
CFU 
colony-forming unit 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
confidence interval 
CQA 
Clinical Quality Assessment 
CRA 
Clinical Research Associate 
CRB 
(electronic) case report book (all the case report forms for a subject) 
CRF 
(electronic) case report form 
CTA 
clinical trial agreement 
CTL 
Clinical Team Leader 
D 
day 
EDC 
electronic data capture 
ECL 
electrochemiluminescent  
EMA 
European Medicines Agency 
FAS 
full analysis set 
FVFS 
first visit, first subject 
FVLS 
first visit, last subject 
GBS 
Guillain-Barré syndrome 
GCI 
Global Clinical Immunology 
GCP 
Good Clinical Practice 
GMC 
geometric mean concentration 
GMT 
geometric mean titer 
GPV 
Global PharmacoVigilance 
hSBA 
serum bactericidal assay using human complement 
IATA 
International Air Transport Association 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
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IM 
intramuscular(ly) 
IMD 
invasive meningococcal disease  
IME 
important medical event 
IOM 
Institute of Medicine 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITP 
idiopathic thrombocytopenic purpura  
IU 
international units 
LLOQ 
lower limit of quantitation 
LLT 
lowest level term 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
milliliter 
NSAID 
non-steroidal anti-inflammatory drug 
PPAS 
per-protocol analysis set 
PS 
polysaccharide 
PT 
preferred term 
PV 
Pharmacovigilance 
RCDC 
reverse cumulative distribution curve 
RMO 
Responsible Medical Officer 
rSBA 
serum bactericidal assay using rabbit complement 
SAE 
serious adverse event 
SafAS 
safety analysis set 
SAP 
statistical analysis plan 
SMT 
Safety Management Team 
TMF 
Trial Master File 
ULOQ 
upper limit of quantitation 
UN 
United Nations 
WHO 
World Health Organization 
 
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1 
Introduction 
1.1 
Background 
This study (MET62) will assess the immunogenicity and safety of a booster dose of the 
investigational quadrivalent Meningococcal Polysaccharide (serogroups A, C, Y, and W) Tetanus 
Toxoid Conjugate Vaccine (hereafter referred to as MenACYW conjugate vaccine) administered 
3 years after a primary dose of MenACYW conjugate vaccine or Nimenrix® was administered to 
toddlers participating in the MET54 study. The persistence of the immune response against 
meningococcal serogroups A, C, Y, and W, 3 years after primary vaccination with either 
MenACYW conjugate vaccine or Nimenrix®, will also be described.  
Invasive meningococcal disease (IMD) is a serious illness caused by the bacterium Neisseria 
meningitidis (N meningitidis), a Gram-negative diplococcus found exclusively in humans. 
Symptoms may include intense headache, fever, nausea, vomiting, photophobia, stiff neck, 
lethargy, myalgia, and a characteristic petechial rash (1). At least 12 different meningococcal 
serogroups have been classified based on the immunochemistry of the capsular polysaccharides 
(PS). Some strains are more likely than others to cause infection (1) (2) (3). Worldwide, most 
cases of meningococcal disease are caused by serogroups A, B, C, X, Y, and W (2) (3) (4). 
Serogroup B is responsible for endemic disease and some outbreaks, while serogroup C is 
responsible for large outbreaks (5). Serogroup A remains the main cause of epidemics in the 
world and is especially dominant in Africa and Asia. Serogroup W has been observed in Africa, 
as well as the United Kingdom, in residents who participated in the Hajj pilgrimage to the 
Kingdom of Saudi Arabia (4) (6) (7) and more recently in Chile (8), Turkey (9) (10), China (11) 
(12), Argentina (13), Brazil (14) (15), and other parts of the world. Serogroup X causes 
substantial meningococcal disease in parts of Africa, but rarely causes disease in other parts of the 
world (2) (16). Serogroup Y has not been associated with outbreaks, but the frequency with which 
it causes sporadic cases has gradually increased in the US and more recently in Canada and 
Europe (17) (18) (19). The Y serogroup is commonly associated with meningococcal pneumonia, 
particularly in older adults ≥ 65 years of age (20). Outbreaks of serogroup B meningococcal 
disease have also been reported on college campuses in the US during the last five-year period; a 
prolonged outbreak of serogroup B on a university campus in Ohio from 2008 – 2010 and 
2 universities in New Jersey and California in 2013 (21) (22). 
The epidemiology of N meningitidis can be described as complex, unpredictable, geographically 
variable, and changing over time. Meningococcal disease occurs worldwide in both endemic and 
epidemic forms with seasonal variation. In Europe, the incidence rate of IMD has remained stable 
over the last 5 to 10 years, with the highest peak occurring in the population less than 4 years of 
age and a smaller peak in the 15 to 19 year old group. The highest incidence rate in Europe is 
caused by serogroup B, followed by C (23). The highest proportion of meningococcal cases was 
due to serogroup B in the population under 5 years of age. The highest proportion of serogroup C 
cases was observed in the population 25 to 44 years of age while the proportion of serogroup Y 
cases was highest in the population aged 65 years and above. Surveillance data from England and 
Wales showed an increase in endemic meningococcal serogroup W disease across all age groups, 
accounting for 15% of all IMD cases in 2013 - 2014 compared with an average of 1% to 2% of all 
IMD cases in earlier years (24). A gradual increase in serogroup Y IMD has also been recently 
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reported in Sweden during 2005 – 2012 (25) (26). Nearly 50% of all IMD was caused by 
serogroup Y in 2012 (25). Similarly, an increase in the proportion of IMD caused by serogroup Y 
has been observed in other Scandinavian countries, accounting for 31% in Norway in 2009 - 2010 
and 38% in Finland in 2010 (27). 
The goal for MenACYW conjugate vaccine is to provide broad protection against IMD caused by 
serogroups A, C, Y, and W in all age groups including children as young as 6 weeks of age, 
adolescents, and adults, including those 56 years of age and older. 
1.2 
Background of the Investigational Product 
1.2.1 
Clinical 
The MenACYW conjugate vaccine formulation was finalized based on data provided by 
2 studies: MET28, a Phase I study in infants, toddlers, and adults 18 to 55 years of age; and 
MET32, a Phase I/II study in toddlers. 
The formulation has been evaluated in over 1639 subjects (infants, toddlers, adolescents, and 
adults > 56 years of age) in completed studies MET39, MET44, MET50, and MET54. 
MenACYW conjugate vaccine is also being evaluated in ongoing Phase III studies (MET51 and 
MET57 in toddlers, MET35 in children (2 to 9 years of age), MET43 and MET56 in adolescents 
and adults, and MET49 in older adults ≥ 56 years of age). The relevant Phase II studies are 
discussed below. 
MenACYW conjugate vaccine was found to be well tolerated and no unanticipated or new 
significant safety concerns have been identified in the clinical trials completed to date or in the 
ongoing MET56 study, where the MenACYW conjugate vaccine is administered to adolescents or 
adults who have received a dose of a meningococcal quadrivalent conjugate vaccine 4 to 10 years 
earlier. 
1.2.1.1 
Study MET39 (Phase II) 
MET39 was a Phase II, randomized, open-label, multi-center study conducted in the US for which 
580 healthy subjects from 2 to 15 months of age were enrolled. This study evaluated the optimal 
vaccination schedule in the infant/toddler population. Subjects in Group 1 through 
Group 4 received 1, 2, or 3 primary doses plus an additional dose of the MenACYW conjugate 
vaccine in the second year of life, concomitantly with routine pediatric vaccines at several 
different vaccination schedules. Subjects in Group 5 received 1 dose of the MenACYW conjugate 
vaccine concomitantly with routine pediatric vaccines. The routine pediatric vaccines given 
concomitantly with MenACYW conjugate vaccine at various schedules included Prevnar® or 
Prevnar 13 vaccine, Pentacel vaccine, ROTARIX® or RotaTeq vaccine, hepatitis B vaccine,  
M-M-RII vaccine, and VARIVAX vaccine. 
Immunogenicity 
After the primary series consisting of 1, 2, or 3 doses of MenACYW conjugate vaccine, protective 
serum bactericidal assay using human complement (hSBA) threshold titers of ≥ 1:8 were attained 
by > 88% of subjects for serogroup C and by 62% to 74% for serogroup A. For serogroups Y and 
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W, ≥ 90% achieved the threshold titer after 3 doses, 75% to 84% after 2 doses, but only 25% after 
a single dose administered at 6 months of age.  
After an additional dose of MenACYW conjugate vaccine in the second year of life (12 or 
15 months), between 91% and 100% of the subjects achieved the protective threshold regardless 
of the number of doses they received in the first year of life 
Safety 
MenACYW conjugate vaccine was well tolerated in infants and toddlers regardless of the 
immunization schedule and the number of doses administered. Safety results were comparable to 
those seen in control group subjects regardless of the immunization schedule and the number of 
doses administered. The safety profile of the licensed vaccines given concomitantly with 
MenACYW conjugate vaccine was similar to that of the licensed vaccines given concomitantly 
without MenACYW conjugate vaccine. 
No deaths occurred within 30 days. There were 2 subjects in Group 4 who died during the study, 
1 as a result of hypoxic ischemic encephalopathy which started 96 days after the 6-month 
vaccination and 1 as a result of non-accidental head trauma 36 days after the 12-month 
vaccination. These events were considered by the Investigator as unrelated to study vaccine. 
There were 2 other subjects who discontinued the study due to a serious adverse event (SAE) and 
the receipt of intravenous immunoglobulin treatment: 1 subject in Group 2 with Kawasaki 
disease, 106 days after the 6-month vaccination; and 1 subject in Group 3 with middle lobe 
pneumonia and Kawasaki disease, 50 and 52 days, respectively, after the 4-month vaccinations. 
One other subject in Group 4 was discontinued due to a non-serious adverse event (AE) (viral 
rash 1 day after the 6-month vaccinations). None of these AEs leading to discontinuation were 
considered by the Investigator as related to the vaccine. There were no related SAEs during this 
study. 
1.2.1.2 
Study MET54 (Phase II)  
MET54 was a Phase II, randomized, open-label, active-controlled, multi-center study conducted 
in Europe (Finland). This study evaluated the immunogenicity and safety profile of a single dose 
of MenACYW conjugate vaccine when given alone in healthy, meningococcal-vaccine naïve 
toddlers compared to that of the licensed vaccine Nimenrix®. A total of 188 meningococcal 
vaccine naïve subjects aged 12 to 23 months on the day of enrollment were randomized to 1 of 
2 groups. Group 1 received a single dose of MenACYW conjugate vaccine and Group 2 received 
a single dose of Nimenrix®. 
Immunogenicity 
Antibody responses to the antigens (serogroups A, C, Y, and W) were evaluated by serum 
bactericidal assay using human complement (hSBA) and baby rabbit complement (rSBA). 
MenACYW conjugate vaccine immune responses evaluated by hSBA and rSBA were generally 
comparable to Nimenrix® immune responses with some variation by serogroup: 
hSBA 
Most subjects in both groups had hSBA titers ≥ 1:8 at D30: the percentages after MenACYW 
conjugate vaccine for serogroups A, Y, and W (ranging from 97.8% [89/91] to 98.9% [90/91]) 
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were comparable to those after Nimenrix® (ranging from 91.9% [79/86] to 100.0% [86/86]). The 
percentage of subjects with hSBA titers ≥ 1:8 for serogroup C was higher after MenACYW 
conjugate vaccine (100.0% [91/91]) than after Nimenrix® (89.5% [77/86]). At D30, most subjects 
in both groups demonstrated an hSBA vaccine seroresponse. The percentage of subjects with an 
hSBA vaccine seroresponse for serogroups A, Y, and W was comparable in both groups (ranging 
from 96.7% [87/90] to 98.9% [90/91] after MenACYW conjugate vaccine and from 91.9% 
[79/86] to 98.8% [85/86] after Nimenrix®). The percentage of subjects with an hSBA vaccine 
seroresponse for serogroup C was higher after MenACYW conjugate vaccine (100.0% [91/91]) 
than after Nimenrix® (86.0% [74/86]). 
rSBA 
Most subjects had rSBA titers ≥ 1:128 at D30. The percentages after MenACYW conjugate 
vaccine were similar (100.0% [91/91] for serogroups A, Y, and W) or numerically higher 
(100.0% [91/91] for serogroup C) compared to Nimenrix® (100.0% [86/86] for serogroups A, Y, 
and W and 94.2% [81/86] for serogroup C). At D30, most subjects in both groups demonstrated 
an rSBA vaccine seroresponse as defined in the SAP and as defined in the protocol. The 
percentage of subjects with any rSBA vaccine seroresponse by either definition for serogroup A 
was numerically lower after MenACYW conjugate vaccine (91.2% [83/91]) than Nimenrix® 
(98.8% [85/86]) and the percentages of subjects with any rSBA vaccine seroresponse by either 
definition were similar or comparable between the 2 groups for serogroups C, Y, and W (all 
> 96%). 
Safety 
Overall, vaccination with MenACYW conjugate vaccine among toddlers aged 12 to 23 months 
was found to be safe with no safety concerns identified. The MenACYW conjugate vaccine was 
well tolerated with no immediate AEs or adverse reactions (ARs), no discontinuations due to an 
SAE or other AE, and no related SAEs. 
The safety profile of MenACYW conjugate vaccine was comparable to that of the licensed 
vaccine, Nimenrix®. 
No new clinically important safety findings were identified with administration of the 
MenACYW conjugate vaccine. The MenACYW conjugate vaccine was well tolerated and 
immunogenic. Single dose of the MenACYW conjugate vaccine demonstrated excellent potential 
to be an alternative vaccine option for toddlers, receiving meningococcal vaccination for the first 
time. 
1.3 
Potential Benefits and Risks 
1.3.1 
Potential Benefits to Subjects 
MenACYW conjugate vaccine is an investigational vaccine that is undergoing active clinical 
investigation. There may be no direct benefit from receiving the MenACYW conjugate vaccine. 
However, based on the data generated from previous studies, the immunogenicity profile of the 
MenACYW conjugate vaccine in different age groups shows that the majority of subjects 
developed seroprotective levels of antibodies after vaccination.  
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In addition, data generated for Nimenrix® (Meningococcal group A, C, W-135, and Y conjugate 
vaccine) showed that booster vaccination of children who had previously received 1 dose of 
MenACWY-TT or MenC conjugate vaccine (MenC-CRM197) at 12–23 months, induced robust 
immune responses for all serogroups with an acceptable safety profile (28). 
The safety evaluation indicates that the vaccine is well-tolerated, and no safety issues have been 
detected to date. In all, the data support further evaluation of the MenACYW conjugate vaccine in 
humans. 
As with any vaccine, MenACYW conjugate vaccine may not protect 100% of individuals against 
the disease it is designed to prevent. 
1.3.2 
Potential Risks to Subjects 
Like other vaccines, MenACYW conjugate vaccine may cause injection site reactions such as 
pain, swelling, and erythema, or certain systemic events such as fever, headache, malaise, and 
myalgia. There may be a rare possibility of an allergic reaction, which could be severe. There may 
also be a risk of febrile convulsion in some children who experience high fever. There may be 
other risks for MenACYW conjugate vaccine that are not yet known. 
 
 
 
 
Importantly, no similar cases have 
been reported following the administration of MenACYW conjugate vaccine in any other trials. 
Guillain-Barré syndrome (GBS) has been reported mostly in persons aged 11 to 19 years who had 
symptom onset within 6 weeks of administration of a US licensed meningococcal conjugate 
vaccine (29). A retrospective cohort study carried out in the US using healthcare claims data 
found no evidence of increased GBS risk associated with the use of that vaccine. The study was 
able to exclude all but relatively small incremental risks (30). 
A review by the Institute of Medicine (IOM) found inadequate evidence to accept or reject a 
causal relationship between tetanus toxoid containing vaccines and GBS (31). The IOM found 
evidence for a causal relation between tetanus toxoid-containing vaccines and brachial neuritis 
(32). Arthus reactions are rarely reported after vaccination and can occur after tetanus toxoid-
containing vaccines (33). 
No occurrences of GBS, brachial neuritis, or Arthus reaction have been reported with the use of 
MenACYW conjugate vaccine in the completed clinical trials. 
The risk of vasovagal syncope exists after any vaccination in the adolescent age group, although it 
has not been specifically reported in the age group under study as part of this protocol (34). A few 
cases of immediate vasovagal-like response or syncope have been observed in adolescent subjects 
who had received MenACYW conjugate vaccine. 
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The potential risks associated with blood drawing include local pain, bruising, and, rarely, 
fainting. Infection at the site of needle insertion could theoretically occur but is exceedingly rare 
when the standard sterile technique is utilized. 
The potential risk listed here are not exhaustive. Refer to the Investigator’s Brochure of the 
investigational vaccine for additional information regarding the potential risks. 
1.4 
Rationale for the Study 
The MenACYW conjugate vaccine is designed for the immunization of individuals of all ages 
(infants 6 weeks of age and older through and including older adults ≥ 56 years of age) against 
IMD. The purpose of the vaccine is to provide broad coverage against circulating meningococcal 
strains from serogroups A, C, Y, and W. Compared to the currently-licensed in many regions 
Sanofi Pasteur meningococcal conjugate vaccine, Menactra®, the MenACYW conjugate vaccine 
is prepared using tetanus toxoid as the carrier protein. Conjugation of polysaccharide antigens to a 
protein carrier can induce T-cell-dependent immune responses, which are anticipated to give rise 
to higher antibody titers, longer duration of the immune response, and enhanced immunologic 
memory that allows for a booster response. 
Meningococcal polysaccharide vaccines have two important limitations: a) the antibody response 
is age-dependent, with infants giving the poorest response; and b) polysaccharides alone are T-cell 
independent immunogens, and therefore no anamnestic response is seen. The immunogenicity of 
polysaccharide vaccines in infants and children has been shown to be improved by conjugating the 
polysaccharides to protein carriers. Among the key advantages expected of the tetanus carrier is 
improved immunogenicity in infants and older adults. Pre-clinical studies using a mouse model 
and investigating different carriers, showed significant levels of polysaccharide-specific total 
immunoglobulin G (IgG) and bactericidal responses in response to the formulations with tetanus 
toxoid as a carrier. Early Phase I/II trials including those with the final formulation (MET39 and 
MET44) showed the potential of the candidate vaccine as a very good immunogen in all age 
groups, including young infants and older adults. The MenACYW conjugate vaccine was found to 
be immunogenic and well tolerated; it did not raise any safety concerns in the above trials using 
the final formulation or in the earlier trials. 
The purpose of MET62 is to describe the immune persistence of the priming dose and describe 
the immunogenicity and safety of a booster dose of MenACYW conjugate vaccine in children in 
Finland who had been vaccinated 3 years earlier as toddlers with either MenACYW conjugate 
vaccine or Nimenrix® as part of the MET54 study. 
2 
Study Objectives 
Immunogenicity 
1) To describe the antibody persistence of meningococcal serogroups A, C, Y, and W before a 
booster dose in children who received either MenACYW conjugate vaccine or Nimenrix® 
3 years earlier as toddlers 
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2) To describe the antibody responses to meningococcal serogroups A, C, Y, and W 30 days 
after a booster dose of MenACYW conjugate vaccine in children who received either 
MenACYW conjugate vaccine or Nimenrix® 3 years earlier as toddlers 
3) To describe the antibody responses against tetanus toxoid 30 days after a booster dose of 
MenACYW conjugate vaccine in children who received either MenACYW conjugate 
vaccine or Nimenrix® 3 years earlier as toddlers 
Safety 
To describe the safety profile of a booster dose of MenACYW conjugate vaccine in children who 
received either MenACYW conjugate vaccine or Nimenrix® 3 years earlier as toddlers. 
The immunogenicity and safety endpoints for the objectives are presented in Section 9.1.1 and 
Section 9.2.2, respectively. 
3 
Investigators and Study Organization 
This study will be conducted in approximately 8 centers in Finland. The Principal Investigators 
and any sub-investigators at the individual sites will be coordinated by 1 Coordinating 
Investigator. Details of the study centers, the Investigators at each center, and the Coordinating 
Investigator are provided in the “List of Investigators and Centers Involved in the Trial” 
document. 
An internal Safety Management Team (SMT) will perform a safety analysis on safety data after 
vaccination. 
The Sponsor’s Responsible Medical Officer (the RMO, the person authorized to sign this protocol 
and any amendments on behalf of the Sponsor) is 
 
. 
4 
Independent Ethics Committee / Institutional Review Board 
Before the investigational product can be shipped to the investigational site and before the 
inclusion of the first subject, this protocol, the informed consent form (ICF), subject recruitment 
procedures, and any other written information to be provided to subjects must be approved by, 
and / or receive favorable opinion from, the appropriate Independent Ethics Committee (IEC) or 
Institutional Review Board (IRB). 
In accordance with Good Clinical Practice (GCP) and local regulations, each Investigator and / or 
the Sponsor are responsible for obtaining this approval and / or favorable opinion before the start 
of the study. If the protocol is subsequently amended, approval must be re-obtained for each 
substantial amendment. Copies of these approvals, along with information on the type, version 
number, and date of document, and the date of approval, must be forwarded by the Investigator to 
the Sponsor together with the composition of the IEC / IRB (the names and qualifications of the 
members attending and voting at the meetings). 
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The Investigator will submit written summaries of the status of the study to the IEC / IRB 
annually, or more frequently if requested. All SAEs occurring during the study that are related to 
the product administered will be reported by the Investigator to the IEC / IRB, according to the 
IEC / IRB policy. 
5 
Investigational Plan 
5.1 
Description of the Overall Study Design and Plan 
5.1.1 
Study Design 
This is a Phase III, open-label, multi-center study to describe the immune persistence of the 
priming dose and describe the immunogenicity and safety of a booster dose of MenACYW 
conjugate vaccine in children in Finland who had been vaccinated 3 years earlier as toddlers with 
either MenACYW conjugate vaccine or Nimenrix® as part of the MET54 study. 
Subjects who were vaccinated 3 years (± 45 days) earlier at 12 to 23 months of age in study 
MET54 will be eligible for enrollment in study MET62. 
All subjects will receive a single dose of MenACYW conjugate vaccine on Day (D) 0. 
All subjects will provide blood samples for immunogenicity assessment at baseline (pre-
vaccination) and at 30 to 44 days after vaccination.  
Solicited AE information will be collected for 7 days after vaccination; unsolicited AE 
information will be collected from Visit 1 (D0) to Visit 2 (D30 [+14 days]), and SAE information 
(including adverse events of special interest [AESIs]) will be collected throughout the study 
period. 
5.1.2 
Justification of the Study Design 
 
 
MET62 is a study that 
will be conducted as part of the Phase III development of MenACYW conjugate vaccine in which 
the vaccine candidate will be evaluated as a booster dose in children. This study will describe the 
immunogenicity and safety of a booster dose of MenACYW conjugate vaccine given 3 years after 
a primary dose of MenACYW conjugate vaccine or Nimenrix® was administered to toddlers. This 
study will also describe the antibody persistence 3 years after primary vaccination prior to 
administration of the booster dose. Subjects who were included in study MET54 are eligible to be 
enrolled in MET62. 
Since all subjects will receive MenACYW conjugate vaccine; this study has been proposed as an 
open-label study. Since MenACYW conjugate vaccine has been evaluated in infants, toddlers, and 
adults without raising any safety concerns, safety assessment will be done up to 30 days after 
vaccination. 
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5.1.3 
Study Plan 
A schedule of assessments and study vaccinations is provided in the Table of Study Procedures. 
Vaccination 
All subjects will receive a single dose of MenACYW conjugate vaccine at Visit 1 (D0). 
Blood Sampling 
All subjects will provide a pre-vaccination blood sample on D0 and a post-vaccination sample at 
Visit 2 (30 to 44 days after the vaccination at Visit 1). 
Collection of Safety Data 
• All subjects will be observed for 30 minutes after vaccination and any unsolicited systemic 
AEs occurring during that time will be recorded as immediate unsolicited systemic AEs in the 
electronic case report form (CRF) (see Section 9.2.3.1). 
• The subject’s parent / legally acceptable representative will record information in a diary card 
(booklet or electronic device [e-diary]) about solicited reactions from D0 to D07 after 
vaccination and unsolicited AEs from D0 to Visit 2. SAEs will be reported throughout the 
duration of the trial. 
• In addition, the subject’s parent / legally acceptable representative will be asked to notify the 
site immediately about potential SAEs at any time during the trial. 
• Alerts will be sent to the e-diary (if applicable) and staff will contact the subject’s parent / 
legally acceptable representative by telephone on D08 (+2 days) to identify the occurrence of 
any SAE not yet reported, and to remind them to complete the diary card (booklet or e-diary) 
up to Visit 2 and to bring it back at Visit 2. 
• The completed diary card (booklet or e-diary) will be reviewed with the subject’s parent / 
legally acceptable representative at Visit 2. 
Note: The diary card may be either a booklet or an electronic device that contains an application 
to enter the information (e-diary). 
5.1.4 
Visit Procedures 
Medical procedures (examinations, injections, etc.) must be conducted by appropriately licensed 
or credentialed study site staff working within the scope of their license/credentials. 
Visit 1 (D0): Inclusion, Randomization, Blood Sample, and Vaccination 
1) Give the subject’s parent / legally acceptable representative information about the trial, answer 
any questions, obtain written informed consent and give the subject’s parent / guardian a 
signed copy of the ICF. 
2) Check inclusion and exclusion criteria for eligibility (see Section 5.2.4 and Section 5.2.5, 
respectively). 
3) Collect relevant demographic information. 
4) Obtain verbal medical history about the subject since participation in MET54. 
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5) Conduct a history-directed physical examination, including temperature (a physical 
examination conducted during the same day as part of routine clinical care may be used for 
this purpose). 
6) Call the interactive response technology (IRT) system for assignment of subject number. 
7) Obtain the first blood sample (5 milliliter [mL]) (see Section 7 for detailed instructions 
regarding the handling of blood samples). If attempts to obtain the first blood draw are 
unsuccessful (no more than 3 attempts), then Visit 1 can be rescheduled to a later date at 
which point informed consent and inclusion/exclusion criteria must be re-validated.a If the 
first blood draw cannot be obtained, the subject will be withdrawn from the study without 
being vaccinated. 
8) Administer MenACYW conjugate vaccine to the subject in the deltoid muscle. The vaccine 
must be administered on the side opposite to that of the blood sampling. 
9) Observe the subject for 30 minutes, and record any AE in the source document. 
10) Give the subject’s parent / legally acceptable representative a diary card (booklet or e-diary), a 
thermometer, and a ruler, and go over the instructions for their use. 
11) Remind the subject’s parent / legally acceptable representative to expect a telephone call 
8 days after Visit 1 and to bring back the diary card (booklet or e-diary) when they return for 
Visit 2 at a specified date and time. 
12) Remind the subject’s parent / legally acceptable representative to notify the site in case of an 
SAE. 
13) Complete the relevant CRFs for this visit. 
Telephone Call 1 (D08 [+2 days] after Visit 1) 
Note: If D08 falls on a weekend or a holiday, the telephone call may be made on the following 
business day. If the subject’s parent / legally acceptable representative is not available, the study 
staff should document the attempts to make contact. 
1) 
Record relevant information concerning the subject’s health status on the telephone contact 
form. If an SAE occurred, follow the instructions in Section 10 for reporting it. 
2) 
Remind the subject’s parent / legally acceptable representative to do the following: 
• Complete the D0 to D07 pages / fields of the diary card (booklet or e-diary).  
• Complete the remaining pages / fields of the diary card (booklet or e-diary), and bring 
them to Visit 2. 
• Notify the site in case of an SAE. 
                                                 
a  If the rescheduled visit is performed within the following 5 days, a physical examination does not need to be 
repeated unless the health status of the subject has visibly changed; however, if the rescheduled visit is performed 
after 5 days, a reassessment of the health status of the subject will be conducted to ensure that the subject is still 
healthy and eligible for participation. 
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An alert may also be sent to the e-diary (as applicable) to remind the subject's parent / legally 
acceptable representative to report any SAEs, including AESIs, not yet reported and to continue to 
use the e-diary up to Visit 2, to bring the e-diary to the study center at Visit 2, and confirm the 
date and time of Visit 2. 
Visit 2 (D30 [+14 days] after Visit 1): Collection of Safety Information and Blood Sample 
1) 
Review the pages / fields of the diary card (booklet or e-diary) with the subject’s parent / 
legally acceptable representative, including any AEs, medications, or therapy that occurred 
since vaccination. 
2) 
Review the temporary contraindications for blood sampling (see Section 5.2.8). 
3) 
Obtain the second blood sample (see Section 7 for detailed instructions regarding the 
handling of blood samples). 
4) 
Complete the relevant CRFs for this visit (including the termination record). 
5) 
If the subject’s parent / legally acceptable representative does not return for Visit 2, and the 
diary card booklet is not received at the site, or the e-diary data has not been completed / 
received at the site, site personnel will contact the subject’s parent / legally acceptable 
representative by telephone. During the telephone call, the subject’s parent / legally 
acceptable representative will be reminded to return the diary card (booklet or e-diary) to the 
study site. Telephone calls will be documented on the Telephone / Interview Record. If the 
study personnel are unable to contact the subject’s parent / legally acceptable representative 
with 3 attempts, the study personnel will follow instructions given in Section 5.2.10. 
Follow-up of Subjects with Related AEs or with AEs That Led to Study/Vaccination 
Discontinuation: 
A subject who experiences an AE (whether serious or non-serious) during the study must be 
followed until the condition resolves, becomes stable, or becomes chronic (even after the end of 
the subject’s participation in the study) if either of the following is true: 
• The AE is considered by the Investigator to be related to the product administered. 
• The AE caused the discontinuation of the subject from the study or from vaccination. 
5.1.5 
Planned Study Calendar 
The following dates are approximate. The actual dates may differ as, for example, the study will 
not start until all the appropriate regulatory and ethical approvals have been obtained. 
Planned subject participation - FVFS (first visit, first subject) to  
LCLS (last contact, last subject):  
 
 
14 February 2018 to 16 October 2018 
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Planned inclusion period - FVFS to  
FVLS (first visit, last subject)a:  
 
 
14 February 2018 to 31 August 2018 
Planned primary vaccination period:  
 
14 February 2018 to 31 August 2018 
Planned end of study:  
 
 
 
16 October 2018 
Planned date of final clinical study report:   
26 September 2019 
5.2 
Enrollment and Retention of Study Population 
5.2.1 
Recruitment Procedures 
Before the start of the trial, the Investigator and / or study staff will contact the parents / legally 
acceptable representatives of subjects who had previously participated in study MET54 and invite 
them to participate in the study. The site will ensure that any advertisements used to recruit 
subjects (e.g. letters, pamphlets, and posters) are submitted to Sanofi Pasteur for review prior to 
submission to the IEC/ IRB for approval. 
5.2.2 
Informed Consent Procedures 
Informed consent is the process by which a subject and / or a subject’s parent or appropriate and 
legally acceptable representative voluntarily confirms his or her willingness to participate / allow 
the child to participate in a particular study. Informed consent must be obtained before any study 
procedures are performed. The process is documented by means of a written, signed, and dated 
ICF. 
In accordance with GCP, prior to signing and dating the consent form, the parent / representative 
must be informed by appropriate study personnel about all aspects of the study that are relevant to 
making the decision to participate, and must have sufficient time and opportunity to ask any 
questions. 
If the subject’s parent / legally acceptable representative is not able to read and sign the ICF, then 
it must be signed and dated by an impartial witness who is independent of the Investigator. A 
witness who signs and dates the consent form is certifying that the information in this form and 
any other written information had been accurately explained to and understood by the subject or 
his / her parent / representative. 
The actual ICF used at each center may differ, depending on local regulations and IEC / IRB 
requirements. However, all versions must contain the standard information found in the sample 
ICF provided by the Sponsor. Any change to the content of the ICF must be approved by the 
Sponsor and the IEC / IRB prior to the form being used. 
If new information becomes available that may be relevant to the parent’s / legally acceptable 
representative’s willingness to continue participation in the study, this will be communicated to 
                                                 
a  Enrollment can be achieved from the 3-year anniversary (±45 days) of the FVFS in study MET54 to the 3-year 
anniversary (±45 days) of the FVLS in MET54. 
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him / her in a timely manner. Such information will be provided via a revised ICF or an 
addendum to the original ICF. 
ICFs will be provided in duplicate, or a photocopy of the signed consent will be made. The 
original will be kept by the Investigator, and the copy will be kept by the subject’s parent / legally 
acceptable representative. 
Documentation of the consent process should be recorded in the source documents. 
Rationale for Including Subjects Unable to Give Consent: 
MET62 is a study to be conducted in children approximately 4 to 5 years of age to obtain safety 
and immunogenicity data (see Section 1.4). 
Since these subjects are unable to give their consent, written informed consent must be obtained 
from the parent or legally acceptable representative in accordance with local practices before 
participation in the study and before any study related procedure is done (e.g., collection of blood 
sample). The signature on the ICF must be dated by the parent / legally acceptable representative 
in accordance with local practices. The parent / legally acceptable representative should be able to 
consent for their child. 
5.2.3 
Screening Criteria 
There are no screening criteria other than the inclusion and exclusion criteria. 
5.2.4 
Inclusion Criteria 
An individual must fulfill all of the following criteria to be eligible for study enrollment: 
1) Participated in and completed (attended Visit 2) study MET54 
2) Informed consent form has been signed and dated by the parent(s) or another legally 
acceptable representative (and by an independent witness, if required by local regulations) 
3) Subject and parent/legally acceptable representative are able to attend all scheduled visits 
and to comply with all trial procedures 
4) Covered by health insurance where applicable 
5.2.5 
Exclusion Criteria 
An individual fulfilling any of the following criteria is to be excluded from study enrollment: 
1) Participation in the 4 weeks preceding the trial vaccination or planned participation during 
the present trial period in another clinical trial investigating a vaccine, drug, medical 
device, or medical procedure  
2) Receipt of any vaccine in the 4 weeks (28 days) preceding the trial vaccination or planned 
receipt of any vaccine prior to Visit 2 except for influenza vaccination, which may be 
received at a gap of at least 2 weeks before or after the study vaccines. This exception 
includes monovalent pandemic influenza vaccines and multivalent influenza vaccines. If 
the subject is due to receive vaccination(s) recommended for his / her age by the national 
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immunization schedule at the time of the study, the subject will be recommended to 
complete his/her immunization schedule after Visit 2. 
3) Previous vaccination against meningococcal disease with either the trial vaccine or another 
vaccine (i.e., mono- or polyvalent, polysaccharide, or conjugate meningococcal vaccine 
containing serogroups A, C, Y, or W; or meningococcal B vaccine) with the exception of 
the single dose of meningococcal vaccine administered as part of study MET54 
4) Receipt of immune globulins, blood or blood-derived products in the past 3 months 
5) Known or suspected congenital or acquired immunodeficiency; or receipt of 
immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within 
the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or 
equivalent for more than 2 consecutive weeks within the past 3 months) 
6) History of meningococcal infection, confirmed either clinically, serologically, or 
microbiologically 
7) At high risk for meningococcal infection during the trial (specifically, but not limited to, 
subjects with persistent complement deficiency, with anatomic or functional asplenia, or 
subjects traveling to countries with high endemic or epidemic disease) 
8) Known systemic hypersensitivity to any of the vaccine components, or history of a life-
threatening reaction to the vaccine used in the trial or to a vaccine containing any of the 
same substancesa 
9) Verbal report of thrombocytopenia, contraindicating intramuscular vaccination in the 
Investigator’s opinion 
10) Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, 
contraindicating intramuscular vaccination 
11) Personal history of Guillain-Barré syndrome (GBS) 
12) Personal history of an Arthus-like reaction after vaccination with a tetanus toxoid-
containing vaccine 
13) Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere 
with trial conduct or completionb 
14) Moderate or severe acute illness/infection (according to Investigator judgment) on the day 
of vaccination or febrile illness (temperature ≥ 38.0°C). A prospective subject should not 
be included in the study until the condition has resolved or the febrile event has subsided 
15) Receipt of oral or injectable antibiotic therapy within 72 hours prior to the first blood draw.   
                                                 
a  The components of the MenACYW conjugate vaccine are listed in Section 6.1.1 and in the Investigator’s 
Brochure. 
b  Chronic illness may include, but is not limited to, cardiac disorders, renal disorders, auto-immune disorders, 
diabetes, psychomotor diseases, and known congenital or genetic diseases 
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16) Identified as a natural or adopted child of the Investigator or employee with direct 
involvement in the proposed study 
If the subject has a primary physician who is not the Investigator, the site must contact this 
physician with the parent’s / legally acceptable representative’s consent to inform him / her of the 
subject’s participation in the study. In addition, the site should ask this primary physician to verify 
exclusion criteria relating to previous therapies, such as receipt of blood products or previous 
vaccines. 
5.2.6 
Medical History 
Prior to enrollment, subjects will be assessed for pre-existing conditions and illnesses, both past 
and ongoing. Any such conditions will be documented in the source document. Significant 
(clinically relevant) medical history (reported as diagnosis) including conditions/illnesses for 
which the subject is or has been followed by a physician or conditions/illnesses that could resume 
during the course of the study or lead to an SAE or to a repetitive outpatient care will be collected 
in the case report book (CRB). The significant medical history section of the CRB contains a core 
list of body systems and disorders that could be used to prompt comprehensive reporting, as well 
as space for the reporting of specific conditions and illnesses. 
For each condition, the data collected will be limited to: 
• Diagnosis (this is preferable to reporting signs and symptoms) 
• Presence or absence of the condition at enrollment 
The reporting of signs and symptoms in lieu of a diagnosis is strongly discouraged. 
Dates, medications, and body systems are not to be recorded, and the information collected will not 
be coded. Its purpose is to assist in the later interpretation of safety data collected during the 
study. 
5.2.7 
Contraindications for Subsequent Vaccinations 
Not applicable. 
5.2.8 
Contraindications for Subsequent Blood Draw 
Should a subject receive oral or injectable antibiotic therapy within 3 days prior to the second 
blood draw, the Investigator will postpone that blood draw until it has been 3 days since the 
subject last received oral or injectable antibiotic therapy. Postponement must still be within the 
timeframe for blood draw (30 to 44 days after vaccination at D0). If postponement would result in 
the sample collection falling outside of this 30 to 44 day timeframe, the blood sample should be 
collected without postponement and it should be documented that the sample was taken less than 
3 days after stopping antibiotic treatment.  
5.2.9 
Conditions for Withdrawal 
Parents / legally acceptable representatives will be informed that they have the right to withdraw 
their child from the study at any time. A subject may be withdrawn from the study: 
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• At the discretion of the Investigator or Sponsor due to safety concerns or significant non-
compliance with the protocol (based on the Investigator’s judgment), without the subject’s 
permission (withdrawal) 
• At the request of the subject’s parent / legally acceptable representative (dropout) 
The reason for a withdrawal or dropout should be clearly documented in the source documents 
and on the CRB.  
The Investigator must determine whether voluntary withdrawal is due to safety concerns (in 
which case, the reason for discontinuation will be noted as “Adverse Event”) or for another 
reason. 
Withdrawn subjects will not be replaced. 
5.2.10 Lost to Follow-up Procedures 
In the case of subjects who fail to return for a follow-up examination, documented reasonable 
effort (i.e., documented telephone calls and certified mail) should be undertaken to locate or recall 
them, or at least to determine their health status while fully respecting their rights. These efforts 
should be documented in the CRB and in the source documents. 
5.2.11 Classification of Subjects Who Discontinue the Study 
For any subject who discontinues the study prior to completion, the most significant reason for 
early termination will be checked in the CRB. Reasons are listed below from the most significant 
to the least significant (refer to the CRF completion instructions for additional details and 
examples): 
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Adverse Event 
To be used when the subject is permanently terminated from the study because 
of an AE (including an SAE), as defined in Section 9.2.1. 
Lost to Follow-up 
To be used when the subject’s parent / legally acceptable representative cannot 
be found or contacted in spite of efforts to locate him/her before the date of 
his/her child’s planned last visit, as outlined in Section 5.2.10. The certified 
letter was sent by the investigator and returned unsigned, and the parent / legally 
acceptable representative did not give any other news and did not bring the child 
to any following visit. 
Protocol Deviation 
To be used: 
• 
In case of significant noncompliance with the protocol (e.g., deviation of the 
Inclusion / Exclusion criteria, non-compliance with time windows, blood 
sampling or vaccination refusal, missed injection/treatment, or error in the 
vaccine / treatment administration). 
• 
The subject or the parent/legally acceptable representative signed the 
certified letter sent by the investigator but did not give any other news and 
did not bring the child to the following visit. 
Withdrawal by Parent 
/ Legally Acceptable 
Representative 
To be used: 
• 
When the subject’s parent / legally acceptable representative indicated 
unwillingness to allow his/her child to continue in the study 
• 
When the subject’s parent / legally acceptable representative made the 
decision to discontinue his/her child’s participation in the study for any 
personal reason other than an SAE/AE (e.g., subject is relocating, inform 
consent withdrawal, etc.) 
5.2.12 Follow-up of Discontinuations 
The site should complete all scheduled safety follow-ups and contact any subject who has 
prematurely terminated the study because of an AE, a protocol deviation, or loss of eligibility, 
including definitive contraindications.  
For subjects where the reason for early termination was lost to follow-up or if the subject 
withdrew informed consent and specified that they do not want to be contacted again and it is 
documented in the source document, the site will not attempt to obtain further safety information. 
If the subject’s status at the end of the study is “Withdrawal by Subject or Parent / Guardian / 
Legally Acceptable Representative”, the site will attempt to contact them except if they specified 
that they do not want to be contacted again, and it is documented in the source document. 
5.3 
Safety Emergency Call 
If, as per the Investigator’s judgment, a subject experiences a medical emergency, the Investigator 
may contact the Sponsor’s RMO for advice on a study related medical question or problem. If the 
RMO is not available, then the Investigator may contact the Call Center—available 24 hours a 
day, 7 days a week—that will forward all safety emergency calls to the appropriate primary or 
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back-up Sanofi Pasteur contact, as needed. The toll-free contact information for the Call Center is 
provided in the Operating Guidelines. 
This process does not replace the need to report an SAE. The investigator is still required to 
follow the protocol-defined process for reporting SAEs to the Global PharmacoVigilance (GPV) 
Department (Please refer to Section 10). 
5.4 
Modification of the Study and Protocol 
Any amendments to this study plan and protocol must be discussed with and approved by the 
Sponsor. If agreement is reached concerning the need for an amendment, it will be produced in 
writing by the Sponsor, and the amended version of the protocol will replace the earlier version. 
All substantial amendments (e.g., those that affect the conduct of the study or the safety of 
subjects) require IEC / IRB approval, and must also be forwarded to regulatory authorities. 
An administrative amendment to a protocol is one that modifies some administrative, logistical, or 
other aspect of the study but does not affect its scientific quality or have an impact on the 
subjects’ safety. The IECs / IRBs may be notified of administrative changes and will provide 
approval according to local regulations. 
The Investigator is responsible for ensuring that changes to an approved study, during the period 
for which IEC / IRB approval has already been given, are not initiated without IEC / IRB review 
and approval, except to eliminate apparent immediate hazards to subjects. 
5.5 
Interruption of the Study 
The study may be discontinued if new data about the investigational product resulting from this or 
any other studies become available; or for administrative reasons; or on advice of the Sponsor, the 
Investigators, the IECs/IRBs, or the governing regulatory authorities in the country where the 
study is taking place.  
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the subjects’ parents / legally 
acceptable representatives and should assure appropriate subject therapy and/or follow-up. 
6 
Vaccines Administered 
6.1 
Identity of the Investigational Product 
6.1.1 
Identity of Study Product 
MenACYW conjugate vaccine: Meningococcal Polysaccharide (Serogroups A, C, Y, and W) 
Tetanus Toxoid Conjugate Vaccine (Sanofi Pasteur Inc., Swiftwater, PA, USA) 
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Form:  
 
Liquid solution 
Dose:  
 
0.5 mL 
Route: 
 
IM 
Batch number: 
To be determined 
6.1.1.1 
Composition 
Each 0.5 mL dose of MenACYW conjugate vaccine is formulated in sodium acetate buffered 
saline solution to contain the following components: 
Meningococcal capsular polysaccharides: 
Serogroup A ............................................................................................................... 10 µg 
Serogroup C ............................................................................................................... 10 µg 
Serogroup Y ............................................................................................................... 10 µg 
Serogroup W .............................................................................................................. 10 µg 
Tetanus toxoid protein carrier  .................................................................... approximately 55 µga 
6.1.1.2 
Preparation and Administration 
MenACYW conjugate vaccine is supplied in single-dose vials (0.5 mL). 
Prior to administration, all study products must be inspected visually for cracks, broken seals, 
correct label content (see Section 6.3.1), and extraneous particulate matter and / or discoloration, 
whenever solution and container permit. If any of these conditions exists, the vaccine must not be 
administered. A replacement dose is to be used, and the event is to be reported to the Sponsor.  
The rubber stopper should not be removed from any of the vaccine vials. 
The site of IM injection should be prepared with a suitable antiseptic prior to administration of 
1 dose (0.5 mL) of MenACYW conjugate vaccine in the deltoid muscle of the arm. After vaccine 
administration, the used syringe and needle will be disposed of in accordance with currently 
established guidelines. 
Subjects must be kept under observation for 30 minutes after vaccination to ensure their safety, 
and any reactions during this period will be documented in the CRB. Appropriate medical 
equipment and emergency medications, including epinephrine (1:1000), must be available on site 
in the event of an anaphylactic, vasovagal, or other immediate allergic reaction. 
6.1.1.3 
Dose Selection and Timing 
All subjects will receive 1 dose of MenACYW conjugate vaccine on D0. 
                                                 
a  Tetanus toxoid protein quantity is approximate and dependent on the polysaccharide-to-protein ratio for the 
conjugates used in each formulation. 
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6.1.2 
Identity of Control Product 
Not applicable. 
6.2 
Identity of Other Products 
Not applicable. 
6.3 
Product Logistics 
6.3.1 
Labeling and Packaging 
MenACYW conjugate vaccine will be supplied in single-dose vials, labeled and packaged with 
the required information according to national regulations. 
6.3.2 
Product Shipment, Storage, and Accountability 
6.3.2.1 
Product Shipment 
The Clinical Logistics Coordinator or designee will contact the Investigator or a designee to 
determine the dates and times of delivery of products. 
Each vaccine shipment will include a temperature-monitoring device to verify maintenance of the 
cold chain during transit. On delivery of the product to the site, the person in charge of product 
receipt will follow the instructions given in the Operating Guidelines, including checking that the 
cold chain was maintained during shipment (i.e., verification of the temperature recorders). If 
there is an indication that the cold chain was broken, this person should immediately quarantine 
the product, alert the Sanofi Pasteur representative, and request authorization from Sanofi Pasteur 
to use the product. 
6.3.2.2 
Product Storage 
The Investigator will be personally responsible for product management or will designate a staff 
member to assume this responsibility. 
At the site, products must be kept in a secure place with restricted access. Vaccines will be stored 
in a refrigerator at a temperature ranging from +2°C to +8°C. The vaccines must not be frozen. 
The temperature must be monitored and documented (see the Operating Guidelines) for the entire 
time that the vaccine is at the study site. In case of accidental freezing or disruption of the cold 
chain, vaccines must not be administered and must be quarantined, and the Investigator or 
authorized designee should contact the Sanofi Pasteur representative for further instructions. 
6.3.2.3 
Product Accountability 
The person in charge of product management at the site will maintain records of product delivery 
to the study site, product inventory at the site, the dose given to each subject, and the disposal of 
or return to the Sponsor of unused doses. 
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The necessary information on the product labels is to be entered into the source document and the 
CRB. If applicable, information may also be entered into the subject’s vaccination card. 
The Sponsor’s monitoring staff will verify the study site’s product accountability records against 
the record of administered doses in the CRBs and the communication from the IRT system (if 
applicable). 
In case of any expected or potential shortage of product during the study, the Investigator or an 
authorized designee should alert the Sanofi Pasteur representative as soon as possible, so that a 
shipment of extra doses can be arranged. 
6.3.3 
Replacement Doses 
If a replacement dose is required (e.g., because the vial broke or particulate matter was observed 
in the syringe), the site personnel must either contact the IRT system to receive the new dose 
allocation, or follow the instructions given in the Operating Guidelines. 
6.3.4 
Disposal of Unused Products 
Unused or wasted products will be either disposed of or returned to the Sponsor in accordance 
with the instructions in the Operating Guidelines. Product accountability will be verified 
throughout the study period. 
6.3.5 
Recall of Products 
If the Sponsor makes a decision to launch a retrieval procedure, the Investigators will be informed 
of what needs to be done. 
6.4 
Blinding and Code-breaking Procedures 
The study is open label and all subjects will receive MenACYW conjugate vaccine; there is no 
need for code-breaking procedures. 
6.5 
Randomization and Allocation Procedures 
Subjects will not be randomized. 
On the day of enrollment, a subject whose parent/legally acceptable representative signs the ICF 
will be assigned a subject number. 
Site staff will connect to the IRT system, enter the identification and security information, and 
confirm a minimal amount of data in response to IRT system prompts. 
Subject numbers that are assigned by the IRT system will consist of a 12-digit string (a 3-digit 
country identifier, a 4-digit study center identifier, and a 5-digit subject identifier). For example, 
Subject 840000100005 is the fifth subject enrolled in Center Number 1 in the US (840 being the 
US country code). 
Subject numbers should not be reassigned for any reason. 
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6.6 
Treatment Compliance 
The following measures will ensure that the vaccine doses administered comply with those planned, 
and that any non-compliance is documented so that it can be accounted for in the data analyses: 
• All vaccinations will be administered by qualified study personnel 
• The person in charge of product management at the site will maintain accountability records 
of product delivery to the study site, product inventory at the site, dose given to each subject, 
and the disposal of unused or wasted doses 
6.7 
Concomitant Medications and Other Therapies 
At the time of enrollment, ongoing medications including but not limited to other therapies (e.g., 
blood products) should be recorded in the source documents. All new medications prescribed for 
new medical conditions / AEs during study participation should also be recorded in the source 
documents.  
Documentation in the CRB of ongoing concomitant medication(s) will be limited to specific 
categories of medication(s) (Categories 1, 2, and 3 as detailed below). Those will include 
Category 1, 2, and 3 medications ongoing at the time of inclusion in the study, or started at any 
time during the subject’s participation in the trial. For Category 3 medication, the period of 
reporting in the CRB will be restricted to only 3 days (72 hours) prior to each blood sampling 
time point.  
Collection Period in Source Documents 
Reportable medications (Category 1, 2, and 3) will be collected in the source documents from the 
day of first vaccination to the end of the trial.a 
Categories of Reportable Medications and Reporting Period 
Reportable medications include medications that impact or may impact the consistency of the safety 
information collected after any vaccination and/or the immune response to vaccination.  
• Category 1: Reportable medications with potential impact on the evaluation of the safety of 
the study vaccines. For example, antipyretics, analgesics, non-steroidal anti-inflammatory 
drugs (NSAIDs), systemic corticosteroids (therapy duration less than 2 weeks), and other 
immune modulators. 
Note: Topical steroids (inhaled, otic, ophthalmic, nasal, etc.) should not be captured or reported. 
• Category 1 medications will be reported in the CRB from the day of first vaccination to 
the end of the solicited and unsolicited follow-up period after each vaccination. 
                                                 
a  Subject’s parents / legally acceptable representatives will be required to document all medications received in the 
diary cards. The sites will focus on only recording the medications belonging to the 3 categories in the other 
source documents. 
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• Category 2: Reportable medications with potential impact on immune response of the study 
vaccine and used to define the Per-Protocol Analysis Set (PPAS). For example: 
• Influenza and other non-study vaccines: Influenza vaccine in the 2 weeks (14 days) 
preceding the trial vaccination up to the last blood draw and any other vaccines (other than 
the study vaccine) in the 4 weeks preceding the trial vaccination up to the last blood draw. 
• Immune globulins, blood or blood-derived products: used in the 3 months preceding the 
first blood draw and up to the last blood draw. 
• Immunosuppressive therapy such as immune-suppressors, immune-modulators with 
immunosuppressive properties, long-term corticosteroid therapy (prednisone or equivalent 
for more than 2 consecutive weeks) within the past 3 months, anti-cancer chemotherapy, 
anti-proliferative drugs such as DNA synthesis inhibitors, or radiation therapy: used in the 
6 months preceding the first trial vaccination, and up to the last blood draw. 
• Category 2 medications will be reported in the CRB according to the collection period 
detailed above up to the last blood draw. 
• Category 3: Systemic (oral or injectable) antibiotics, as they may interfere with bioassays used 
for antibody testing when taken before a blood draw. 
• Category 3 medications will be reported in the CRB for the period of 3 days (72 hours) 
before each blood draw. 
Note: Topical antibiotics (inhaled, otic, ophthalmic, nasal, etc.) should not be captured or 
reported. 
The information reported in the CRB for each reported medication will be limited to: 
• Trade name 
• Rationale for the origin of prescription: Whether it was a prophylactica medication. 
Prophylactic medications will be recorded in the “Action Taken” section of the AE collection 
tables. 
• Medication category (1, 2, or 3) 
• Start and stop dates 
Dosage and administration route and homeopathic medication will not be recorded. 
If the subject has received medications other than those listed in Categories 1, 2, and 3, the 
detailed information will be collected in the source documents only. 
Medications given in response to an AE will be captured in the “Action Taken” section of the AE 
CRB only. No details will be recorded in the concomitant medication CRB unless the medication(s) 
received belongs to one of the prelisted categories.  
                                                 
a  Medication(s) prescribed for preventing AE occurrence (e.g., paracetamol to reduce the risk of fever) 
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7 
Management of Samples 
Blood samples for the assessment of antibody responses will be collected at Visits 1 and 2. See 
the Table of Study Procedures and Section 5.1.3 for details of the sampling schedule. 
7.1 
Sample Collection 
At Visits 1 and 2, 5 mL of blood will be collected in tubes provided by or recommended by the 
Sponsor. Immediately prior to the blood draw, the staff member performing the procedure will 
verify the subject’s identity; will write the assigned subject’s number on the pre-printed label that 
contains that subject’s number and the sampling stage; and will attach the label to the tube. Blood 
is to be taken from the limb opposite to the one that will be used for vaccination. 
7.2 
Sample Preparation 
Detailed instructions on how to prepare blood samples for assessment of immune response are 
contained in the Operating Guidelines provided to the site. An overview of the procedures is 
provided here. 
Following the blood draw, the sample tubes are to be left undisturbed, positioned vertically and 
not shaken, for a minimum of 1 hour and a maximum of 24 hours in order to allow the blood to 
clot. Samples can be stored at room temperature for up to 2 hours; beyond 2 hours, they must be 
refrigerated at a temperature of +2°C to +8°C and must be centrifuged within a maximum of 
24 hours. 
The samples are then centrifuged, and the separated serum is transferred to the appropriate 
number of aliquoting tubes. These tubes are pre-labeled with adhesive labels that identify the 
study code, the subject’s number and the sampling stage or visit number. 
The subject’s number and the date of sampling, the number of aliquots obtained, the date and time 
of preparation, and the parent’s / legally acceptable representative’s consent for future use of his / 
her child’s samples are to be specified on a sample identification list and recorded in the source 
document. Space is provided on this list for comments on the quality of samples. 
7.3 
Sample Storage and Shipment 
During storage, serum tubes are to be kept in a freezer whose temperature is set and maintained at 
-20°C or below. The temperature will be monitored and documented on the appropriate form 
during the entire study. If it rises above -10°C for any period of time, the Clinical Logistics 
Coordinator must be notified. See the Operating Guidelines for further details. 
Shipments to the laboratory will be made only after appropriate monitoring, and following 
notification of the Clinical Logistics Coordinator. Sera will be shipped frozen, using dry ice to 
maintain them in a frozen state, in the packaging container provided by the carrier. Again, 
temperatures will be monitored. Shipments must be compliant with the United Nations (UN) 
Class 6.2 specifications and the International Air Transport Association (IATA) 602 packaging 
instructions. 
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Samples will be shipped to GCI at Sanofi Pasteur. The address is provided in the Operating 
Guidelines.  
7.4 
Future Use of Stored Serum Samples for Research 
Any unused part of the serum samples will be securely stored at the Sanofi Pasteur serology 
laboratory (GCI) for at least 5 years after the last license approval in the relevant market areas has 
been obtained for the vaccine being tested. 
Subjects’ parents / legally acceptable representatives will be asked to indicate in the ICF whether 
they will permit the future use of any unused stored serum samples for other tests. If they refuse 
permission, the samples will not be used for any testing other than that directly related to this 
study. If they agree to this use, they will not be paid for giving permission. Anonymity of samples 
will be ensured. The aim of any possible future research is unknown today, and may not be related 
to this particular study. It may be to improve the knowledge of vaccines or infectious diseases, or 
to improve existing tests or develop new tests to assess vaccines. Human genetic tests will never 
be performed on these samples without specific individual informed consent. 
8 
Clinical Supplies 
Sanofi Pasteur will supply the study sites with protocols, ICFs, CRBs, SAE reporting forms, diary 
cards (booklets or e-diaries), and other study documents, as well as with the following study 
materials: all study vaccines, blood collection tubes, cryotubes, cryotube storage boxes, cryotube 
labels, temperature recorders, shipping containers, rulers, and digital thermometers. 
The means for performing Electronic Data Capture (EDC) will be defined by Sanofi Pasteur. If a 
computer is provided by Sanofi Pasteur, it will be retrieved at the end of the study. 
The Investigator will supply all vaccination supplies, phlebotomy, and centrifugation equipment, 
including biohazard and / or safety supplies. The biohazard and safety supplies include needles 
and syringes, examination gloves, laboratory coats, sharps disposal containers, and absorbent 
countertop paper. The site will ensure that all biohazard wastes are autoclaved and disposed of in 
accordance with local practices. The Investigator will also supply appropriate space in a 
temperature-monitored refrigerator for the storage of the products and for the blood samples, and 
appropriate space in a temperature-monitored freezer for serum aliquots. 
In the event that additional supplies are required, study staff must contact Sanofi Pasteur Clinical 
Logistics Coordinator and/or Service Provider, indicating the quantity required. Contact 
information is provided in the Operating Guidelines.  
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9 
Endpoints and Assessment Methods 
9.1 
Immunogenicity 
9.1.1 
Immunogenicity Endpoints 
The endpoints for the evaluation of immunogenicity are: 
1) Antibody titers against meningococcal serogroups A, C, Y, and W measured by hSBA and 
rSBA: 
a) At D0 (baseline) and D30 in toddlers after having received a single dose of either 
MenACYW conjugate vaccine or Nimenrix®, as part of study MET54 
b) At D0 (baseline) in children before receiving a booster dose of MenACYW conjugate 
vaccine as part of study MET62 (3 years after having received a single dose of either 
MenACYW conjugate vaccine or Nimenrix®) 
2) Antibody titers against meningococcal serogroups A, C, Y, and W measured by hSBA and 
rSBA at D0 (baseline) and D30 after the administration of a booster dose of MenACYW 
conjugate vaccine in children who received either MenACYW conjugate vaccine or 
Nimenrix® 3 years earlier as toddlers 
Tetanus toxoid is contained as a carrier protein in both the investigational vaccine and the control 
vaccine that was used in study MET54. Therefore, blood samples will also be tested to assess: 
3) Antibody concentrations against tetanus toxoid at D0 (baseline) and D30 after the 
administration of a booster dose of MenACYW conjugate vaccine in children who received 
either MenACYW conjugate vaccine or Nimenrix® 3 years earlier as toddlers 
9.1.2 
Immunogenicity Assessment Methods 
 
 
 
 
 
 
 
 
 
 
 
 
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9.2 
Safety 
9.2.1 
Safety Definitions 
The following definitions are taken from the International Council for Harmonisation (ICH) E2A 
Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting. 
Adverse Event (AE): 
An AE is any untoward medical occurrence in a patient or in a clinical investigation subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
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abnormal laboratory finding, for example), symptom or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product.  
Therefore an AE may be: 
• A new illness 
• The worsening of a pre-existing condition 
• An effect of the vaccination, including the comparator 
• A combination of the above 
All AEs include serious and non-serious AEs. 
Surgical procedures are not AEs; they are the actions taken to treat a medical condition. It is the 
condition leading to the action taken that is the AE (if it occurs during the study period). 
Pre-existing medical conditions are not to be reported as AEs. However, if a pre-existing medical 
condition worsens following study interventions in frequency or intensity, or if according to the 
Investigator there is a change in its clinical significance, this change should be reported as an AE 
(exacerbation). This applies equally to recurring episodes of pre-existing conditions (e.g., asthma) 
if the frequency or intensity increases post-vaccination. 
Serious Adverse Event (SAE): 
Serious and severe are not synonymous. The term severe is often used to describe the intensity of 
a specific event as corresponding to Grade 3. This is not the same as serious which is based on 
subject / event outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or functioning. Seriousness, not severity, serves as a guide for defining regulatory 
reporting obligations. 
An SAE is any untoward medical occurrence that at any dose  
• Results in death 
• Is life-threateninga 
• Requires inpatient hospitalization or prolongation of existing hospitalizationb 
• Results in persistent or significant disability / incapacityc 
• Is a congenital anomaly / birth defect 
• Is an important medical event (IME) 
                                                 
a  The term “life-threatening” refers to an event in which the subject was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it were more severe. 
b  All medical events leading to hospitalizations will be recorded and reported as SAEs, with the exception of: 
hospitalization planned before inclusion into the study or outpatient treatment with no hospitalization.  
c  “Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s ability 
to carry out normal life functions. 
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Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as IMEs that may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the health of the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These IMEs 
should also usually be considered serious. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse, new-onset diabetes, or autoimmune disease. 
Adverse Reaction (AR): 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered ARs. 
(The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility) 
The following additional definitions are used by Sanofi Pasteur: 
Immediate Event/Reaction: 
Immediate events are recorded to capture medically relevant unsolicited systemic AEs (including 
those related to the product administered) that occur within the first 30 minutes after vaccination. 
Solicited Reaction: 
A solicited reaction is an “expected” adverse reaction (sign or symptom) observed and reported 
under the conditions (nature and onset) prelisted in the protocol and CRB (e.g., injection site pain 
or headache occurring between D0 and D07 post-vaccination). 
By definition, solicited reactions are to be considered as being related to the product administered. 
For injectable vaccines, solicited reactions can either be solicited injection site reactions or 
solicited systemic reactions. 
The assessment of these reactions by the investigator is mandatory. 
Unsolicited AE / AR: 
An unsolicited AE is an observed AE that does not fulfill the conditions prelisted in the CRB in 
terms of diagnosis and/or onset window post-vaccination. For example, if headache between D0 
and D07 is a solicited reaction (i.e., prelisted in the protocol and CRB), then a headache starting 
on D07 is a solicited reaction, whereas headache starting on D08 post-vaccination is an 
unsolicited AE. Unsolicited AEs includes both serious (SAEs) and non-serious unsolicited AEs. 
Injection Site Reaction: 
An injection site reaction is an AR at and around the injection site. Injection site reactions are 
commonly inflammatory reactions. They are considered to be related to the product administered. 
Systemic AE: 
Systemic AEs are all AEs that are not injection or administration site reactions. They therefore 
include systemic manifestations such as headache, fever, as well as localized or topical 
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manifestations that are not associated with the vaccination or administration site (e.g., erythema 
that is localized but that is not occurring at the injection site). 
Adverse Event of Special Interest (AESI): 
An adverse event of special interest is one of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
investigator to the sponsor can be appropriate. Such an event might warrant further investigation 
in order to characterize and understand it. Depending on the nature of the event, rapid 
communication by the study Sponsor to other parties (e.g., regulators) might also be warranted. 
9.2.2 
Safety Endpoints 
The endpoints for the evaluation of safety are: 
• Occurrence, nature (Medical Dictionary for Regulatory Activities [MedDRA] preferred term 
[PT]), duration, intensity, and relationship to vaccination of any unsolicited systemic AEs 
reported in the 30 minutes after vaccination 
• Occurrence, time of onset, number of days of occurrence, intensity, action taken, and whether 
the reaction led to early termination from the study, of solicited (prelisted in the subject’s 
diary card [booklet or e-diary] and CRB) injection site reactions occurring up to 7 days after 
vaccination. 
• Occurrence, time of onset, number of days of occurrence, intensity, action taken, and whether 
the reaction led to early termination from the study, of solicited (prelisted in the subject’s 
diary card [booklet or e-diary] and CRB) systemic reactions occurring up to 7 days after 
vaccination. 
• Occurrence, nature (MedDRA PT), time of onset, duration, intensity, action taken, 
relationship to vaccination (for systemic AEs only), and whether the event led to early 
termination from the study, of unsolicited AEs up to Visit 2 after vaccination. 
• Occurrence, nature (MedDRA PT), time of onset, duration, seriousness criteria, relationship to 
vaccination, outcome, and whether the SAE led to early termination from the study, of SAEs, 
including AESIs, throughout the trial. 
9.2.3 
Safety Assessment Methods 
At Visit 2, the Investigator or a delegate will ask the subject’s parent / legally acceptable 
representative about any solicited reactions and unsolicited AEs recorded in the diary card 
(booklet or e-diary), as well as about any other AEs that may have occurred since the previous 
visit. All relevant data will be transcribed into the CRB according to the instructions provided by 
the Sponsor. 
9.2.3.1 
Immediate Post-vaccination Observation Period 
Subjects will be kept under observation for 30 minutes after vaccination to ensure their safety. 
The post-vaccination observation should be documented in the source document. Any AE that 
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occurs during this period will be noted on the source document and recorded in the CRB, as 
follows: 
• Unsolicited systemic AEs will be recorded as immediate AEs in the CRB (presence marked as 
“yes” and details collected). 
• Solicited and unsolicited injection site reactions and solicited systemic reactions will be 
recorded in the CRB in the same way as any reactions starting on the day of vaccination.  
• SAEs will be recorded in the CRB and reported to the Sponsor in the same way as any other 
SAEs, according to the procedures described in Section 10. 
9.2.3.2 
Reactogenicity (Solicited Reactions From Day 0 to Day 07 After Vaccination) 
After vaccination, subject’s parents / legally acceptable representatives will be provided with a 
diary card (booklet or e-diary), a digital thermometer, and a flexible ruler, and will be instructed 
how to use them. The following items will be recorded by the subject’s parents / legally 
acceptable representatives in the diary card (booklet or e-diary) on the day of vaccination and for 
the next 7 days (i.e., D0 to D07) until resolution: 
• Daily temperature, with the route by which it was taken 
• Daily measurement or intensity grade of all other solicited injection site and systemic 
reactions 
• Action taken for each event (e.g., medication) 
The action(s) taken by the subject’s parent / legally acceptable representative to treat and/or 
manage any solicited reactions will be classified in the CRB using the following list (all 
applicable items should be checked): 
• None 
• Medication 
• Health care provider contact 
• Hospitalized 
Subjects’ parents / legally acceptable representatives will be contacted by telephone 8 days after 
vaccination to remind them to record all safety information in the diary card (booklet or e-diary). 
If the timing of the telephone call should fall on a weekend or a holiday, the call should be made 
on the next business day. If contact is not made on the designated day, study staff will continue 
calling until contact is made. Every telephone attempt and its outcome will be documented in the 
source document. 
Table 9.1 and Table 9.2 present, respectively, the injection site reactions and systemic reactions 
that are prelisted in the diary cards (booklets or e-diaries) and CRB, together with the intensity 
scales. 
 
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Table 9.1: Solicited injection site reactions: terminology, definitions, and intensity scales 
CRB term 
(MedDRA 
lowest level 
term [LLT]) 
Injection site pain 
Injection site erythema 
Injection site swelling  
MedDRA 
PT 
Injection site pain 
Injection site erythema 
Injection site swelling 
Diary card 
(booklet or 
e-diary) 
term 
Pain 
Redness 
Swelling 
Definition 
Pain either present 
spontaneously or when the 
injection site is touched or 
injected limb is mobilized 
Presence of a redness 
including the approximate 
point of needle entry 
Swelling at or near the 
injection site 
Swelling or edema is 
caused by a fluid 
infiltration in tissue or 
cavity and, depending on 
the space available for the 
fluid to disperse, swelling 
may be either soft 
(typically) or firm (less 
typical) to touch and thus 
can be best described by 
looking at the size of the 
swelling 
Intensity 
scale* 
 
Grade 1: Easily tolerated 
Grade 2: Sufficiently 
discomforting to interfere 
with normal behavior or 
activities 
Grade 3: Incapacitating, 
unable to perform usual 
activities 
Grade 1: > 0 to < 25 mm 
Grade 2: ≥ 25 to < 50 mm 
Grade 3: ≥ 50 mm 
Grade 1: > 0 to < 25 mm 
Grade 2: ≥ 25 to < 50 mm 
Grade 3: ≥ 50 mm 
*  For the subjective reaction of pain, parents / legally acceptable representatives will record the intensity level 
(Grade 1, 2, or 3) in the diary card (booklet or e-diary). For the measurable reactions of redness and swelling, they 
will record just the size of the reaction, and the classification as Grade 1, 2, or 3 will be assigned at the time of the 
statistical analysis. 
 
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Table 9.2: Solicited systemic reactions: terminology, definitions, and intensity scales 
CRB term 
(MedDRA 
LLT) 
Fever 
Headache 
Malaise 
Myalgia 
MedDRA 
PT 
Pyrexia 
Headache 
Malaise 
Myalgia 
Diary card 
(booklet or 
e-diary) 
term 
Temperature 
Headache 
Feeling unwell 
Muscle aches and 
pains 
Definition 
Elevation of 
temperature to 
≥ 38.0°C (≥ 100.4°F) 
Pain or discomfort in 
the head or scalp. 
Does not include 
migraine. 
General ill feeling. 
Malaise is a 
generalized feeling of 
discomfort, illness, or 
lack of well-being that 
can be associated with 
a disease state. It can 
be accompanied by a 
sensation of 
exhaustion or 
inadequate energy to 
accomplish usual 
activities. 
Muscle aches and 
pains are common 
and can involve 
more than one 
muscle at the same 
time. Muscle pain 
can also involve the 
soft tissues that 
surround muscles. 
These structures, 
which are often 
referred to as 
connective tissues, 
include ligaments, 
tendons, and fascia 
(thick bands of 
tendons). 
Does not apply to 
muscle pain at the 
injection site which 
should be reported 
as injection site 
pain. 
Intensity 
scale* 
Grade 1: ≥ 38.0°C to 
≤ 38.4°C, 
or ≥ 100.4°F to 
≤ 101.1°F 
Grade 1: A type of 
adverse event that is 
usually transient and 
may require only 
minimal treatment or 
therapeutic 
intervention. The 
event does not 
generally interfere 
with usual activities of 
daily living. 
Grade 1: A type of 
adverse event that is 
usually transient and 
may require only 
minimal treatment or 
therapeutic 
intervention. The 
event does not 
generally interfere 
with usual activities of 
daily living. 
Grade 1: A type of 
adverse event that is 
usually transient 
and may require 
only minimal 
treatment or 
therapeutic 
intervention. The 
event does not 
generally interfere 
with usual activities 
of daily living. 
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CRB term 
(MedDRA 
LLT) 
Fever 
Headache 
Malaise 
Myalgia 
MedDRA 
PT 
Pyrexia 
Headache 
Malaise 
Myalgia 
Diary card 
(booklet or 
e-diary) 
term 
Temperature 
Headache 
Feeling unwell 
Muscle aches and 
pains 
 
Grade 2: ≥ 38.5°C to 
≤ 38.9°C, 
or ≥ 101.2°F to 
≤ 102.0°F 
Grade 2: A type of 
adverse event that is 
usually alleviated with 
additional therapeutic 
intervention. The 
event interferes with 
usual activities of 
daily living, causing 
discomfort but poses 
no significant or 
permanent risk of 
harm to the research 
participant. 
Grade 2: A type of 
adverse event that is 
usually alleviated with 
additional therapeutic 
intervention. The 
event interferes with 
usual activities of 
daily living, causing 
discomfort but poses 
no significant or 
permanent risk of 
harm to the research 
participant. 
Grade 2: A type of 
adverse event that is 
usually alleviated 
with additional 
therapeutic 
intervention. The 
event interferes 
with usual activities 
of daily living, 
causing discomfort 
but poses no 
significant or 
permanent risk of 
harm to the research 
participant. 
 
Grade 3: ≥ 39.0°C 
 
 
or ≥ 102.1°F 
Grade 3: A type of 
adverse event that 
interrupts usual 
activities of daily 
living, or significantly 
affects clinical status, 
or may require 
intensive therapeutic 
intervention. 
Grade 3: A type of 
adverse event that 
interrupts usual 
activities of daily 
living, or significantly 
affects clinical status, 
or may require 
intensive therapeutic 
intervention. 
Grade 3: A type of 
adverse event that 
interrupts usual 
activities of daily 
living, or 
significantly affects 
clinical status, or 
may require 
intensive 
therapeutic 
intervention. 
*  For all reactions but fever, parents / legally acceptable representatives will record the intensity level (Grade 1, 2, 
or 3) in the diary card (booklet or e-diary). For fever, they will record the body temperature, and the classification 
as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis based on the unit used to measure the 
temperature and the intensity scale. 
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Important notes for the accurate assessment of temperature: 
Parents / legally acceptable representatives are to measure body temperature once per day, 
preferably always at the same time. The optimal time for measurement is the evening, when body 
temperature is the highest. Temperature is also to be measured at the time of any apparent fever. 
The observed daily temperature and the route of measurement are to be recorded in the diary card 
(booklet or e-diary) and the highest temperature will be recorded by the site in the CRB. The 
preferred route for this study is axillary. Pre-vaccination temperature is also systematically 
collected by the investigator on the source document. Tympanic thermometers must not be used. 
9.2.3.3 
Unsolicited Adverse Events 
In addition to recording solicited reactions, parents / legally acceptable representatives will be 
instructed to record any other medical events that may occur during the 30-day period after 
vaccination. Space will be provided in the diary card (booklet or e-diary) for this purpose.  
Information on SAEs will be collected and assessed throughout the study, from the time of 
vaccination until 30 days (+14 days) after vaccination. Any SAE occurring at any time during the 
study will be reported by the Investigator in the CRB according to the completion instructions 
provided by the Sponsor; this includes checking the “Serious” box on the AE CRF and 
completing the appropriate Safety Complementary Information CRFs. All information concerning 
the SAE is to be reported either as part of the initial reporting or during follow-up reporting if 
relevant information became available later (e.g., outcome, medical history, results of 
investigations, copy of hospitalization reports). In case a subject experiences febrile convulsion 
(neurological event associating fever and seizure), the assessment will be performed according to 
the “Guideline for definition and collection of cases of febrile convulsion”, and this event will be 
considered an SAE. See Section 10 for further details on SAE reporting. 
For each unsolicited AE (whether serious or non-serious), the following information is to be 
recorded: 
• Start and stop datesa  
• Intensity of the event: 
For measurable unsolicited AEs that are part of the list of solicited reactions, the size of the 
AE as well as the temperature for fever will be collected and analyzed based on the 
corresponding scale used for solicited reactions (see Table 9.1 and Table 9.2). 
All other unsolicited AEs will be classified according to the following intensity scale: 
• Grade 1: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
                                                 
a  The stop date of all related AEs will be actively solicited. For other events, the investigator will provide the stop 
date when it becomes available. AEs for which no stop date was obtained during the course of the study will be 
considered as ongoing at the end of the study. 
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• Grade 2: A type of AE that is usually alleviated with additional therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research participant.  
• Grade 3: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
• Whether the AE was related to the investigational product (for unsolicited systemic AEs) 
The Investigator will assess the causal relationship between the AE and the investigational 
product as either “Not related” or “Related”, as described in Section 9.2.3.5. 
• Action taken for each AE (e.g., medication) 
The action(s) taken by the parent / legally acceptable representative to treat and/or manage 
any unsolicited AEs will be classified in the CRB using the following list (all applicable items 
should be checked): 
• None 
• Medication 
• Health care provider contact 
• Hospitalized 
• Whether the AE was serious 
For each SAE, the investigator will complete all seriousness criteria that apply (outcome, 
elapsed time, and relationship to study procedures) 
• Whether the AE caused study discontinuation 
9.2.3.4 
Adverse Events of Special Interest 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
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9.2.3.5 
Assessment of Causality 
The Investigator will assess the causal relationship between each unsolicited systemic AE and 
the product administered as either not related or related, based on the following definitions: 
Not related – The AE is clearly / most probably caused by other etiologies such as an 
underlying condition, therapeutic intervention, or concomitant therapy; or the delay 
between vaccination and the onset of the AE is incompatible with a causal relationship; or 
the AE started before the vaccination (screening phase, if applicable) 
Related – There is a “reasonable possibility” that the AE was caused by the product 
administered, meaning that there is evidence or arguments to suggest a causal relationship 
Note: By convention, all AEs reported at the injection site (whether solicited or unsolicited) and 
all solicited systemic AEs are considered to be related to the administered product and therefore 
are referred to as reactions and do not require the Investigator’s opinion on relatedness. 
Adverse events likely to be related to the product, whether serious or not, that persist at the end of 
the study will be followed up by the Investigator until their complete disappearance or the 
stabilization of the subject’s condition. The Investigator will inform the Sponsor of the date of 
final disappearance of the event or the date of “chronicity” establishment. 
9.3 
Efficacy 
No clinical efficacy data will be obtained in the study. 
10 Reporting of Serious Adverse Events  
To comply with current regulations on SAE reporting to health authorities, the Investigator must 
document all SAEs regardless of causal relationship, and notify the Sponsor and the Clinical 
Research Associate (CRA) within the notification timelines stated in the following sections. The 
Investigator will give access and provide the Sponsor and the CRA with all necessary information 
to allow the Sponsor to conduct a detailed analysis of the safety of the investigational product. It 
is the responsibility of the Investigator to request all necessary documentation (e.g., medical 
records, discharge summary, autopsy) in order to provide comprehensive safety information. All 
relevant information must then be transcribed onto the AE CRF and the appropriate Safety 
Complementary Information CRFs. 
10.1 Initial Reporting by the Investigator 
Serious adverse events occurring during a subject’s participation in the study or experiment must 
be reported within 24 hours to the Sponsor’s GPV Department and to the CRA. Every SAE must 
be reported, even if the Investigator considers that it is not related to the vaccine. The investigator 
(licensed physician [M.D. or D.O.]) must validate the information entered on the AE CRF by 
completing the investigator validation form. 
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The Investigator must indicate on the AE CRF that the event was serious and must complete the 
relevant SAE section of this form as well as the appropriate Safety Complementary Information 
CRFs. An e-mail alert will automatically be sent by the EDC system to the GPV mailbox, the 
CRA and the CTL with relevant SAE information details. 
If the EDC system is unavailable, the site must notify the Sponsor, using the paper version of the 
CRB, as described in the Operating Guidelines: 
The Investigator must complete the paper copies of the AE CRF and of the appropriate Safety 
Complementary Information CRFs and send them to the Sponsor by one of the following means: 
• By fax, to the following number: 
 
• In PDF format to the following e-mail address, using a method of transmission that 
includes password protection: 
 (see the Operating Guidelines 
for directions on how to send a password protected email) 
• By express mail, to the following address:   Sanofi Pasteur Inc. 
Reception and Triage – Case Management 
Global PharmacoVigilance 
Mail Drop: 45D38 
Discovery Drive 
Swiftwater, PA 18370, USA 
When the EDC system becomes available, the Investigator must transcribe the information from 
the paper forms into the EDC system. 
If there is need for urgent consultation, the Investigator is to contact the RMO. If the RMO cannot 
be reached, the Investigator may contact the Call Center as described in Section 5.3.  
10.2 Follow-up Reporting by the Investigator 
The AE CRF completed initially must be updated within 24 hours after the Investigator has 
become aware of any new relevant information concerning the SAE (e.g., outcome, precise 
description of medical history, results of the investigation). All relevant information must be 
included directly in the AE CRF and the appropriate Safety Complementary Information CRFs. 
An e-mail alert will be sent automatically to the GPV Department and to the CRA. Copies of 
documents (e.g., medical records, discharge summary, autopsy) may be requested by the GPV 
Department. 
The anonymity of the subject must always be respected when forwarding this information. 
10.3 Reporting of SAEs Occurring After a Subject Has Completed the Study 
Any SAE that occurs after a subject has completed the study but that is likely to be related to the 
investigational product(s), other products (e.g., a benefit vaccine), or to the experiment must also 
be reported as soon as possible. In such a case, the reporting procedure to be followed is identical 
to that described in Section 10.1. 
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10.4 Assessment of Causality 
The causal relationship between the SAE and the product administered will be evaluated by the 
Investigator as described in Section 9.2.3.5. 
Following this, the Sponsor’s Pharmacovigilance (PV) Global Safety Expert will also assess the 
causal relationship to the product, based on the available information and current medical 
knowledge. 
The causal relationship to study procedures will be also assessed in the CRB. 
The decision to modify or discontinue the study may be made after mutual agreement between the 
Sponsor and the Investigator(s). 
10.5 Reporting SAEs to Health Authorities and IECs / IRBs 
The Sponsor will inform the relevant health authorities of any reportable SAEs according to the 
local regulatory requirements. Reporting to the health authorities will be according to the 
Sponsor’s standard operating procedures. 
The Sponsor’s RMO, 
 will notify the 
Investigators in writing of the occurrence of any reportable SAEs. The Investigators / Sponsor 
will be responsible for informing the IECs or IRBs that reviewed the study protocol. 
11 Data Collection and Management 
11.1 Data Collection and CRB Completion 
Individual diary cards (booklets or e-diaries), specifically designed for this study by the Sponsor 
and provided to the study sites, will be given to study participants’ parents / legally acceptable 
representatives for the recording of daily safety information as described in Section 9.2.3. These 
diary cards (booklets or e-diaries) will include prelisted terms and intensity scales (see Table 9.1 
and Table 9.2) as well as areas for free text to capture additional safety information or other 
relevant details. Parents / legally acceptable representatives will also be provided with rulers for 
measuring the size of injection site reactions, and with standard digital thermometers for 
measuring daily temperatures. To ensure consistency of reporting, the study sites will instruct 
parents / legally acceptable representatives on how to correctly use these tools.  
At specified intervals, the Investigator or an authorized designee will interview the parents / 
legally acceptable representatives to collect the information recorded in the diary card (booklet or 
e-diary), and will attempt to clarify anything that is incomplete or unclear. All clinical study 
information gathered by the study site will be reported electronically by the Investigator or 
authorized designee using a web-based CRB. Data from the e-diary will be integrated into the 
CRB. (Any information that was not documented in the diary card [booklet or e-diary] will first 
be captured in the source document and then reported electronically.) The CRB has been designed 
specifically for this study under the responsibility of the Sponsor, using a validated Electronic 
Records / Electronic Signature-compliant platform (21 CFR Part 11). 
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To ensure the correct and consistent completion of the CRBs, the Sponsor or authorized 
representative will provide all necessary tools, instructions, and training to all site staff involved 
in data entry prior to study start. Additional instructional documents such as training manuals and 
completion instructions will be provided to assist with data entry during the course of the study. 
Upon completion of training, each user requiring access to the EDC system will be issued a 
unique username and password. In the event of a change in study personnel, each newly assigned 
individual will receive a unique username and password; the username and password of a 
previous user may not be reissued. If any study personnel leave the study, the Investigator is 
responsible for informing the Sponsor immediately so that their access is deactivated. An audit 
trail will be initiated in the EDC system at the time of the first data entry to track all modifications 
and ensure database integrity. 
The Investigator is responsible for the timeliness, completeness, and accuracy of the information 
in the CRBs; must provide explanations for all missing information; and must sign the CRB using 
an e-signature. 
11.2 Data Management 
Management of SAE Data 
During the study, SAE data (reported on the AE and Safety Complementary Information CRFs) 
will be integrated into the Sponsor’s centralized GPV database upon receipt of these forms and 
after a duplicate check. Each case will be assigned a case identification number. Each case will be 
assessed by the case management platform or its delegate before being reported to the relevant 
authorities as necessary. The assessment of related cases will be done in collaboration with the PV 
Global Safety Expert and the RMO. Follow-up information concerning a completed case will be 
entered into the GPV database, and a new version of the case will be created. 
The information from the GPV database cases will be reconciled with that in the clinical database. 
Management of Clinical and Laboratory Data 
Clinical data, defined as all data reported in the CRB, and laboratory data will be handled by the 
Sponsor’s Clinical Data Management (CDM) platform or authorized representative. 
During the study, clinical data reported in the CRB will be integrated into the clinical database 
under the responsibility of the Sanofi Pasteur CDM platform. Data monitoring at the sites and 
quality control in the form of computerized logic and / or consistency checks will be 
systematically applied to detect errors or omissions. In addition, data reviews may be performed 
several times by the Sponsor’s staff in the course of the study. Any questions pertaining to the 
reported clinical data will be submitted to the investigator for resolution using the EDC system. 
Each step of this process will be monitored through the implementation of individual passwords 
to maintain appropriate database access and to ensure database integrity. 
The validation of the immunogenicity data will be performed at the laboratory level following the 
laboratory’s procedures. Information from the laboratory will be checked for consistency before 
integration into the clinical Datawarehouse. 
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After integration of all corrections in the complete set of data, and after the SAE information 
available from CDM and the GPV Department has been reconciled, the database will be released for 
statistical analysis. 
11.3 Data Review 
A review of the data is anticipated through the data review process led by Data Management 
before database lock. The safety of the investigational product will be continuously monitored by 
the Sponsor. Periodic safety data review will be performed by the Sponsor’s SMT. 
12 Statistical Methods and Determination of Sample Size 
12.1 Statistical Methods 
Clinical data will be analyzed under the responsibility of the Biostatistics Platform of the Sponsor. 
A statistical analysis plan (SAP) will be written and peer reviewed before any analyses. In 
accordance with the protocol, the SAP will describe all analyses to be performed by the Sponsor 
and all the conventions to be taken. 
12.1.1 Hypotheses and Statistical Methods for the Objective 
12.1.1.1 Hypotheses 
No hypotheses will be tested. Descriptive statistics will be presented. 
12.1.1.2 Statistical Methods 
Immunogenicity 
Descriptive statistics will be provided for the hSBA and rSBA antibody titers against 
meningococcal serogroups (A, C, Y, and W) and for antibody concentrations against tetanus 
toxoid contained in MenACYW conjugate vaccine.  
In general, categorical variables will be summarized and presented by frequency counts, 
proportion percentages, and confidence intervals (CIs). The 95% CIs of point estimates will be 
calculated using the normal approximation for quantitative data and the exact binomial 
distribution (Clopper-Pearson method) for percentages (43). For geometric mean titers (GMTs), 
95% CIs of point estimates will be calculated using normal approximation assuming they are log-
normally distributed.  
Reverse cumulative distribution curve (RCDC) figures will be provided for the antibody titers 
against meningococcal serogroups or antibody concentrations against tetanus toxoid contained in 
MenACYW conjugate vaccine. 
In summary, descriptive analyses on A, C, Y, and W serogroups will include but not be limited to: 
• hSBA and rSBA GMTs and 95% CI 
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• hSBA and rSBA titer distribution and RCDC 
• Percentage of subjects with hSBA titer ≥ 1:4 and ≥ 1:8 and 95% CI 
• Percentage of subjects with rSBA titer ≥ 1:8 and ≥ 1:128 and 95% CI 
• Percentage of subjects with hSBA and rSBA titer ≥4-fold rise from pre-vaccination to post-
vaccination, and 95% CI 
• Percentage of subjects with hSBA and rSBA vaccine seroresponsea rate and 95% CI 
In summary, descriptive analyses on anti-tetanus antibody concentrations will include but not be 
limited to: 
• Geometric mean concentrations (GMCs) and 95% CI 
• The percentage of subjects with antibody concentrations to tetanus toxoid ≥ 0.IU/mL and 
≥ 0.1 IU/mL and 95% CI 
Data from MET54 and MET62 will also be combined and paired to evaluate antibody persistence 
and overall trend over 3 years. 
Safety 
For this trial, the safety data will be assessed by applying descriptive statistical methods, 
supplemented by the calculation of CIs to aid interpretation. The exact binomial distribution 
(Clopper-Pearson method) for proportions will be used in the calculation of the 95% CIs of 
events. 
The frequency and percentage of subjects who had solicited injection site and systemic reactions 
and their 95% CIs will be provided. These events will be tabulated by type of reactions and 
intensity for each study group. These events will also be summarized by other categories specified 
in the endpoints (e.g., time of onset, number of days of occurrence, action taken). 
Unsolicited AEs will be collected, coded, and summarized by MedDRA system organ class and 
PT. For each unsolicited AE, the number of subjects with at least one instance of that event will 
                                                 
a  hSBA vaccine seroresponse (definition proposed by the Center for Biologics Evaluation and Research 
[CBER] in 2016) for serogroups A, C, Y, and W is defined as: 
 
 
• For a subject with a pre-vaccination titer < 1:8, the post-vaccination titer must be ≥ 1:16. 
 
 
• For a subject with a pre-vaccination titer ≥ 1:8, the post-vaccination titer must be at least 4-fold greater than 
 
   the pre-vaccination titer. 
 
hSBA vaccine seroresponse (definition used in study MET54) for serogroups A, C, Y, and W is defined as: 
 
 
• For a subject with a pre-vaccination titer < 1:8, the post-vaccination titer must be ≥ 1:8. 
 
 
• For a subject with a pre-vaccination titer ≥ 1:8, the post-vaccination titer must be at least 4-fold greater than 
 
  the pre-vaccination titer. 
rSBA vaccine seroresponse is defined as: 
 
 
• a post-vaccination rSBA titer ≥ 1:32 for subjects with pre-vaccination rSBA titer < 1:8, 
 
   or  
 
• a post-vaccination titer ≥ 4 times the pre-vaccination titer for subjects with pre-vaccination rSBA titer 
 
≥ 1:8. 
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be reported. Unsolicited AEs will also be tabulated by intensity and relatedness of study vaccine 
and by other categories specified in the endpoints. 
Immediate reactions, SAEs, and any event that leads to subject withdrawal from the study will be 
tabulated separately. 
12.2 Analysis Sets 
Three analysis sets will be used: the Full Analysis Set (FAS), the PPAS, and the Safety Analysis 
Set (SafAS). 
12.2.1 Full Analysis Set 
The FAS is defined as the subset of subjects who received at least 1 dose of the study vaccine and 
had a valid post-vaccination blood sample result. 
12.2.2 Safety Analysis Set 
The SafAS is defined as those subjects who have received at least one dose of the study vaccinea 
and have any safety data available. All subjects will have their safety analyzed according to the 
vaccine they actually received. 
Safety data recorded for a vaccine received out of the protocol design will be excluded from the 
analysis (and listed separately). 
12.2.3 Per-Protocol Analysis Set 
The PPAS is a subset of the FAS. The subjects presenting with at least one of the following 
relevant protocol deviations will be excluded from the PPAS: 
• Subject did not meet all protocol-specified inclusion criteria or met at least one of the 
protocol-specified exclusion criteria 
• Subject did not receive vaccine 
• Subject received a vaccine other than the one that he / she was planned to receive 
• Preparation and / or administration of vaccine was not done as per-protocol 
• Subject did not receive vaccine in the proper time window 
• Subject did not provide the post-dose serology sample at Visit 2 in the proper time window or 
a post-dose serology sample was not drawn 
• Subject received a protocol-prohibited therapy / medication / vaccine 
• Subject had another protocol deviations that affected the subject’s immune response, as 
determined by the clinical team before locking the database 
                                                 
a  for which safety data are scheduled to be collected 
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In addition to the reasons listed above, subjects will also be excluded from the PPAS if their post-
vaccination serology sample did not produce a valid test result (i.e., results for all antigens are 
missing). 
In the event of a local or national immunization program with a pandemic influenza vaccine, 
subjects who receive 1 or more doses of a pandemic influenza vaccine at any time during the 
study will not be withdrawn from the study. 
12.2.4 Populations Used in Analyses 
All immunogenicity analyses will be performed on the PPAS. Additional immunogenicity 
analyses will be performed for exploratory purposes on the FAS. All safety analyses will be 
performed on the SafAS. All analyses will be based on the overall study population as well as the 
type of meningococcal vaccine received in MET54 (subjects who received MenACYW conjugate 
vaccine and subjects who received Nimenrix® 3 years earlier as toddlers). 
12.3 Handling of Missing Data and Outliers 
12.3.1 Safety 
No replacement will be done. 
12.3.2 Immunogenicity 
Missing data will not be imputed. No test or search for outliers will be performed. 
In order to appropriately manage extreme values (undetectable responses < LLOQ and ≥ upper 
limit of quantitation [ULOQ]), the following computational rule is applied to the values provided 
in the clinical database for each blood sample drawn for analysis purposes: 
• If a value is < LLOQ, then use the computed value LLOQ/2 
• If a value is between ≥ LLOQ and < ULOQ, then use the value 
• If a value is ≥ ULOQ, then use the computed value ULOQ 
The derived endpoint of fold-rise is computed as follows for extreme values, to minimize the 
numerator and maximizes the denominator: 
• If the baseline computed value is < LLOQ and the post-baseline computed value is < LLOQ 
then the fold-rise is 1 
• If the baseline computed value is ≥ LLOQ and the post-baseline computed value is ≥ LLOQ 
then the fold-rise is post-baseline computed value / baseline computed value 
• If the baseline computed value is ≥ LLOQ and the post-baseline computed value is < LLOQ 
then the fold-rise is (LLOQ/2) / baseline computed value 
• If the baseline computed value is < LLOQ and the post-baseline computed value is ≥ LLOQ 
then the fold-rise is post-baseline computed value /LLOQ 
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12.4 Interim / Preliminary Analysis 
No preliminary analyses are planned. 
12.5 Determination of Sample Size and Power Calculation 
This is an exploratory study with no hypothesis-driven primary objectives. All available subjects 
who participated in and completed the MET54 study and received either MenACYW conjugate 
vaccine or Nimenrix® vaccine, as a part of the study, will be enrolled. 
13 Ethical and Legal Issues and Investigator / Sponsor Responsibilities 
13.1 Ethical Conduct of the Study / Good Clinical Practice 
The conduct of this study will be consistent with the standards established by the Declaration of 
Helsinki and compliant with the ICH guidelines for GCP as well as with all local and / or national 
regulations and directives. 
13.2 Source Data and Source Documents 
“Source data” are the data contained in source documents. Source documents are original 
documents or certified copies, and include, but are not limited to, diary cards (booklets or e-
diaries), medical and hospital records, screening logs, informed consent / assent forms, telephone 
contact logs, and worksheets. The purpose of study source documents is to document the 
existence of subjects and to substantiate the integrity of the study data collected. Investigators 
must maintain source documents so that they are accurate, complete, legible, and up to date. 
For missing or discrepant data on a diary card (booklet), the study coordinator will obtain verbal 
clarification from the subject, enter the response into the “investigator’s comment” page of the 
diary card (booklet), and transfer the information to the CRB. For missing or discrepant data on a 
diary card (e-diary), the study site staff will obtain verbal clarification from the subject, enter the 
response in the source document, and transfer the information to the CRB. 
The subject pre-screening log should list all individuals contacted by the Investigators to 
participate in the study, regardless of the outcome. 
The Investigator must printa any electronic records on an ongoing basis, sign and date them 
immediately after creation, and keep the printouts on file as source documents that can be verified 
by the Sponsor or an inspector against the electronic records. Any subsequent changes of an 
electronic record require the record to be re-printed, dated (with an indication of the date of 
change), and signed. Such records must also be kept together with the original printed copy. 
                                                 
a  Unless the electronic medical records are managed by validated computerized systems that are compliant with US 
21 CFR Part 11, in which case they are acceptable on their own. 
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If an e-diary is used in this trial, the e-diary data, which has been integrated into the CRB, will be 
available on the vendor’s web-based portal for review. At the end of the trial, data in the web-
based portal will be stored and then will later be destroyed according to local regulation. 
Good Documentation Practice should be followed by the Investigator and the site staff managing 
source documents. 
13.3 Confidentiality of Data and Access to Subject Records 
Prior to initiation of the study, the Investigator will sign a fully executed confidentiality 
agreement with Sanofi Pasteur. 
Sanofi Pasteur personnel (or designates), the IECs / IRBs, and regulatory agencies, require direct 
access to all study records, and will treat these documents in a confidential manner. 
In the event a subject’s medical records are not at the investigational site, it is the responsibility of 
the investigator to obtain those records if needed. 
13.4 Monitoring, Auditing, and Archiving 
13.4.1 Monitoring  
Before the start of the study (i.e., before the inclusion of the first subject in the first center), the 
Investigators and the Sponsor’s staff or a representative will meet at the site-initiation visit to 
discuss the study protocol and the detailed study procedures. Emphasis will be placed on inclusion 
and exclusion criteria, visit timing, safety procedures, informed consent procedures, SAE 
reporting procedures, CRB completion, and the handling of samples and products. The Sponsor’s 
staff or a representative will ensure and document that all material to be used during the study has 
been received at the site; and that the study investigator team and local Sponsor/delegate staff 
have been properly informed about the study, GCP and regulatory requirements, and the 
Sponsor’s procedures. Specific training sessions for the study investigator team and the CRAs on 
these topics may be performed as necessary, and should be documented. 
The following instruction manuals will be provided: the CRF Completion Instructions for entering 
data into the CRB, and the Operating Guidelines for detailed study procedures such as the product 
management and sample-handling procedures. 
After the start of the study, the Sponsor’s staff or a representative will be in regular contact with 
the investigational team through telephone calls and regular follow-up visits. The Investigator or 
delegate must be available for these visits, and must allow the Sponsor/delegate staff direct access 
to subject medical files and CRFs. During these visits, the Sponsor/delegate staff will: 
• Evaluate the quality of the study progress (adherence to protocol and any study-specific 
guidelines, quality of data collection and document completion, signature of consent forms, 
occurrence of SAEs, sample and product management, cold-chain monitoring, archiving) 
• Source-verify completed CRFs and any corresponding answered queries 
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• Determine the number of complete or ongoing issues identified at monitoring visits (e.g., 
protocol deviations, SAEs). Any identified problems will be discussed with the Investigator, 
and corrective or preventive actions will be determined, as appropriate. 
• After all protocol procedures have been completed and the data have been entered into the 
CRB, the Investigator must still be available to answer any queries forwarded by the Sponsor. 
All data-related queries must be completed prior to database lock. 
At the end of the study, a close-out visit will be performed to ensure that: 
• The center has all the documents necessary for archiving 
• All samples have been shipped to the appropriate laboratories 
• All unused materials and products have been either destroyed or returned to the Sponsor 
13.4.2 Audits and Inspections 
A quality assurance audit may be performed at any time by the Sponsor’s Clinical Quality 
Assessment department (CQA) or by independent auditors to verify that the study has been 
conducted according to the protocol, GCP and ICH requirements, and other applicable 
regulations. An inspection may be conducted by regulatory authorities. The Investigator must 
allow direct access to study documents during these inspections and audits. 
13.4.3 Archiving 
The Investigator must keep all study documents after the completion or discontinuation of the 
study, whatever the nature of the investigational center (private practice, hospital, or institution), 
for as long as required by applicable laws and regulations. In the absence of any applicable laws 
or regulations, study documents will be kept at a minimum for the duration indicated on the 
Clinical Trial Agreement (CTA). In no event, should study personnel destroy or permit the 
destruction of any study documents upon less than 90 days advance written notification to the 
Sponsor. In addition, study documents should continue to be stored, at Sponsor's sole expense, in 
the event that the Sponsor requests in writing that such storage continues for a period of time that 
exceeds that required by any applicable law or regulation or the CTA. The Investigator will 
inform Sanofi Pasteur of any address change or if they will no longer be able to house the study 
documents. 
Archived data may be held on electronic records, provided that a back-up exists and that a hard 
copy can be obtained if required. The protocol, documentation, approvals, and all other 
documents related to the study will be kept by the Sponsor in the Trial Master File (TMF). Data 
on AEs are included in the TMF. All data and documents will be made available if requested by 
relevant authorities. 
13.5 Financial Contract and Insurance Coverage 
A CTA will be signed by all the parties involved in the study’s performance, if relevant. The 
Sponsor has an insurance policy to cover any liabilities that may arise from use of the product and 
/ or the study protocol. 
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13.6 Stipends for Participation 
Subjects may be provided with a stipend according to local practice to compensate for the time 
and travel required for study visits and procedures. 
13.7 Publication Policy 
Data derived from this study are the exclusive property of Sanofi Pasteur. Any publication or 
presentation related to the study must be submitted to Sanofi Pasteur for review before submission 
of the manuscript. After publication of the results of the study, any participating center may 
publish or otherwise use its own data provided that any publication of data from the study gives 
recognition to the study group. In addition, Sanofi Pasteur shall be offered an association with all 
such publications, it being understood that Sanofi Pasteur is entitled to refuse the association. 
Sanofi Pasteur must have the opportunity to review all proposed abstracts, manuscripts, or 
presentations regarding this study at least 90 days prior to submission for publication / 
presentation. Any information identified by Sanofi Pasteur as confidential must be deleted prior to 
submission, it being understood that the results of this study are not to be considered confidential. 
Sanofi Pasteur’s review can be expedited to meet publication guidelines. 
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14 Reference List 
 
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28 
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Bonhoeffer J, Menkes J, Gold MS, et al. Generalized convulsive seizure as an adverse event 
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41 
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seven methods. Stat Med. 1998;17:857-72. 
 
 
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15 Signature Page 
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