Immunogenicity and Safety of an Investigational Quadrivalent Meningococcal Conjugate Vaccine Administered Concomitantly With Other Pediatric Vaccines in Healthy Toddlers
Phase: PHASE3
Conditions: Meningitis, Meningococcal
Sponsor: Sanofi Pasteur, a Sanofi Company

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Immunogenicity and Safety of an Investigational Quadrivalent 
Meningococcal Conjugate Vaccine Administered Concomitantly 
with Other Pediatric Vaccines in Healthy Toddlers 
Phase III, open-label (immunology laboratory technicians will be blinded to group assignment), 
randomized, parallel-group, active-controlled, multi-center study to describe the 
immunogenicity and safety of a single dose of MenACYW conjugate vaccine when 
administered alone and when administered concomitantly with other pediatric vaccines in 
healthy toddlers in South Korea, Thailand, the Russian Federation, and Mexico 
Clinical Trial Protocol, Amendment 3 
Health Authority File Numbers: 
Korea, Republic of (or South Korea): 
20160036536 
The Russian Federation:  
Not available 
The United Mexican States (Mexico): 
163300410A0093 
Thailand 
Not available 
WHO Universal Trial Number 
(UTN): 
U1111-1161-2787 
Trial Code: 
MET57 
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 
Indication For This Study: 
MenACYW conjugate vaccine as a single dose in toddlers 12 to 23 months 
old 
Manufacturer: 
Same as Sponsor 
Coordinating Investigators: 
Korea: 
 
The Russian Federation:  
 
 
Mexico: 
 
 
 
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NCT Number: NCT03205371 

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Principal Investigators: 
Thailand: 
 
 
 
 
 
 
 
Sponsor’s Responsible Medical 
Officer: 
 
, Sanofi Pasteur Inc. 
Tel:  
 
Fax: 
 
Regional Directors of Clinical 
Development: 
 
 
Sanofi Pasteur Inc. 
Address: 
 
  
 
Fax: 
 
 
, Sanofi Pasteur Inc. 
Address: 
 
Tel: 
 
Fax: 
 
 
, Sanofi Pasteur Ltd. 
Address:  
 
Tel: 
 
Fax: 
 
Product Safety Officer: 
 
, Sanofi Pasteur Inc. 
Tel:  
 
Fax: 
 
Regional Clinical Trial 
Managers: 
 
, Sanofi Pasteur, SA 
Address: 
 
Tel: 
 
 
 Sanofi Pasteur Inc. 
Address: 
 
Tel: 
 
  
, Sanofi Pasteur, México 
Address: 
 
Tel: 
 
 
, Sanofi Pasteur, Ltd. 
Address: 
 
Tel: 
 
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Version and Date of the Protocol: 
Version 4.0 dated 11 September 2017 
This protocol version 4.0 is the third amendment to the initial trial protocol version 1.0, dated 15 January 2016. It 
is preceded by Amendment 1 (protocol version 2.0, dated 11 July 2016) and Amendment 2 (protocol version 3.0, 
dated 05 May 2017). 
 
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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Table of Contents 
List of Tables .................................................................................................................................... 9 
Synopsis .......................................................................................................................................... 10 
Table of Study Procedures - Subjects in South Korea, Mexico, and Thailand ....................... 25 
Table of Study Procedures - Subjects in the Russian Federation Only.................................... 26 
List of Abbreviations ..................................................................................................................... 28 
1 
Introduction ..................................................................................................................... 31 
1.1 
Background ..................................................................................................................... 31 
1.2 
Background of the Investigational Product ..................................................................... 32 
1.2.1 
Non-clinical Safety ....................................................................................................... 32 
1.2.2 
Clinical ......................................................................................................................... 32 
1.2.2.1 
Study MET32 (Phase I/II) .......................................................................................... 33 
1.2.2.2 
Study MET39 (Phase II) ............................................................................................ 33 
1.2.2.3 
Study MET44 (Phase II) ............................................................................................ 34 
1.2.2.4 
Study MET54 (Phase II) ............................................................................................ 35 
1.3 
Potential Benefits and Risks ........................................................................................... 36 
1.3.1 
Potential Benefits to Subjects ....................................................................................... 36 
1.3.2 
Potential Risks to Subjects ........................................................................................... 37 
1.4 
Rationale for the Trial ..................................................................................................... 38 
2 
Trial Objectives ............................................................................................................... 38 
2.1 
Primary Objective ........................................................................................................... 38 
2.2 
Secondary Objective ....................................................................................................... 38 
2.3 
Observational Objectives ................................................................................................ 39 
3 
Investigators and Trial Organization ............................................................................ 39 
4 
Independent Ethics Committee / Institutional Review Board .................................... 39 
5 
Investigational Plan ......................................................................................................... 40 
5.1 
Description of the Overall Trial Design and Plan ........................................................... 40 
5.1.1 
Trial Design .................................................................................................................. 40 
5.1.2 
Justification of the Trial Design ................................................................................... 42 
5.1.3 
Trial Plan ...................................................................................................................... 43 
5.1.4 
Visit Procedures ............................................................................................................ 46 
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5.1.5 
Planned Trial Calendar ................................................................................................. 50 
5.1.6 
Early Safety Data Review............................................................................................. 50 
5.2 
Enrollment and Retention of Trial Population ................................................................ 50 
5.2.1 
Recruitment Procedures ................................................................................................ 50 
5.2.2 
Informed Consent Procedures ...................................................................................... 50 
5.2.3 
Screening Criteria ......................................................................................................... 51 
5.2.4 
Inclusion Criteria .......................................................................................................... 52 
5.2.5 
Exclusion Criteria ......................................................................................................... 53 
5.2.6 
Medical History ............................................................................................................ 54 
5.2.7 
Contraindications for Subsequent Vaccinations ........................................................... 55 
5.2.8 
Temporary Contraindications for Visit 2 Blood Draw ................................................. 55 
5.2.9 
Conditions for Withdrawal ........................................................................................... 55 
5.2.10 
Lost to Follow-up Procedures....................................................................................... 56 
5.2.11 
Classification of Subjects Who Discontinue the Trial.................................................. 56 
5.2.12 
Follow-up of Discontinuations ..................................................................................... 57 
5.3 
Safety Emergency Call ................................................................................................... 57 
5.4 
Modification of the Trial and Protocol ........................................................................... 57 
5.5 
Interruption of the Trial .................................................................................................. 57 
6 
Vaccines Administered ................................................................................................... 58 
6.1 
Identity of the Investigational Products .......................................................................... 58 
6.1.1 
Identity of Trial Product 1 ............................................................................................ 58 
6.1.1.1 
Composition ............................................................................................................... 58 
6.1.1.2 
Preparation and Administration ................................................................................. 58 
6.1.1.3 
Dose Selection and Timing ........................................................................................ 59 
6.1.2 
Identity of Trial Product 2 - Measles, Mumps, Rubella Vaccine ................................. 59 
6.1.2.1 
Composition ............................................................................................................... 59 
6.1.2.2 
Preparation and Administration ................................................................................. 59 
6.1.2.3 
Dose Selection and Timing ........................................................................................ 60 
6.1.3 
Identity of Trial Product 3 - Varicella Vaccine ............................................................ 60 
6.1.3.1 
Composition ............................................................................................................... 60 
6.1.3.2 
Preparation and Administration ................................................................................. 61 
6.1.3.3 
Dose Selection and Timing ........................................................................................ 61 
6.1.4 
Identity of Trial Product 4 - Hexavalent Vaccine ........................................................ 61 
6.1.4.1 
Composition ............................................................................................................... 62 
6.1.4.2 
Preparation and Administration ................................................................................. 62 
6.1.4.3 
Dose Selection and Timing ........................................................................................ 63 
6.1.5 
Identity of Trial Product 5 - Pneumococcal Vaccine ................................................... 63 
6.1.5.1 
Composition ............................................................................................................... 63 
6.1.5.2 
Preparation and Administration ................................................................................. 63 
6.1.5.3 
Dose Selection and Timing ........................................................................................ 64 
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6.1.6 
Identity of Control Products ......................................................................................... 64 
6.2 
Identity of Other Products ............................................................................................... 64 
6.3 
Product Logistics ............................................................................................................ 64 
6.3.1 
Labeling and Packaging ............................................................................................... 64 
6.3.2 
Product Shipment, Storage, and Accountability ........................................................... 64 
6.3.2.1 
Product Shipment ....................................................................................................... 64 
6.3.2.2 
Product Storage .......................................................................................................... 65 
6.3.2.3 
Product Accountability ............................................................................................... 65 
6.3.3 
Replacement Doses....................................................................................................... 65 
6.3.4 
Disposal of Unused Products ........................................................................................ 65 
6.3.5 
Recall of Products ......................................................................................................... 66 
6.4 
Blinding and Code-breaking Procedures ........................................................................ 66 
6.5 
Randomization and Allocation Procedures ..................................................................... 66 
6.6 
Treatment Compliance .................................................................................................... 66 
6.7 
Concomitant Medications and Other Therapies ............................................................. 67 
7 
Management of Samples ................................................................................................. 68 
7.1 
Sample Collection ........................................................................................................... 68 
7.1.1 
Blood Samples .............................................................................................................. 68 
7.1.2 
Urine Samples for Urine Chemistry (Sites in the Russian Federation Only) ............... 68 
7.2 
Sample Preparation ......................................................................................................... 69 
7.2.1 
Serum Samples ............................................................................................................. 69 
7.2.2 
Urine Samples for Urine Chemistry (Sites in the Russian Federation Only) ............... 69 
7.3 
Sample Storage and Shipment ........................................................................................ 69 
7.3.1 
Serum Samples ............................................................................................................. 69 
7.3.2 
Urine Samples for Urine Chemistry (Sites in the Russian Federation Only) ............... 70 
7.4 
Future Use of Stored Serum Samples for Research ........................................................ 70 
8 
Clinical Supplies .............................................................................................................. 71 
9 
Endpoints and Assessment Methods ............................................................................. 71 
9.1 
Primary Endpoints and Assessment Methods ................................................................. 71 
9.1.1 
Immunogenicity ............................................................................................................ 71 
9.1.1.1 
Immunogenicity Endpoints ........................................................................................ 71 
9.1.1.2 
Immunogenicity Assessment Methods ...................................................................... 71 
9.1.2 
Safety ............................................................................................................................ 72 
9.1.3 
Efficacy ......................................................................................................................... 72 
9.2 
Secondary Endpoints and Assessment Methods ............................................................. 72 
9.2.1 
Immunogenicity ............................................................................................................ 72 
9.2.1.1 
Immunogenicity Endpoints ........................................................................................ 72 
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9.2.1.2 
Immunogenicity Assessment Methods ...................................................................... 73 
9.2.2 
Safety ............................................................................................................................ 77 
9.2.3 
Efficacy ......................................................................................................................... 77 
9.3 
Observational Endpoints and Assessment Methods ....................................................... 77 
9.3.1 
Immunogenicity ............................................................................................................ 77 
9.3.1.1 
Immunogenicity Endpoints ........................................................................................ 77 
9.3.1.2 
Immunogenicity Assessment Methods ...................................................................... 77 
9.3.2 
Safety ............................................................................................................................ 78 
9.3.2.1 
Safety Definitions ....................................................................................................... 78 
9.3.2.2 
Safety Endpoints ........................................................................................................ 81 
9.3.2.3 
Safety Assessment Methods ....................................................................................... 81 
9.3.2.3.1 
Immediate Post-vaccination Surveillance Period .................................................... 81 
9.3.2.3.2 
Reactogenicity (Solicited Reactions From Day 0 to Day 7 After Vaccination) ...... 82 
9.3.2.3.3 
Unsolicited Non-serious Adverse Events From Day 0 to Day 30 After 
Vaccination .............................................................................................................. 85 
9.3.2.3.4 
Serious Adverse Events ........................................................................................... 86 
9.3.2.3.5 
Adverse Events of Special Interest .......................................................................... 86 
9.3.2.3.6 
Assessment of Causality .......................................................................................... 86 
9.3.3 
Biological Safety Assessment Methods (Sites in the Russian Federation Only) ......... 87 
9.3.3.1 
Complete Blood Count ............................................................................................... 87 
9.3.3.2 
Blood Chemistry ........................................................................................................ 87 
9.3.3.3 
Urinalysis ................................................................................................................... 88 
9.3.4 
Efficacy ......................................................................................................................... 88 
10 
Reporting of Serious Adverse Events ............................................................................ 88 
10.1 
Initial Reporting by the Investigator ............................................................................... 88 
10.2 
Follow-up Reporting by the Investigator ........................................................................ 89 
10.3 
Reporting of SAEs Occurring After a Subject Has Completed the Study ...................... 89 
10.4 
Assessment of Causality ................................................................................................. 89 
10.5 
Reporting SAEs to Health Authorities and IECs / IRBs................................................. 90 
11 
Data Collection and Management ................................................................................. 90 
11.1 
Data Collection and CRF Completion ............................................................................ 90 
11.2 
Data Management ........................................................................................................... 91 
11.3 
Data Review .................................................................................................................... 92 
12 
Statistical Methods and Determination of Sample Size ............................................... 92 
12.1 
Statistical Methods .......................................................................................................... 92 
12.1.1 
Hypotheses and Statistical Methods for Primary Objective ......................................... 92 
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12.1.1.1 
Hypotheses ................................................................................................................. 92 
12.1.1.2 
Statistical Methods ..................................................................................................... 93 
12.1.2 
Hypotheses and Statistical Methods for Secondary Objective ..................................... 93 
12.1.2.1 
Hypotheses ................................................................................................................. 93 
12.1.2.2 
Statistical Methods ..................................................................................................... 93 
12.1.3 
Statistical Methods for Observational Objectives ........................................................ 94 
12.2 
Analysis Sets ................................................................................................................... 95 
12.2.1 
Full Analysis Set ........................................................................................................... 95 
12.2.2 
Safety Analysis Set ....................................................................................................... 95 
12.2.3 
Per-Protocol Analysis Set ............................................................................................. 95 
12.2.4 
Populations Used in Analyses ...................................................................................... 95 
12.3 
Handling of Missing Data and Outliers .......................................................................... 96 
12.3.1 
Safety ............................................................................................................................ 96 
12.3.2 
Immunogenicity ............................................................................................................ 96 
12.4 
Interim / Preliminary Analysis ........................................................................................ 96 
12.5 
Determination of Sample Size and Power Calculation ................................................... 96 
13 
Ethical and Legal Issues and Investigator / Sponsor Responsibilities........................ 97 
13.1 
Ethical Conduct of the Trial / Good Clinical Practice .................................................... 97 
13.2 
Source Data and Source Documents ............................................................................... 97 
13.3 
Confidentiality of Data and Access to Subject Records ................................................. 97 
13.4 
Monitoring, Auditing, and Archiving ............................................................................. 98 
13.4.1 
Monitoring .................................................................................................................... 98 
13.4.2 
Audits and Inspections ................................................................................................. 99 
13.4.3 
Archiving ...................................................................................................................... 99 
13.5 
Financial Contract and Insurance Coverage ................................................................... 99 
13.6 
Stipends for Participation ................................................................................................ 99 
13.7 
Publication Policy ........................................................................................................... 99 
14 
References List ............................................................................................................... 101 
15 
Signature Pages ............................................................................................................. 105 
 
 
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List of Tables 
Table 5.1: Schedules of blood sampling and antigen testing .......................................................... 44 
Table 9.1: Solicited injection site reactions: terminology, definitions, and intensity scales ........... 83 
Table 9.2: Solicited systemic reactions: terminology, definitions, and intensity scales ................. 84 
 
 
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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 Concomitantly with 
Other Pediatric Vaccines in Healthy Toddlers 
Development Phase: 
Phase III 
Coordinating Investigators: 
Korea: 
 
 
 
 
The Russian Federation:  
 
 
 
 
Mexico: 
 
 
 
 
 
Principal Investigators:  
Thailand: 
 
 
 
 
 
 
 
 
 
Trial Centers: 
This will be a multi-center, multinational trial conducted at approximately 
29 sites: approximately 13 in South Korea, 2 in Thailand, 3 in Mexico, and 
11 in the Russian Federation. 
Investigators and sites are listed in the “List of Investigators and Centers 
Involved in the Trial” document. 
Planned Trial Period: 
4Q 2016 to 2Q 2018 
Trial Design and Methodology: 
This will be a Phase III, open-label (immunology laboratory technicians will 
be blinded to group assignment), randomized, parallel-group, active-
controlled, multi-center study to describe the immunogenicity and safety of 
a single dose of MenACYW conjugate vaccine when administered alone and 
when administered concomitantly with other pediatric vaccine(s) in healthy 
toddlers in South Korea, and Thailand (measles-mumps-rubella vaccine 
[MMR] + varicella vaccine [V] ), Mexico (diphtheria, tetanus, acellular 
pertussis, hepatitis B, poliomyelitis and Haemophilus influenzae type-b 
conjugate vaccine [DTaP-IPV-HB-Hib]), and the Russian Federation 
(pneumococcal conjugate vaccine [PCV13]). 
In South Korea and Mexico, healthy, meningococcal-vaccine naïve 
toddlers aged 12 to 23 months on the day of enrollment will be randomized 
in a 2:1:1 ratio (by country) to the following groups: 
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South Korea: 
Group 1: 
MenACYW conjugate vaccine + MMR + V on Day (D) 0 
Group 2: 
MenACYW conjugate vaccine on D0  
Group 3: 
MMR + V on D0 
 
Mexico: 
Group 4: MenACYW conjugate vaccine + DTaP-IPV-HB-Hib on D0 
Group 5: MenACYW conjugate vaccine on D0 
Group 6: DTaP-IPV-HB-Hib on D0 
 
In the Russian Federation, healthy, meningococcal-vaccine naïve toddlers 
aged 12 to 14 months or 16 to 23 months on the day of enrollment will be 
assigned to Group 8 with a balanced population distribution of half of the 
subjects aged 12 to 14 months and half of the subjects aged 16 to 23 months. 
Healthy, meningococcal-vaccine naïve toddlers, who have not received the 
3rd dose of PCV13, aged 15 to 23 months on the day of enrollment will be 
randomized in a 2:1 ratio to Groups 7 and 9, in order to comply with the 
National Immunization Calendar of the Russian Federation: 
 
The Russian Federation: 
Group 7:  MenACYW conjugate vaccine + PCV13 on D0  
Group 8:  MenACYW conjugate vaccine on D0 
Group 9: PCV13 on D0 
Note about Visits: 
Visit 0 = Screening visit for subjects in the Russian Federation only 
Visit 1 = D0, vaccination visit (all countries) 
Visit 2 = D30 (+14 days), 30 to 44 days after D0 (all countries) 
In the Russian Federation, Visit 0 and Visit 1 may take place on the same 
day, or Visit 1 may take place up to 5 days after Visit 0. 
In Thailand, healthy, meningococcal-vaccine naïve toddlers aged 12 to 
23 months on the day of enrollment will be randomized in a 2:1:1 ratio to 
the following groups: 
Thailand: 
Group 10: MenACYW conjugate vaccine + MMR + V on Day (D) 0 
Group 11: MenACYW conjugate vaccine on D0  
Group 12: MMR + V on D0 
All Subjects: 
All subjects will provide blood samples for immunogenicity assessment at 
baseline (pre-vaccination) and at Visit 2 (30 to 44 days after vaccination[s]). 
Solicited adverse event (AE) information will be collected for 7 days after 
vaccination(s); unsolicited AE information will be collected from Visit 1 
(D0) to Visit 2, and serious adverse event (SAE) information will be 
collected throughout the study period from Visit 1 through Visit 2.  
 
Upon completion of all study procedures and termination from the trial at 
Visit 2, study participants should receive the remainder of the recommended 
toddler vaccines, which are part of the respective National Immunization 
Programs (NIP) for each country, from their health care provider. 
Note: In this document, “days” refers to calendar days. 
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Sanofi Pasteur 
MET57 
395 – MenACYW Conjugate Vaccine 
Confidential/Proprietary Information 
Page 17 of 105 
Investigational Products 
 
Trial Product 1: 
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 mL dose of MenACYW conjugate vaccine is formulated in 
sodium acetate buffered saline solution to contain the following 
ingredients: 
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 65 µg 
 Route: 
Intramuscular (IM) 
 Batch Number: 
To be determined 
Trial Product 2: 
M-M-R®II (MMR): Measles, Mumps, and Rubella Virus Vaccine Live 
(Merck & Co., Inc., Whitehouse Station, NJ, USA); (licensed in South Korea 
and Thailand) 
 Form: 
Solution for injection supplied as lyophilized vaccine and diluent for 
reconstitution 
 Composition: 
Each 0.5 mL dose of reconstituted vaccine is formulated to contain the 
following components: 
 Measles virus: not less than 1000 tissue culture infectious doses (TCID50) 
 Mumps virus: not less than 12,500 TCID50 
 Rubella virus: not less than 1000 TCID50 
 
Each 0.5 mL dose is also formulated to contain the following inactive 
ingredients: sorbitol (14.5 milligrams [mg]), sodium phosphate, sucrose 
(1.9 mg), sodium chloride, hydrolyzed gelatin (14.5 mg), recombinant 
human albumin (≤ 0.3 mg), fetal bovine serum (< 1 part per million [ppm]), 
other buffer and media ingredients, and approximately 25 µg of neomycin. 
The product contains no preservative. 
 Route: 
Subcutaneous (SC) 
 Batch Number: 
To be determined 
Trial Product 3: 
VARIVAX® (V): Varicella Virus Vaccine Live (Merck, Sharp & Dohme, 
Haarlem, The Netherlands); (licensed in South Korea and Thailand) 
 Form: 
Suspension for injection supplied as lyophilized vaccine to be reconstituted 
using the accompanying sterile diluent 
Sanofi Pasteur 
 
Confidential/Proprietary Information 
                
MET57
395 – MenACYW Conjugate Vaccine
Protocol Version 4.0
Page 17 of 106

Sanofi Pasteur 
MET57 
395 – MenACYW Conjugate Vaccine 
Confidential/Proprietary Information 
Page 18 of 105 
 Composition: 
Each 0.5 mL dose of vaccine is formulated to contain a minimum of 
1350 plaque-forming units (PFU) of Oka/Merck varicella virus. 
Each 0.5 mL dose also contains approximately 25 mg of sucrose, 12.5 mg 
hydrolyzed gelatin,3.2 mg of sodium chloride, 0.5 mg of monosodium L-
glutamate, 0.45 mg of sodium phosphate dibasic, 0.08 mg of potassium 
phosphate monobasic, and 0.08 mg of potassium chloride. The product also 
contains residual components of Medical Research Council cell strain 5 
(MRC-5) cells including deoxyribonucleic acid (DNA) and protein and 
trace quantities of sodium phosphate monobasic, 
ethylenediaminetetraacetic acid (EDTA), neomycin, and fetal bovine 
serum. The product contains no preservative. 
 Route: 
SC 
 Batch Number: 
To be determined 
Trial Product 4: 
Hexaxim®(DTaP-IPV-HB-Hib): Diphtheria, tetanus, pertussis (acellular, 
component), hepatitis B (recombinant deoxyribonucleic acid [rDNA]), 
poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate 
vaccine (adsorbed); (Sanofi Pasteur SA, Marcy l’Etoile, France); (licensed 
in Mexico as Hexacima) 
 Form: 
Suspension for injection 
 Composition: 
Each 0.5 mL dose is formulated to contain the following components: 
Diphtheria Toxoid ............................................ ≥ 20 international units (IU) 
Tetanus Toxoid ................................................................................. ≥ 40 IU 
Bordetella pertussis antigens 
 
Pertussis Toxoid ...................................................................... 25 µg 
 
Filamentous Haemagglutinin ................................................... 25 µg 
Poliovirus (Inactivated) 
 
Type 1 (Mahoney) ............................................... 40 D antigen units 
 
Type 2 (MEF-1) ..................................................... 8 D antigen units 
 
Type 3 (Saukett) .................................................. 32 D antigen units 
Hepatitis B surface antigen .................................................................. 10 µg 
Haemophilus influenzae type b polysaccharide ................................... 12 µg 
(Polyribosylribitol Phosphate) 
conjugated to Tetanus Protein ........................................................ 22-36 µg 
 
The vaccine also contains the excipients: disodium hydrogen phosphate, 
potassium dihydrogen phosphate, trometamol, saccharose, essential amino 
acids including L-phenylalanine, water for injections 
The vaccine may contain traces of glutaraldehyde, formaldehyde, 
neomycin, streptomycin, and polymyxin B, which are used during the 
manufacturing process. 
 Route: 
IM 
 Batch Number: 
To be determined 
Sanofi Pasteur 
 
Confidential/Proprietary Information 
                
MET57
395 – MenACYW Conjugate Vaccine
Protocol Version 4.0
Page 18 of 106

Sanofi Pasteur 
MET57 
395 – MenACYW Conjugate Vaccine 
Confidential/Proprietary Information 
Page 19 of 105 
Trial Product 5: 
Prevenar 13® (PCV13): Pneumococcal 13-valent Conjugate Vaccine 
(Diphtheria CRM197 Protein) (Pfizer Ireland Pharmaceuticals, Ireland) 
(licensed in the Russian Federation) 
 Form: 
Suspension for IM injection 
 Composition: 
Each 0.5 mL vaccine dose is formulated to contain approximately 2.2 µg of 
each of Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 
18C, 19A, 19F, and 23F saccharides, 4.4 µg of 6B saccharides; 34 µg 
CRM197 carrier protein, 100 µg polysorbate 80, 295 µg succinate buffer, 
and 125 µg aluminum as aluminum phosphate adjuvant. 
 Route: 
IM 
 Batch Number: 
To be determined 
Screening Criteria: 
For subjects in South Korea, Mexico, and Thailand, there are no screening 
criteria other than the inclusion and exclusion criteria. 
For the Russian Federation, as per Guideline for the conduct of clinical 
trials of the Russian Federation Health Authorities and in accordance with 
local practices, in addition to being tested for study vaccine 
immunogenicity assessment, the blood of subjects enrolled at sites in the 
Russian Federation will be tested for complete blood count (CBC) and 
blood chemistry. These subjects will also provide a urine sample for 
urinalysis. According to recommendations of Russian Health Authorities, 
the subjects will be examined by a neurologist.  
The examination by a neurologist and additional biological analyses have 
been implemented for subjects enrolled at sites in the Russian Federation 
per the request of the Russian Federation Health Authorities only and not to 
address any concern of the Sponsor regarding safety issues. 
Inclusion Criteria: 
An individual must fulfill all of the following criteria in order to be eligible 
for trial enrollment: 
1) For South Korea: Korean males and females aged 12 to 23 months on 
the day of the first study visit 
For Mexico: Males and females aged 12 to 23 months on the day of 
the first study visit 
For the Russian Federation: Males and females aged 12 to 14 months 
or 16 to 23 months on the day of the first study visit (eligible for 
enrollment to Group 8) or 15 to 23 months on the day of the first study 
visit (eligible for enrollment to Group 7 or 9) 
For Thailand: Thai males and females aged 12 to 23 months on the 
day of the first study visit 
Sanofi Pasteur 
 
Confidential/Proprietary Information 
                
MET57
395 – MenACYW Conjugate Vaccine
Protocol Version 4.0
Page 19 of 106

Sanofi Pasteur 
MET57 
395 – MenACYW Conjugate Vaccine 
Confidential/Proprietary Information 
Page 20 of 105 
 
2) Subject had received all recommended standard of care vaccinations 
according to his/her age as per local regulations.*  
For the Russian Federation only, subjects aged 15 to 23 months on 
the day of the first study visit (eligible for enrollment to Group 7 or 9) 
must not have received the third PCV13 vaccination corresponding to 
his or her age as per the country’s NIP. The 2nd dose of PCV13 must 
have been administered at least 4 weeks before the 3rd dose of PCV13 
is administered in the study. 
For South Korea, subjects must not have received the MMR or V 
vaccination corresponding to his or her age at inclusion.  
For Mexico, subjects must not have received the DTaP-IPV-HB-Hib 
vaccination corresponding to his or her age at inclusion. 
For Thailand, subjects must not have received the any dose of MMR 
or V vaccination. 
3) Informed consent form has been signed and dated by the parent(s) or 
guardian if allowed by local regulations (and by independent witnesses 
if required by local regulations)† 
4) Subject and parent/guardian are able to attend all scheduled visits and 
to comply with all trial procedures 
*Subjects must have received the total number of doses expected for each 
vaccine recommended for his/her age in the respective NIPs, but inclusion 
of subjects with variations in the vaccine administration timeframes is 
considered acceptable if the total number of doses for the corresponding 
vaccines have been completed (e.g., in Mexico, 3 infant doses of the 
pentavalent vaccine must have been administered but the 4th dose due in 
the 2nd year of life should not have been administered for subjects to be 
included in the trial). For the Russian Federation only, subjects that have 
not received a seasonal flu vaccination from 6 months of age according to 
the Russian NIP are still eligible to participate in this study. For Thailand 
only, subjects who may have received a vaccine ahead of the schedule can 
still be included in the study provided the first doses of MMR and V 
vaccines have not been administered prior to inclusion. 
†In the Russian Federation, as per local regulations, only the subject’s 
parent(s) are entitled to sign an ICF. A child under the responsibility of a 
guardian will not be included in the study. 
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 first 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 first trial 
vaccination or planned receipt of any vaccine prior to Visit 2 except for 
influenza vaccination, which may be received at least 2 weeks before 
or after the study investigational vaccines. This exception includes 
monovalent pandemic influenza vaccines and multivalent influenza 
vaccines. 
 
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) 
Sanofi Pasteur 
 
Confidential/Proprietary Information 
                
MET57
395 – MenACYW Conjugate Vaccine
Protocol Version 4.0
Page 20 of 106

Sanofi Pasteur 
MET57 
395 – MenACYW Conjugate Vaccine 
Confidential/Proprietary Information 
Page 21 of 105 
 
4) For subjects enrolled at sites in the Russian Federation: previous 
vaccination with the third dose of PCV13 in subjects 15 to 23 months 
of age (eligible for Group 7 or 9) 
 
5) For subjects enrolled at sites in Mexico: known history of seizures, 
or uncontrolled neurologic disorder (including epilepsy); or 
encephalopathy of unknown etiology occurring within 7 days 
following previous vaccination with pertussis containing vaccine; 
previous vaccination with DTaP-IPV-HB-Hib or DTaP-containing 
vaccine at 12 to 23 months of age 
 
6) For subjects enrolled at sites in South Korea and Thailand: known 
history of seizures, cerebral injury, or encephalopathy; previous 
vaccination with MMR or V at or before 12 to 23 months of age 
7) Receipt of immune globulins, blood or blood-derived products in the 
past 3 months 
8) 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) 
 
9) History of meningococcal infection, confirmed either clinically, 
serologically, or microbiologically 
10) At high risk for meningococcal infection during the trial, according to 
the Investigator’s judgment (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) 
11) Known systemic hypersensitivity to any of the vaccine components, or 
history of a life-threatening reaction to the vaccine(s) used in the trial 
or to a vaccine containing any of the same substances 
12) Verbal report of thrombocytopenia, as reported by the parent/guardian, 
contraindicating intramuscular vaccination by the Investigator’s 
judgment 
13) Known bleeding disorder, or receipt of anticoagulants in the 3 weeks 
preceding inclusion, contraindicating intramuscular vaccination by the 
Investigator’s judgment 
14) Personal history of Guillain-Barré syndrome (GBS) 
15) Personal history of an Arthus-like reaction after vaccination with a 
tetanus toxoid-containing vaccine 
16) Chronic illness that, in the opinion of the investigator, is at a stage 
where it might interfere with trial conduct or completion 
 
17) For subjects enrolled at sites in South Korea, Mexico, and 
Thailand: Moderate or severe acute illness/infection (according to 
investigator’s 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. 
Sanofi Pasteur 
 
Confidential/Proprietary Information 
                
MET57
395 – MenACYW Conjugate Vaccine
Protocol Version 4.0
Page 21 of 106

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Table of Study Procedures - Subjects in South Korea, Mexico, and 
Thailand 
Phase III Trial, 2 Visits, 1 Vaccination Visit (1, 2, or 3 Vaccinations), 1 Telephone Call,  
2 Blood Samples, 30 Days Duration Per Subject 
Visit/Contact 
Visit 1 
Telephone Call 
Visit 2 
Trial timelines (days) 
Day 0 
Day 8 
Day 30 
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 
Randomization/allocation of subject number 
X 
 
 
Blood sampling (BL), 5 mL‡ 
BL1 
 
BL2 
Vaccination§ 
X 
 
 
Immediate surveillance under supervision by a responsible healthcare 
professional at each study site (30 minutes) 
X 
 
 
Diary card 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 
To be reported throughout the study period 
Diary card reviewed and collected 
 
 
X 
Collection of reportable concomitant medications 
X 
 
X 
Termination of the trial 
 
 
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 this 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(s) 
§Subjects in Groups 2, 5, and 11 will receive 1 dose of MenACYW conjugate vaccine. Subjects in Groups 1 and 10 will 
receive 1 dose each of MenACYW conjugate vaccine, MMR, and V. Subjects in Groups 3 and 12 will receive 1 dose each of 
MMR and V. Subjects in Group 4 will receive 1 dose each of MenACYW conjugate vaccine and DTaP-IPV-HB-Hib 
vaccine. Subjects in Group 6 will receive 1 dose of DTaP-IPV-HB-Hib 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 not yet reported, and will remind the subject’s parent/guardian to continue using the diary card up to 
Visit 2, to bring the diary card to the study center at Visit 2, and confirm the date and time of Visit 2 
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Table of Study Procedures - Subjects in the Russian Federation Only 
Phase III Trial, 3 Visits, 1 Vaccination Visit (1 or 2 Vaccinations), 1 Telephone Call,  
2 Blood Samples, 2 Urine Samples, 30 Days Duration Per Subject 
Visit/Contact 
Visit 0  
Visit 1* 
Telephone Call 
Visit 2 
Trial timelines (days) 
Day -5 
Day 0 
Day 8 
Day 30 
Time windows (days) 
+ 5 days 
-- 
+2 days 
+14 days 
Informed consent  
X 
 
 
 
Inclusion/exclusion criteria 
X 
X† 
 
 
Collection of demographic data 
X 
 
 
 
Medical history 
X 
 
 
 
Physical examination‡ 
X 
X† 
 
 
Neurological examination by a neurologist 
X§ 
 
 
X 
Review of temporary contraindications for blood 
sampling** 
 
 
 
X 
Allocation of subject number 
X 
 
 
 
Blood sampling (BL) (complete blood count, blood 
chemistry, and immunogenicity) approximately 7 mL 
BL1†† 
 
 
BL2 
Urine sample, approximately 8 mL  
X‡‡ 
 
 
X 
Randomization of subject 
 
X 
 
 
Vaccination§§ 
 
X 
 
 
Immediate surveillance under supervision by a 
responsible healthcare professional at each study site 
(30 minutes) 
 
X 
 
 
Diary card 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 
 
To be reported throughout the study period  
Diary card reviewed and collected 
 
 
 
X 
Collection of reportable concomitant medications 
X 
X† 
 
X 
Termination of the trial 
 
 
 
X 
*Visit 0 and Visit 1 are separate visits that may take place on the same day. However, Visit 1 can be performed up to 5 days 
after Visit 0. 
†Only performed when activities planned for Visit 1 are not conducted on the same day as Visit 0 
‡Temperature needs to be measured and recorded in source documents. When Visit 0 and Visit 1 take place on different days, 
temperature needs to be measured and recorded at both Visits. Temperature must be measured on the day of vaccination, 
before administration of vaccine(s). 
§ The results (discharge summary) of the neurologist’s examination, performed for the subject in terms of routine practice, can 
be used, if the examination was done within 7 days before Visit 0. 
**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 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.  
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††The results of CBC and biochemistry laboratory tests, performed for the subject in terms of routine practice, can be used, if 
the tests were done within 7 days before Visit 0. In this case, the blood sample volume collected at Visit 0 will be 5 mL. 
‡‡The results of urine laboratory tests, performed for the subject in terms of routine practice, can be used, if the tests were done 
within 7 days before Visit 0. In this case, no urine sample will be collected at Visit 0. 
§§Subjects in Group 8 will receive 1 dose of MenACYW conjugate vaccine. Subjects in Group 7 will receive 1 dose each of 
MenACYW conjugate vaccine and PCV13 vaccine. Subjects in Group 9 will receive 1 dose of PCV13 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 not yet reported, and will remind the subject’s parent to continue using the diary card up to Visit 2, to 
bring the diary card to the study center at Visit 2, and confirm the date and time of Visit 2. 
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List of Abbreviations 
µg 
microgram(s) 
µL 
microliter(s) 
Ab 
antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
AR 
adverse reaction 
AST 
aspartate aminotransferase 
BL 
blood sampling 
CBC 
complete blood count 
CBER 
Center for Biologics Evaluation and Research 
CDM 
Clinical Data Management 
CFU 
colony-forming unit 
CI 
confidence interval 
C&MQO 
Clinical and Medical Quality Operations 
COFEPRIS 
Comisión Federal para la Protección contra Riesgos Sanitarios  
(English: Federal Commission for Protection against Sanitary Risks) (Mexican 
Health Authority) 
CPM 
counts per minute 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CRF 
electronic case report form 
CTA 
clinical trial agreement 
CTL  
Clinical Team Leader  
D 
Day 
DNA 
deoxyribonucleic acid 
DOD 
delta optical density 
DT 
diphtheria toxoid 
ECL 
electrochemiluminescent 
EDC 
electronic data capture 
EDTA 
ethylenediaminetetraacetic acid 
EIA 
enzyme immunoassay 
ELISA 
enzyme-linked immunosorbent assay 
eSAE 
electronic Serious Adverse Event (Form) 
EU 
ELISA units 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
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FHA 
filamentous hemagglutinin  
FIM2,3 
fimbriae types 2 and 3 
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 
gp 
glycoprotein 
gpELISA 
glycoprotein enzyme-linked immunosorbent assay 
GPV 
Global PharmacoVigilance  
HBsAg 
hepatitis B surface antigen  
HepB 
hepatitis B 
HRP 
horseradish peroxidase 
hSBA 
serum bactericidal assay using human complement 
IATA 
International Air Transport Association 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IM 
intramuscular 
IMD 
invasive meningococcal disease 
IOM 
Institute of Medicine 
IRB 
Institutional Review Board 
IU  
international unit(s) 
IWRS 
interactive web response system 
LCLS 
last contact, last subject 
LDH 
lactate dehydrogenase 
LLT 
lowest level term 
LLOQ 
lower limit of quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSD 
MesoScale Discovery 
MFDS 
Korean Ministry of Food and Drug Safety  
MIT 
Micrometabolic Inhibition Test 
mg 
milligram(s) 
mIU 
milli-international units 
mL 
milliliter(s) 
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MRC-5 
Medical Research Council cell strain 5 
NIP 
National Immunization Program 
NSAID 
non-steroidal anti-inflammatory drug 
OD 
optical density 
PFU 
plaque-forming units 
PnPS 
pneumococcal capsular polysaccharide 
PPAS 
Per-Protocol Analysis Set 
ppm 
parts per million 
PRN 
pertactin 
PRP 
polyribosyl-ribitol phosphate 
PS 
polysaccharide(s) 
PSO 
Product Safety Officer 
PT 
pertussis toxoid 
RCDC 
reverse cumulative distribution curve 
rDNA 
recombinant deoxyribonucleic acid 
RIA 
radioimmunoassay 
RLU 
relative light units 
RMO 
Responsible Medical Officer 
rSBA 
serum bactericidal assay using baby rabbit complement 
SAE 
serious adverse event 
SafAS 
Safety Analysis Set 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SMT 
safety management team 
SPC 
Summary of Product Characteristics 
SUSAR 
suspected unexpected serious adverse reaction 
TCC 
tissue culture control 
TCID 
tissue culture infectious doses  
TMF 
trial master file 
TT 
tetanus toxoid 
UAR 
unexpected adverse reaction 
ULOQ 
upper limit of quantitation 
WHO 
World Health Organization 
WT 
wild-type 
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1 
Introduction 
1.1 
Background 
This trial will evaluate the immunogenicity and safety of a single dose of the quadrivalent 
Meningococcal Polysaccharide (Serogroups A, C, Y and W) Tetanus Toxoid Conjugate Vaccine 
(hereafter referred to as MenACYW conjugate vaccine) in toddlers 12 to 23 months of age. The 
purpose of MET57 is to demonstrate that the immunogenicity and safety profiles of the 
MenACYW conjugate vaccine are comparable to when MenACYW conjugate vaccine is given 
concomitantly with licensed pediatric vaccine(s). 
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 distinct 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 is the main cause of epidemics in the world, and is especially dominant in Africa and 
Asia. Serogroup W has been seen in Africa, as well as in 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), and Brazil (14) (15) and in 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 its frequency as a cause of sporadic cases has gradually increased in the US and 
more recently in Canada and Europe (17) (18) (19). This 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 reported in Sweden during 2005-2012 (25) (26). 
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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 recent spread of the serogroups W, which started in Saudi Arabia in 2000, has caused large 
meningococcal disease epidemics in the African meningitis belt and endemic disease in South 
America, Europe and China (28). The serogroup W associated disease has also been reported from 
Singapore (29), China (30), Taiwan (31), Malaysia (32), India (33), and Japan (34). Similar cases 
of serogroup W linked IMD have also been reported from Brazil, Chile, and Argentina (35) (36). 
A sudden increase in the number of serogroup Y associated IMD cases, some associated with 
country specific outbreaks, have been reported from various countries across Europe more notably 
Switzerland, Sweden, Norway, and Finland (37). 
Even though traditionally the vaccination against meningococcal disease has been limited to 
vaccination against either serogroups A or C, the recent evolution of the global epidemiology does 
merit vaccination against serogroups Y and W thus building a case for a quadrivalent (A, C, Y, 
and W) conjugated meningococcal vaccine. 
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: 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 
Non-clinical Safety 
 
 
 
 
 
1.2.2 
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 > 55 years of age) in MET39, MET44, MET50, and MET54. MenACYW conjugate 
vaccine has also been evaluated in a Phase III study (MET56 in adolescents and adults). The 
relevant Phase II studies are discussed below. 
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The 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. 
1.2.2.1 
Study MET32 (Phase I/II) 
MET32 was a Phase I/II, exploratory, randomized, observer-blinded, active-controlled, parallel, 
multi-center study in toddlers conducted in Australia. This study evaluated 5 formulations of 
MenACYW conjugate vaccine. Subjects in Group 1 through Group 3 received 1 dose of 
MenACYW conjugate vaccine formulation 1 (low-, intermediate-, and high-dose polysaccharides, 
respectively); subjects in Group 4 and Group 6 received 1 dose of MenACYW conjugate vaccine 
formulation 2 (low- and high-dose polysaccharides, respectively). Group 7 received 1 dose of 
NeisVac-C®. 
Immunogenicity 
The 5 formulations evaluated were all immunogenic in toddlers. The percentage of subjects 
achieving a serum bactericidal assay using human complement (hSBA) threshold titer of ≥ 1:8 
ranged from 75% to 100%, 84% to 96%, 66% to 91%, and 62% to 70% for serogroups A, C, Y, 
and W, respectively. There was a trend toward higher antibody responses in the high dose groups. 
Safety 
All formulations of MenACYW conjugate vaccine were well tolerated. There were no significant 
differences in the overall safety profiles of any of the treatment groups. The safety profile of a 
single administration of MenACYW conjugate vaccine at different doses was comparable to that 
of a single administration of the licensed comparator vaccine (NeisVac-C®). 
No deaths occurred in the study. Of 7 SAEs that occurred,
 
 
 
. There 
were no AEs or SAEs that led to study discontinuation. 
1.2.2.2 
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®, 
Pentacel®, ROTARIX® or RotaTeq®, hepatitis B vaccine, M-M-R®II, and VARIVAX®. 
Immunogenicity 
After the primary series consisting of 1, 2, or 3 doses of MenACYW conjugate vaccine, protective 
serum 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 W, ≥ 90% achieved the threshold titer after 
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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. 
1.2.2.3 
Study MET44 (Phase II) 
MET44 was a Phase II, randomized, open-label (the laboratory technicians were blinded to group 
assignment), multi-center study conducted in the US. This study evaluated the immunogenicity 
and safety profiles of a single dose of MenACYW conjugate vaccine when administered to adults 
56 years of age and older. A total of 301 subjects aged 56 years and older on the day of 
enrollment were randomized to receive a single dose of MenACYW conjugate vaccine or 
Menomune® - A/C/Y/W-135 vaccine; each group was stratified according to age into 2 subsets 
(subjects 56 to 64 years of age and subjects ≥ 65 years of age). 
Immunogenicity 
The proportions of subjects with hSBA titers ≥ 1:8 obtained after MenACYW conjugate vaccine 
administration (Group 1) for serogroups A and C were comparable to, or for serogroups Y and W 
higher than, those obtained after Menomune - A/C/Y/W-135 vaccine administration (Group 2): 
93.8% in Group 1 and 85.1% in Group 2 for serogroup A; 74.9% in Group 1 and 62.8% in 
Group 2 for serogroup C; 80.5% in Group 1 and 59.6% in Group 2 for serogroup Y; 79.5% in 
Group 1 and 60.6% in Group 2 for serogroup W. 
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Safety 
Vaccination with MenACYW conjugate vaccine or Menomune - A/C/Y/W-135 vaccine among 
adults 56 years of age and older was found to be well tolerated, with no safety concerns identified. 
There were no immediate unsolicited AEs/reactions reported in either group. There were no 
deaths, SAEs or AEs that led to study discontinuation reported during the study. 
1.2.2.4 
Study MET54 (Phase II) 
MET54 was a Phase II, randomized, open-label, active-controlled, multi-center study conducted 
in Europe (Finland) in 2015. 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 rSBA and 
hSBA. MenACYW conjugate vaccine immune responses evaluated by rSBA and hSBA were 
generally comparable to Nimenrix® immune responses with some variation by serogroup: 
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%). 
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]) 
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]). 
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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 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 findings were identified with administration of the MenACYW 
conjugate vaccine. 
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 it. However, based on the data from 
previous studies, evaluation of the immunogenicity profile of MenACYW conjugate vaccine in 
different age groups shows that the majority of subjects develop seroprotective levels of antibodies 
after vaccination. The safety evaluation indicates that the vaccine is well-tolerated, and no safety 
issues have been detected to date. In all, the data support the further evaluation of MenACYW 
conjugate vaccine in humans. 
Subjects who receive the measles-mumps-rubella vaccine (MMR) and the varicella vaccine (V) 
will likely be protected against measles, mumps, rubella, and varicella. Subjects who receive the 
pneumococcal conjugate vaccine (PCV13) will likely be protected against infection with 
13 pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) of 
Streptococcus pneumoniae bacteria. Subjects who receive the hexavalent vaccine (DTaP-IPV-HB-
Hib) will likely be protected against diphtheria, tetanus, pertussis, polio, hepatitis B, and invasive 
disease caused by Haemophilus influenzae type b bacteria. 
As with any vaccine, MenACYW conjugate vaccine and the licensed pediatric vaccines included 
in this study may not protect 100% of individuals against the disease they are designed to prevent. 
Following completion of the trial, subjects who received only licensed pediatric vaccine(s) (in 
Groups 3, 6, 9, and 12) will be offered vaccination with a licensed quadrivalent conjugated 
meningococcal vaccine available in each country to provide protection against meningococcal 
infection as a benefit for participation in this trial. This vaccine is offered outside of the scope of 
the protocol, free of charge. 
In Mexico for the subjects in Group 5 (MenACYW conjugate vaccine), as a benefit for 
participation in this trial and to ensure a benefit equal to that of the other trial subjects, DTaP-IPV-
HB-Hib vaccine will be offered after completion of the trial in case the vaccine is not yet launched 
in the country. This vaccine is offered outside of the scope of the protocol, free of charge. 
In Thailand, for subjects in Group 11 (MenACYW conjugate vaccine), as a benefit for 
participation in this trial and to ensure a benefit equal to that of the other trial subjects, MMR and 
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Varicella vaccines will be offered after completion of the trial. These vaccines will be offered 
outside of the scope of the protocol, free of charge.  
1.3.2 
Potential Risks to Subjects 
Like other vaccines, MenACYW conjugate vaccine and the licensed pediatric vaccines included 
in this study may cause injection site reactions such as pain, swelling, and erythema, or certain 
systemic events such as fever, irritability, drowsiness, loss of appetite, abnormal crying, and 
vomiting. Some of the other common reactions following the licensed pediatric vaccines also 
include (but are not limited to) injection site rash, pruritus, and induration, and systemic events of 
decreased sleep and diarrhea. There may be a rare possibility of an allergic reaction, which could 
be severe, and febrile convulsion in toddlers who experience high fever. Extensive limb swelling 
and hypotonic-hyporesponsive episodes have been rarely reported following administration of 
DTaP-IPV-HB-Hib vaccine. 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 (38). 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 (39).  
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 (40). The IOM found 
evidence for a causal relation between tetanus toxoid-containing vaccines and brachial neuritis  
(41). Arthus reactions are rarely reported after vaccination and can occur after tetanus toxoid-
containing vaccines (42). 
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 potential risks associated with blood drawing include local pain, bruising and, rarely, fainting 
or infection. 
The potential risks listed here are not exhaustive. Refer to the package inserts / summaries of 
product characteristics (SPCs) of the marketed vaccines (43) (44) (45) (46) and the Investigator’s 
Brochure of the investigational vaccine for additional information regarding potential risks. 
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1.4 
Rationale for the Trial 
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 > 65 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. The MenACYW conjugate vaccine is prepared using 
tetanus toxoid as the carrier protein. Conjugation of PS antigens to a protein carrier can induce T-
cell-dependent immune responses, which are anticipated to give rise to higher antibody (Ab) 
titers, longer duration of the immune response, and enhanced immunologic memory that allows 
for a booster response. 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 PS-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 MET57 is to demonstrate that the immunogenicity and safety profiles of a single 
MenACYW conjugate vaccine in toddlers 12 to 23 months old are comparable to when 
MenACYW conjugate vaccine is given concomitantly with licensed pediatric vaccine(s), and that 
the immunogenicity and safety of vaccines routinely administered to toddlers are not affected by 
concomitant administration with the MenACYW conjugate vaccine. 
2 
Trial Objectives 
2.1 
Primary Objective 
To describe the immunogenicity profile of MenACYW conjugate vaccine administered alone or 
concomitantly with licensed pediatric vaccine(s) (MMR+V, DTaP-IPV-HB-Hib, or PCV13). 
The endpoints for the primary objective are presented in Section 9.1.1.1. 
2.2 
Secondary Objective 
To describe the immunogenicity profile of licensed pediatric vaccine(s) (MMR+V, DTaP-IPV-
HB-Hib, or PCV13) when administered alone or concomitantly with MenACYW conjugate 
vaccine. 
The endpoints for the secondary objective are presented in Section 9.2.1.1. 
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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). 
The Investigator or Sponsor will submit written summaries of the status of the trial to the IEC / 
IRB annually, or more frequently if requested.  
All SAEs occurring during the trial that are related to vaccination will be reported by the 
Investigator to the IEC / IRB, according to the IEC / IRB policy and to local regulatory 
requirements.  
In South Korea: All SAEs that occur during the study whether related to vaccination or not must 
be reported to the Health Authority and to the IRB, according to local regulatory requirements.  
In Mexico: All SAEs that occur in subjects enrolled at Mexican sites, whether related to 
vaccination or not, must be reported to the IEC and Ministry of Health of Mexico. 
In the Russian Federation: The Sponsor will inform the National Ethics Board and relevant 
Health Authorities of any reportable SAEs (suspected unexpected serious adverse reaction 
[SUSAR] cases only) according to local regulatory requirements. 
In Thailand: All SAEs that occur during the study whether related to vaccination or not must be 
reported to the IRB. Any reportable SAEs (suspected unexpected serious adverse reaction) will be 
reported to Health Authority, according to local regulatory requirements. 
5 
Investigational Plan 
5.1 
Description of the Overall Trial Design and Plan 
5.1.1 
Trial Design 
This is a Phase III, open-label (immunology laboratory technicians will be blinded to group 
assignment), randomized, parallel-group, active-controlled, multi-center study to describe the 
immunogenicity and safety of a single dose of MenACYW conjugate vaccine when administered 
alone compared to when administered concomitantly with other pediatric vaccine(s) in healthy 
toddlers in South Korea and Thailand (measles-mumps-rubella vaccine [MMR] + varicella 
vaccine [V] ), Mexico (diphtheria, tetanus, acellular pertussis, hepatitis B, poliomyelitis and 
Haemophilus influenzae type-b conjugate vaccine [DTaP-IPV-HB-Hib]), and the Russian 
Federation (pneumococcal conjugate vaccine [PCV13]). 
In South Korea and Mexico, healthy, meningococcal vaccine-naïve toddlers aged 12 to 
23 months on the day of enrollment will be randomized in a 2:1:1 ratio (by country) to the 
following groups: 
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South Korea: 
Group 1:   
MenACYW conjugate vaccine + MMR + V on Day (D) 0 
Group 2:  
MenACYW conjugate vaccine on D0  
Group 3: 
MMR + V on D0 
Mexico: 
Group 4: 
MenACYW conjugate vaccine + DTaP-IPV-HB-Hib vaccine on D0 
Group 5: 
MenACYW conjugate vaccine on D0  
Group 6: 
DTaP-IPV-HB-Hib on D0 
In the Russian Federation, healthy, meningococcal-vaccine naïve toddlers aged 12 to 14 months 
or 16 to 23 months on the day of enrollment will be assigned to Group 8 with a balanced 
population distribution of half of the subjects aged 12 to 14 months and half of the subjects aged 
16 to 23 months. Healthy, meningococcal-vaccine naïve toddlers, who have not received the 3rd 
dose of PCV13, aged 15 to 23 months on the day of enrollment will be randomized in a 2:1 ratio 
to Groups 7 and 9 in order to comply with the National Immunization Calendar of the Russian 
Federation: 
The Russian Federation: 
Group 7:  
MenACYW conjugate vaccine + PCV13 on D0 
Group 8:  
MenACYW conjugate vaccine on D0 
Group 9: 
PCV13 on D0 
Note about Visits: 
Visit 0 = Screening visit for subjects in the Russian Federation only 
Visit 1 = D0, vaccination visit (all countries) 
Visit 2 = D30 (+14 days), 30 to 44 days after D0 (all countries) 
In the Russian Federation, Visit 0 and Visit 1 may take place on the same day, or Visit 1 may 
take place up to 5 days after Visit 0. 
In Thailand, healthy, meningococcal-vaccine naïve toddlers aged 12 to 23 months on the day of 
enrollment will be randomized in a 2:1:1 ratio to the following groups: 
Thailand: 
Group 10:   
MenACYW conjugate vaccine + MMR + V on D0 
Group 11:  
MenACYW conjugate vaccine on D0  
Group 12: 
MMR + V on D0 
All Subjects: 
All subjects will provide blood samples for immunogenicity assessment at baseline (pre-
vaccination) and at Visit 2 (30 to 44 days after vaccination[s]). Solicited AE information will be 
collected for 7 days after vaccination(s); unsolicited AE information will be collected from 
Visit 1(D0) to Visit 2, and SAE information will be collected throughout the study period from 
Visit 1 through Visit 2.  
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Upon completion of all study procedures and termination from the trial at Visit 2, study 
participants should receive the remainder of the recommended toddler vaccines, which are part of 
the respective National Immunization Programs (NIP) for each country, from their health care 
provider.  
Note: In this document, “days” refers to calendar days. 
For sites in the Russian Federation only: 
Per Guideline for the conduct of clinical trials of the Russian Federation Health Authorities and in 
accordance with local practices, in addition to being tested for study vaccine immunogenicity 
assessment, the blood of subjects enrolled at sites in the Russian Federation will be tested for 
complete blood count (CBC) and blood chemistry. These subjects will also provide a urine sample 
for urinalysis. Samples will be provided at Visit 0 (screening visit, baseline) and at Visit 2 
(30 days [+14 days] after the vaccination[s] at Visit 1). According to recommendations of Russian 
Health Authorities, the subjects will be examined by a neurologist at Visit 0 and at Visit 2. 
The examinations by a neurologist and additional biological analyses have been implemented for 
subjects enrolled at sites in the Russian Federation per the request of the Russian Federation 
Health Authorities only and not to address any concern of the Sponsor regarding biological safety 
issues. 
5.1.2 
Justification of the Trial Design 
The purpose of MET57 is to demonstrate that the immunogenicity and safety profiles of a single 
dose of MenACYW conjugate vaccine in toddlers 12 to 23 months old are comparable to when 
MenACYW conjugate vaccine is given concomitantly with licensed pediatric vaccine(s). 
The concomitant administration of standard of care pediatric vaccines together with 5 different 
administration schedules of the MenACYW conjugate vaccine has been assessed in 
infants/toddlers 2 to 15 months of age in the US in the MET39 study. The subjects received 
during, or prior to the study, a number of licensed recommended vaccines at 2, 4, and 6 months of 
age: Pentacel®, either Prevnar® or Prevnar 13®, RotaTeq® or ROTARIX®, and ENGERIX-B® or 
RECOMBIVAX HB®. All subjects received M-M-R® II and VARIVAX® at 12 months. A total of 
457 subjects completed the study. Samples from the subjects were assessed for both 
meningococcal antibodies (using both rSBA and hSBA) and antibodies elicited in response to 
selected licensed infant and toddler vaccines administered concomitantly. The immunogenicity 
profiles of selected licensed pediatric vaccines (Pentacel®, Prevnar® or Prevnar 13®, M-M-R® II, 
and VARIVAX®) were assessed when administered either concomitantly with or without 
MenACYW conjugate vaccine. There was no evidence of interference with the pediatric routine 
vaccines administered concomitantly with MenACYW conjugate vaccine. 
Four countries (i.e., Mexico, the Russian Federation, South Korea, and Thailand) have been 
selected for the conduct of the MET57 study. The concomitant pediatric vaccines selected to be 
administered together with MenACYW conjugate vaccine in each country were determined taking 
into consideration their respective pediatric vaccination schedule: DTaP-IPV-HB-Hib for Mexico, 
pneumococcal conjugate vaccine (PCV13) for the Russian Federation, and measles-mumps-
rubella vaccine (MMR) + varicella vaccine (V) for South Korea and Thailand. These countries 
and the concomitant vaccines to be administered have been strategically selected based on vaccine 
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395 – MenACYW Conjugate Vaccine
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Confidential/Proprietary Information 
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Blood Sampling 
All subjects will provide a pre-vaccination blood sample at Visit 0 (screening visit in the Russian 
Federation only) or Visit 1 (in South Korea, Mexico and Thailand) and a post-vaccination sample 
at Visit 2 (30 to 44 days after the vaccination[s] on D0). Table 5.1 presents the antibodies that will 
be measured (in the respective assays) for each group. 
Table 5.1: Schedules of blood sampling and antigen testing 
Group 
Blood Sampling / Antigen Testing* 
Visit 0 / Visit 1† 
(pre-vaccination) 
Day 30 (+14 days) 
1 
MenACYW conjugate vaccine‡ 
MMR+V vaccines§ 
MenACYW conjugate vaccine‡ 
MMR+V vaccines§ 
2 
MenACYW conjugate vaccine‡ 
MenACYW conjugate vaccine‡ 
3 
MMR+V vaccines§ 
MMR+V vaccines§ 
4 
MenACYW conjugate vaccine‡ 
DTaP-IPV-HB-Hib vaccine** 
MenACYW conjugate vaccine‡ 
DTaP-IPV-HB-Hib vaccine**,†† 
5 
MenACYW conjugate vaccine‡ 
MenACYW conjugate vaccine‡ 
6 
DTaP-IPV-HB-Hib vaccine** 
DTaP-IPV-HB-Hib vaccine**,†† 
7 
MenACYW conjugate vaccine‡ 
PCV13 vaccine‡‡ 
MenACYW conjugate vaccine‡ 
PCV13 vaccine‡‡ 
8 
MenACYW conjugate vaccine‡ 
MenACYW conjugate vaccine‡ 
9 
PCV13 vaccine‡‡ 
PCV13 vaccine‡‡ 
10 
MenACYW conjugate vaccine‡ 
MMR+V vaccines§ 
MenACYW conjugate vaccine‡ 
MMR+V vaccines§ 
11 
MenACYW conjugate vaccine‡ 
MenACYW conjugate vaccine‡ 
12 
MMR+V vaccines§ 
MMR+V vaccines§ 
*Sera will be tested for antibodies elicited by the antigens contained in the respective vaccines. 
†At Visit 0 for subjects in the Russian Federation; at Visit 1 for subjects in Mexico, South Korea, and Thailand 
‡Ab titers against meningococcal serogroups A, C, Y, and W measured by hSBA (in 100% of subjects) and by rSBA (in 
50 subjects per group in Groups 2, 5, and 8; and in 100 subjects per group in Groups 1, 4, and 7). 
§Anti-measles, anti-mumps, anti-rubella, and anti-varicella Ab concentrations 
**Anti-tetanus and anti-pertussis (pertussis toxoid [PT] and filamentous hemagglutinin [FHA] Ab concentrations measured at 
Visit 1 and Day 30 
††Anti-diphtheria, anti-polyribosyl-ribitol phosphate (PRP), anti-hepatitis B surface antigen Ab concentrations, and anti-poliovirus 
types 1, 2, and 3 Ab titers measured at Day 30 
‡‡Anti-pneumococcal Ab concentrations for serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F 
For sites in the Russian Federation only: 
Subjects enrolled at sites in the Russian Federation will also provide approximately 2 mL of 
additional blood sample, (depending on local laboratory needs) for CBC and blood chemistry 
testing Visit 0 (screening visit) and at Visit 2 (30 days [+14 days] after D0) per Health Authority 
Sanofi Pasteur 
 
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395 – MenACYW Conjugate Vaccine
Protocol Version 4.0
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MET57 
395 – MenACYW Conjugate Vaccine 
Confidential/Proprietary Information 
Page 46 of 105 
5.1.4 
Visit Procedures 
Visit 0: Inclusion, Allocation of Subject’s number, Blood Sample (For the Russian Federation 
only) 
1) Give the subject’s parent(s) information about the trial, answer any questions, obtain written 
informed consent in duplicate (in 2 originals) and give him / her 1 signed original as per local 
regulations and practice. 
2) Check inclusion and exclusion criteria for eligibility. 
3) Collect demographic data. 
4) Obtain medical history about the subject. 
5) Perform a physical examination, including but not limited to examination of the head 
(including ear, nose, and throat), neck, thorax (including heart and lungs), abdomen, and 
extremities. If a routine examination, including examination by a neurologist, CBC, 
biochemistry, and urinalysis laboratory tests, had been performed within the last 7 days 
before Visit 0 by the Investigator, a sub-Investigator, or a licensed practitioner; it does not 
need to be repeated unless the Investigator considers it is necessary to repeat. 
6) Perform a neurological examination by a neurologista 
7) Take the subject’s temperature by the axillary route. 
8) Connect to the Interactive Web Response System (IWRS) for allocation of subject 
identification number  
9) Obtain the first 7-mL blood sampleb (see Section 7 for detailed instructions regarding the 
handling of blood samples). If attempts to obtain the first blood draw are unsuccessful (after 
reasonable attempts as per local regulations / practice), then Visit 0 can be rescheduled to a 
later date at which point inclusion/exclusion criteria must be re-validated. If the first blood 
draw cannot be obtained, the subject will be withdrawn from the study without being 
vaccinated. 
10) Obtain a urine sample (approximately 8 mL)c 
11) Collect reportable concomitant medications information 
12) Complete relevant source documentation and CRF pages for the visit 
13) Confirm subject’s eligibility based on the results of the baseline testing of CBC, blood 
chemistry, and urinalysis, and neurological examination. 
                                                 
a  The results (discharge summary) of the neurologist’s examination, performed for the subject in terms of routine 
practice, can be used, if the examination was done within 7 days before Visit 0. 
b  The results of CBC and biochemistry laboratory tests, performed for the subject in terms of routine practice, can 
be used, if the tests were done within 7 days before Visit 0. In this case, the blood sample volume collected at 
Visit 0 will be 5 mL. 
c  The results of urine laboratory tests, performed for the subject in terms of routine practice, can be used if the tests 
were done within 7 days before Visit 0. In this case, no urine sample will be collected at Visit 0. 
Sanofi Pasteur 
 
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395 – MenACYW Conjugate Vaccine
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Note: If Visit 1 (the vaccination visit) is performed on the same day as Visit 0, only the 
procedures from step number 4 onwards in the Study Procedures listed under Visit 1 below are to 
be followed. 
Visit 1 (D0): Randomization and Vaccination (For the Russian Federation only) 
Steps 1 through 3 only for subjects with Visit 0 and Visit 1 not on the same day: 
1) Check inclusion and exclusion criteria for eligibility 
2) Perform a physical examination 
3) Take the subject’s temperature by the axillary route. 
Steps 4 through 10 for all subjects: 
4) Connect to the Interactive Web Response System (IWRS) for subject randomization and 
obtain group of vaccination allocated. 
5) Inject the appropriate study vaccine(s). For Group 7, MenACYW conjugate vaccine should 
be given first. Each vaccine should be given in an assigned location (either the right or left 
respective limb) and documented appropriately.  
MenACYW conjugate vaccine (Groups 7 and 8): Inject IM into the anterolateral area 
of the thigh or the deltoid muscle of the arm. 
PCV13 vaccine (Groups 7 and 9, the Russian Federation only): Inject IM into the 
anterolateral area of the thigh or the deltoid muscle of the arm. 
6) Keep the subject under observation for 30 minutes, and record any AE in the source 
document. 
7) Give the parent a diary card, a thermometer, and a ruler, and go over the instructions for their 
use. 
8) Remind the parent to expect a telephone call 8 days (+2 days) after Visit 1 and to bring back 
the diary card when they return for Visit 2 at a specified date and time. 
9) Remind the parent to notify the site in case of an SAE. 
10) Complete the relevant CRF pages for this visit. 
 
Visit 1 (D0): Inclusion, Randomization, Blood Sample, and Vaccination (for South Korea, 
Mexico, and Thailand) 
1) Give the subject’s parent(s) / guardian information about the trial, answer any questions, 
obtain written informed consent in duplicate (in 2 originals, or a photocopy of the signed 
consent) and give him / her 1 signed original or the copy as per local regulations and practice. 
2) Check inclusion and exclusion criteria for eligibility. 
3) Collect demographic data. 
4) Obtain verbal medical history about the subject. 
Sanofi Pasteur 
 
Confidential/Proprietary Information 
                
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395 – MenACYW Conjugate Vaccine
Protocol Version 4.0
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Sanofi Pasteur 
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395 – MenACYW Conjugate Vaccine 
Confidential/Proprietary Information 
Page 48 of 105 
5) Perform a physical examination, including but not limited to examination of the head 
(including ear, nose, and throat), neck, thorax (including heart and lungs), abdomen, and 
extremities. If a routine examination had been performed within the last month by the 
investigator, a sub-investigator, or a licensed nurse practitioner, it does not need to be 
repeated unless there were some changes in health status, in which case it may be limited to 
the affected area. 
6) Take the subject’s temperature by either the rectal or axillary route. 
7) Connect to the Interactive Web Response System (IWRS) for subject identification number 
and randomization. 
8) Obtain the first 5-mL blood sample (see Section 7 for detailed instructions regarding the 
handling of blood samples). If attempts to obtain the first blood draw are unsuccessful (after 
reasonable attempts as per local regulations / practice), then Visit 1 can be rescheduled to a 
later date at which point informed consent and inclusion/exclusion criteria must be re-
validated. If the first blood draw cannot be obtained, the subject will be withdrawn from the 
study without being vaccinated. 
9) Inject the appropriate study vaccine(s). Of the injected vaccines, MenACYW conjugate 
vaccine should be given first. Each vaccine should be given in an assigned location (either the 
right or left respective limb) and documented appropriately.  
For South Korea and Thailand only, the order of the remaining vaccines is not critical, as 
long as each is given in an assigned location and documented appropriately. To avoid 
confusion, staff should follow normal office procedure for order of vaccine administration. If 
injections are given in the same limb, the injection sites should be at least 2.5 cm (1 inch) 
apart. If injection(s) and blood sampling are done in the same limb, the injection site(s) and 
blood sampling site should be at least 2.5 cm (1 inch) apart or can be done according to local 
clinical practice as per the Investigator’s judgment. 
MenACYW conjugate vaccine (Groups 1, 2, 4, 5, 10, and 11): Inject IM into the 
anterolateral area of the thigh or the deltoid muscle of the arm. 
MMR vaccine and V vaccine (Groups 1, 3, 10, and 12; South Korea and Thailand 
only): Inject SC into the fatty tissue over the triceps on the upper arm or fatty tissue over 
the anterolateral thigh muscle  
DTaP-IPV-HB-Hib vaccine (Groups 4 and 6, Mexico only): Inject IM into the 
anterolateral area of the thigh or the deltoid muscle of the arm. 
10) Keep the subject under observation for 30 minutes, and record any AE in the source 
document. 
11) Give the parent / guardian a diary card, a thermometer, and a ruler, and go over the 
instructions for their use. 
12) Remind the parent / guardian to expect a telephone call 8 days (+2 days) after Visit 1 and to 
bring back the diary card when they return for Visit 2 at a specified date and time. 
13) Remind the parent / guardian to notify the site in case of an SAE. 
14) Complete the relevant CRF pages for this visit. 
Sanofi Pasteur 
 
Confidential/Proprietary Information 
                
MET57
395 – MenACYW Conjugate Vaccine
Protocol Version 4.0
Page 48 of 106

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5.1.5 
Planned Trial Calendar 
The following dates are approximate. The actual dates may differ as, for example, the trial will not 
start until all the appropriate regulatory and ethical approvals have been obtained. 
Planned subject participation – FVFS (first visit, first subject) to  
LVLS (Last visit, last subject): 
 
 
07 November 2016 to 11 June 2018 
Planned inclusion period - FVFS to  
FVLS (first visit, last subject):  
 
 
07 November 2016 to 30 April 2018 
Planned vaccination period:   
 
 
07 November 2016 to 30 April 2018 
Planned end of trial (last assay results available):  04 September 2018 
Planned date of final clinical study report:   
31 January 2019 
The date that the last assay results are available is considered as the end of the study. 
5.1.6 
Early Safety Data Review 
This trial will not include an early safety data review (i.e., no early safety review[s] of preliminary 
safety data occurring at pre-determined milestones defined in the protocol, with pause in 
enrollment). However, it may be interrupted at any time if new data about the investigational 
product become available, and/or on advice of the Sponsor, the IECs / IRBs, or the governing 
regulatory authorities in the country where the trial is taking place. 
If the trial is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, the IECs / IRBs, and the regulatory authorities of the reason for the termination or 
suspension. If the trial is prematurely terminated for any reason, the Investigator will promptly 
inform the subject’s parents / guardian and should assure appropriate therapy and follow-up. 
5.2 
Enrollment and Retention of Trial Population 
5.2.1 
Recruitment Procedures 
Before the start of the trial, the Investigator and / or study staff may contact the parent / guardian 
of an appropriate pool of potential subjects 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) 
(if applicable, according to country regulation and practice) are submitted to Sanofi Pasteur for 
review prior to submission to the IEC/ IRB for approval. 
In addition, a parent who brings a child to the trial site for a routine visit will be invited to enroll 
the subject in the trial, if eligible. Subjects may also be recruited from the general population. 
5.2.2 
Informed Consent Procedures 
Informed consent is the process by which a subject’s parent(s) / guardian voluntarily confirms his 
or her willingness to allow the child to participate in a particular trial. Informed consent must be 
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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 subject’s parent / 
guardian must be informed by appropriate study personnel about all aspects of the trial that are 
relevant to making the decision to participate, and must have sufficient time and opportunity to 
ask any questions. 
For subjects enrolled in Mexico, South Korea, and Thailand: If the subject’s parent / guardian is 
not able to read and sign the ICF, then it must be signed and dated by an impartial witness(es) 
who is independent of the Investigator, according to local regulations. 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 
representative. This does not apply to subjects enrolled in the Russian Federation. 
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 and the appropriate regulatory agencies according to local regulations 
prior to the form being used. 
If new information becomes available that may be relevant to the subject’s parent / guardian’s 
willingness to continue participation in the trial, this will be communicated to 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 (as originals), or a photocopy of the signed consent will be 
made, as per local regulations and practice. The original will be kept by the Investigator, and the 
copy, or the other original (as applicable) will be kept by the subject’s parent / guardian. 
Documentation of the consent process should be recorded in the source documents. 
In the Russian Federation 
In the Russian Federation, as per local regulations, only the subject’s parent(s) are entitled to sign 
an ICF. A child under the responsibility of a guardian will not be included in the study. 
The signature of only one of the parents will be required on the ICF. 
5.2.3 
Screening Criteria 
For South Korea, Mexico, and Thailand, there are no screening criteria other than the inclusion 
and exclusion criteria. 
For the Russian Federation, as per Guideline for the conduct of clinical trials of the Russian 
Federation Health Authorities and in accordance with local practices, in addition to being tested 
for study vaccine immunogenicity assessment, the blood of subjects enrolled at sites in the 
Russian Federation will be tested for complete blood count (CBC) and blood chemistry. These 
subjects will also provide a urine sample for urinalysis. According to recommendations of Russian 
Health Authorities, the subjects will be examined by a neurologist. 
Sanofi Pasteur 
 
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The examinations by a neurologist and additional biological analyses have been implemented for 
subjects enrolled at sites in the Russian Federation per the request of the Russian Federation 
Health Authorities only and not to address any concern of the Sponsor regarding safety issues. 
5.2.4 
Inclusion Criteria 
An individual must fulfill all of the following criteria in order to be eligible for trial enrollment: 
1) For South Korea: Korean males and females aged 12 to 23 months on the day of the first 
study visita 
For Mexico: Males and females aged 12 to 23 months on the day of the first study visit 
For the Russian Federation: Males and females aged 12 to 14 months or 16 to 23 months on 
the day of the first study visit (eligible for enrollment to Group 8) or 15 to 23 months on the 
day of the first study visit (eligible for enrollment to Group 7 or 9).b 
For Thailand: Thai males and females aged 12 to 23 months on the day of the first study 
visit.a 
2) Subject had received all recommended standard of care vaccinations according to his/her age 
as per local regulations.c  
For the Russian Federation only, subjects aged 15 to 23 months on the day of the first study 
visit (eligible for enrollment to Group 7 or 9) must not have received the third PCV13 
vaccination corresponding to his or her age as per the country’s NIP. The 2nd dose of PCV13 
must have been administered at least 4 weeks before the 3rd dose of PCV13 is administered 
in the study.  
For South Korea, subjects must not have received the MMR or V vaccination corresponding 
to his or her age at inclusion.  
For Mexico, subjects must not have received the DTaP-IPV-HB-Hib vaccination 
corresponding to his or her age at inclusion. 
For Thailand, subjects must not have received the MMR or V vaccination corresponding to 
his or her age at inclusion.  
                                                 
a  “12 to 23 months” means from the 1st day of the 12th month after birth to the day before the 24th month after 
birth 
b  “12 to 14 months” means from the 1st day of the 12th month after birth to the day before the 15th month after 
birth; “15 to 23 months” means from the 1st day of the 15th month after birth to the day before the 24th month 
after birth; “16 to 23 months” means the 1st day of the 16th month after birth to the day before the 24th month 
after birth. 
c  Subjects must have received the total number of doses expected for each vaccine recommended for his/her age in 
the respective NIPs, but inclusion of subjects with variations in the vaccine administration timeframes is 
considered acceptable if the total number of doses for the corresponding vaccines have been completed (e.g., in 
Mexico, 3 infant doses of the pentavalent vaccine must have been administered but the 4th dose due in the 2nd 
year of life should not have been administered for subjects to be included in the trial). For the Russian 
Federation only, subjects that have not received a seasonal flu vaccination from 6 months of age according to the 
Russian NIP are still eligible to participate in this study. For Thailand only, subjects who may have received a 
vaccine ahead of the schedule can still be included in the study provided the first doses of MMR and V vaccines 
have not been administered prior to inclusion.   
Sanofi Pasteur 
 
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3) Informed consent form has been signed and dated by the parent(s) or guardian if allowed by 
local regulations (and by independent witnesses if required by local regulations)a 
4) Subject and parent/guardian are able to attend all scheduled visits and to comply with all trial 
procedures 
5.2.5 
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 first 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 first trial vaccination or 
planned receipt of any vaccine prior to Visit 2 except for influenza vaccination, which may be 
received at least 2 weeks before or after the study investigational vaccines. This exception 
includes monovalent pandemic influenza vaccines and multivalent influenza vaccines. 
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) 
4) For subjects enrolled at sites in the Russian Federation: previous vaccination with the 
third dose of PCV13 in subjects 15 to 23 months of age (eligible for Group 7 or 9) 
5) For subjects enrolled at sites in Mexico: known history of seizures, or uncontrolled 
neurologic disorder (including epilepsy); or encephalopathy of unknown etiology occurring 
within 7 days following previous vaccination with pertussis containing vaccine; previous 
vaccination with DTaP-IPV-HB-Hib or DTaP-containing vaccine at 12 to 23 months of age.  
6) For subjects enrolled at sites in South Korea and Thailand: known history of seizures, 
cerebral injury, or encephalopathy; previous vaccination with MMR or V at or before 12 to 
23 months of age. 
7) Receipt of immune globulins, blood or blood-derived products in the past 3 months 
8) 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) 
9) History of meningococcal infection, confirmed either clinically, serologically, or 
microbiologically 
10) At high risk for meningococcal infection during the trial, according to the Investigator’s 
judgment (specifically, but not limited to, subjects with persistent complement deficiency, 
                                                 
a  In the Russian Federation, as per local regulations, only the subject’s parent(s) are entitled to sign an ICF. A 
child under the responsibilities of a guardian will not be included in the study. 
Sanofi Pasteur 
 
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with anatomic or functional asplenia, or subjects traveling to countries with high endemic or 
epidemic disease) 
11) Known systemic hypersensitivity to any of the vaccine components, or history of a life-
threatening reaction to the vaccine(s) used in the trial or to a vaccine containing any of the 
same substancesa 
12) Verbal report of thrombocytopenia, as reported by the parent/guardian, contraindicating 
intramuscular vaccination by the Investigator’s judgment 
13) Known bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, 
contraindicating intramuscular vaccination by the Investigator’s judgment 
14) Personal history of Guillain-Barré syndrome (GBS) 
15) Personal history of an Arthus-like reaction after vaccination with a tetanus toxoid-containing 
vaccine 
16) Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere 
with trial conduct or completionb 
17) For subjects enrolled at sites in South Korea, Mexico, and Thailand: Moderate or severe 
acute illness/infection (according to Investigator’s 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. 
18) For subjects enrolled at sites in the Russian Federation: Acute disease of any severity on 
the day of vaccination or febrile illness (axillary temperature ≥ 37.0°C). A prospective subject 
should not be included in the study until the condition has resolved or the febrile event has 
subsided. 
19) Receipt of oral or injectable antibiotic therapy within 72 hours prior to the first blood draw 
20) Identified as a natural or adopted child of the Investigator or employee with direct 
involvement in the proposed study 
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 
medical history (reported as diagnosis) including conditions for which the subject is or has been 
followed by a physician or conditions 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 CRF. The significant medical 
history section of the CRF contains a core list of body systems and disorders that could be used to 
                                                 
a  The components of the MenACYW conjugate vaccine are listed in Section 6.1.1.1 and in the Investigator’s 
Brochure. The components of MMR, V, DTaP-IPV-HB-Hib, and PCV13 are listed in Section 6.1.2.1,  
Section 6.1.3.1, Section 6.1.4.1, and Section 6.1.5.1., respectively. 
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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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 trial because of an SAE, other type of AE, non-compliance with the 
protocol, or loss of eligibility, including definite 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. 
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 trial 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 
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 Global PharmacoVigilance (GPV) 
(Please refer to Section 10). 
In case of emergency code-breaking, the Investigator is required to follow the code-breaking 
procedures described in Section 6.4. 
5.4 
Modification of the Trial and Protocol 
Any amendments to this trial 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.  
An administrative amendment to a protocol is one that modifies some administrative or logistical 
aspect of the trial but does not affect its design or objectives or have an impact on the subjects’ 
safety. A substantial amendment to a protocol is one that affects the conduct of the trial or the 
safety of the subjects. Protocol amendments will be submitted for approval and implementation 
according to local IEC / IRB / HA policy. 
The Investigator is responsible for ensuring that changes to an approved trial, 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 Trial 
The trial may be discontinued if new data about the investigational product resulting from this or 
any other trials become available; or for administrative reasons; or on advice of the Sponsor, the 
Investigators, and / or the IECs / IRBs. If the trial is prematurely terminated or suspended, the 
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Sponsor shall promptly inform the Investigators, the regulatory authorities, and the IECs / IRBs of 
the reason for termination or suspension, as specified by the applicable regulatory requirements. 
The Investigator shall promptly inform the trial subjects’ parent(s) or guardian(s) (if applicable) 
and assure appropriate therapy and / or follow-up for them. 
6 
Vaccines Administered 
6.1 
Identity of the Investigational Products 
6.1.1 
Identity of Trial Product 1 
MenACYW conjugate vaccine: Meningococcal Polysaccharide (Serogroups A, C, Y, and W) 
Tetanus Toxoid Conjugate Vaccine (Sanofi Pasteur Inc., Swiftwater, PA, USA) 
Form:  
Liquid solution 
Dose:  
0.5 milliliter (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 ingredients: 
Meningococcal capsular polysaccharides: 
Serogroup A...................................................................................................................... 10 µg 
Serogroup C ...................................................................................................................... 10 µg 
Serogroup Y...................................................................................................................... 10 µg 
Serogroup W ..................................................................................................................... 10 µg 
Tetanus toxoid protein carrier ........................................................................ approximately 65 µg 
6.1.1.2 
Preparation and Administration 
MenACYW conjugate vaccine is supplied in single-dose (0.5 mL) vials. 
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. Another 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. 
One dose (0.5 mL) of MenACYW will be administered IM into the anterolateral area of the thigh 
or the deltoid muscle of the arm, as per local country preferences, the Investigator’s criteria, and 
depending upon the number of vaccinations received. The site of injection should be documented. 
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The site of injection should be prepared with a suitable antiseptic. After administration of the 
vaccine, 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 under the supervision of 
a responsible healthcare professional at each study site to ensure their safety, and any reactions 
during this period will be documented in the CRF. Appropriate medical equipment and emergency 
medications, including epinephrine (1:1000), must be available on site in the event of an 
anaphylactic or other immediate allergic reaction. 
6.1.1.3 
Dose Selection and Timing 
All subjects in Groups 1, 2, 4, 5, 7, and 8 will receive 1 dose of MenACYW conjugate vaccine on 
D0. 
6.1.2 
Identity of Trial Product 2 - Measles, Mumps, Rubella Vaccine 
M-M-R®II (MMR): Measles, Mumps, and Rubella Virus Vaccine Live (Merck & Co., Inc., 
Whitehouse Station, NJ, USA); (licensed vaccine in South Korea and Thailand) 
Form: 
Solution for injection supplied as lyophilized vaccine and diluent for 
 
reconstitution 
Dose:  
0.5 mL 
Route:  
Subcutaneous (SC) 
Batch number: To be determined 
6.1.2.1 
Composition 
Each 0.5 mL dose of reconstituted vaccine is formulated to contain the following components: 
 
Measles virus: not less than 1000 tissue culture infectious doses (TCID50) 
 
Mumps virus: not less than 12,500 TCID50 
 
Rubella virus: not less than 1000 TCID50 
Each 0.5 mL dose is also formulated to contain the following inactive ingredients: sorbitol 
(14.5 milligrams [mg]), sodium phosphate, sucrose (1.9 mg), sodium chloride, hydrolyzed gelatin 
(14.5 mg), recombinant human albumin (≤ 0.3 mg), fetal bovine serum (< 1 part per million 
[ppm]), other buffer and media ingredients, and approximately 25 µg of neomycin. The product 
contains no preservative. 
6.1.2.2 
Preparation and Administration 
M-M-R®II is supplied as a vial of lyophilized vaccine and a vial of diluent for reconstitution to 
prepare a single dose (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. Another dose is to be used, and the event is to be reported to the Sponsor. 
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One dose (0.5 mL) of M-M-R®II will be administered SC into the fatty tissue over the triceps on 
the upper arm or fatty tissue over the anterolateral thigh muscle, as per local country preferences, 
the Investigator’s criteria, and depending upon the number of vaccinations received. The site of 
injection should be documented. The site of injection should be prepared with a suitable 
antiseptic. After administration of the vaccine, 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 under the supervision of 
a responsible healthcare professional at each study site to ensure their safety, and any reactions 
during this period will be documented in the CRF. Appropriate medical equipment and emergency 
medications, including epinephrine (1:1000), must be available on site in the event of an 
anaphylactic or other immediate allergic reaction. 
The procedures for preparing and administering the M-M-R®II are detailed in the package insert 
(43). 
6.1.2.3 
Dose Selection and Timing 
All subjects in Groups 1 and 3 will receive 1 dose of M-M-R®II on D0. 
6.1.3 
Identity of Trial Product 3 - Varicella Vaccine 
VARIVAX® (V): Varicella Virus Vaccine Live (Merck, Sharp & Dohme, Haarlem, The 
Netherlands (47)) (licensed in South Korea and Thailand) 
Form:  
Suspension for injection supplied as lyophilized vaccine to be reconstituted 
 
using the accompanying sterile diluent 
Dose: 
0.5 mL 
Route: 
SC 
Batch number: To be determined 
 
VARIVAX [Patient Information Leaflet] Haarlem, (The Netherlands): Sanofi Pasteur MSD. 
https://www.medicines.org.uk/emc/medicine/17494 
 
6.1.3.1 
Composition 
Each 0.5 mL dose of vaccine is formulated to contain a minimum of 1350 plaque-forming units 
(PFU) of Oka/Merck varicella virus. 
Each 0.5 mL dose also contains approximately 25 mg of sucrose, 12.5 mg hydrolyzed 
gelatin,3.2 mg of sodium chloride, 0.5 mg of monosodium L-glutamate, 0.45 mg of sodium 
phosphate dibasic, 0.08 mg of potassium phosphate monobasic, and 0.08 mg of potassium 
chloride. The product also contains residual components of Medical Research Council cell strain 5 
(MRC-5) cells including deoxyribonucleic acid (DNA) and protein and trace quantities of sodium 
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phosphate monobasic, ethylenediaminetetraacetic acid (EDTA), neomycin, and fetal bovine 
serum. The product contains no preservative. 
6.1.3.2 
Preparation and Administration 
VARIVAX® is supplied as a vial of lyophilized vaccine and a vial of diluent for reconstitution to 
prepare a single dose (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. Another dose is to be used, and the event is to be reported to the Sponsor. 
One dose (0.5 mL) of VARIVAX® will be administered SC into the fatty tissue over the triceps on 
the upper arm or fatty tissue over the anterolateral thigh muscle, as per local country preferences, 
the Investigator’s criteria, and depending upon the number of vaccinations received. The site of 
injection should be documented. The site of injection should be prepared with a suitable 
antiseptic. After administration of the vaccine, 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 under the supervision of 
a responsible healthcare professional at each study site to ensure their safety, and any reactions 
during this period will be documented in the CRF. Appropriate medical equipment and emergency 
medications, including epinephrine (1:1000), must be available on site in the event of an 
anaphylactic or other immediate allergic reaction. 
The procedures for preparing and administering the VARIVAX® are detailed in the SPC (44). 
6.1.3.3 
Dose Selection and Timing 
All subjects in Groups 1 and 3 will receive 1 dose of VARIVAX® of D0. 
6.1.4 
Identity of Trial Product 4 - Hexavalent Vaccine 
Hexaxim® (DTaP-IPV-HB-Hib): Diphtheria, tetanus, pertussis (acellular, component), hepatitis 
B (recombinant deoxyribonucleic acid [rDNA]), poliomyelitis (inactivated), and Haemophilus 
influenzae type b conjugate vaccine (adsorbed) (Sanofi Pasteur SA, Marcy L’Etoile, France); 
(licensed in Mexico as Hexacima) 
Form: 
Suspension for injection 
Dose: 
0.5 mL 
Route: 
IM 
Batch number: To be determined 
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6.1.4.1 
Composition 
Each 0.5 mL dosea is formulated to contain the following components: 
Diphtheria Toxoid .................................................................. ≥ 20 international units (IU)b 
Tetanus Toxoid ........................................................................................................ ≥ 40 IUb 
Bordetella pertussis antigens 
 
Pertussis Toxoid ............................................................................... 25 µg 
 
Filamentous Haemagglutinin ........................................................... 25 µg 
Poliovirus (Inactivated)c 
 
Type 1 (Mahoney) ...................................................... 40 D antigen unitsd 
 
Type 2 (MEF-1) ........................................................... 8 D antigen unitsb 
 
Type 3 (Saukett) ......................................................... 32 D antigen unitsb 
Hepatitis B surface antigene ......................................................................................... 10 µg 
Haemophilus influenzae type b polysaccharide ........................................................... 12 µg 
(Polyribosylribitol Phosphate) 
conjugated to Tetanus Protein ................................................................................ 22-36 µg 
The vaccine also contains the excipients: disodium hydrogen phosphate, potassium dihydrogen 
phosphate, trometamol, saccharose, essential amino acids including L-phenylalanine, and water 
for injections. 
The vaccine may contain traces of glutaraldehyde, formaldehyde, neomycin, streptomycin, and 
polymyxin B, which are used during the manufacturing process. 
6.1.4.2 
Preparation and Administration 
Hexaxim® is supplied as a suspension for IM injection in 0.5 mL single-dose prefilled syringes. 
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. Another dose is to be used, and the event is to be reported to the Sponsor. 
One dose (0.5 mL) of Hexaxim® will be administered IM into the anterolateral area of the thigh or 
the deltoid muscle of the arm, as per local country preferences, the Investigator’s criteria, and 
depending upon the number of vaccinations received. The site of injection should be documented. 
The site of injection should be prepared with a suitable antiseptic. After administration of the 
vaccine, the used syringe and needle will be disposed of in accordance with currently established 
guidelines. 
                                                 
a  Adsorbed on aluminium hydroxide, hydrated (0.6 mg Al3+) 
b  As lower confidence limit (p=0.95) 
c  Produced on Vero cells 
d  Or equivalent antigenic quantity determined by a suitable immunochemical method 
e  Produced in yeast Hansenula polymorpha cells by recombinant DNA technology 
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Subjects must be kept under observation for 30 minutes after vaccination under the supervision of 
a responsible healthcare professional at each study site to ensure their safety, and any reactions 
during this period will be documented in the CRF. Appropriate medical equipment and emergency 
medications, including epinephrine (1:1000), must be available on site in the event of an 
anaphylactic or other immediate allergic reaction. 
The procedures for preparing and administering the Hexaxim® are detailed in the SPC (46). 
6.1.4.3 
Dose Selection and Timing 
All subjects in Groups 4 and 6 will receive 1 dose of Hexaxim® on D0. 
6.1.5 
Identity of Trial Product 5 - Pneumococcal Vaccine 
Prevenar 13® (PCV13): Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 
Protein) (Pfizer Ireland Pharmaceuticals, Ireland) (licensed in the Russian Federation) 
Form: 
Suspension for IM injection 
Dose: 
0.5 mL 
Route: 
IM 
Batch number: To be determined 
6.1.5.1 
Composition 
Each 0.5 mL vaccine dose is formulated to contain approximately 2.2 µg of each of Streptococcus 
pneumoniae serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, and 23F saccharides, 4.4 µg of 
6B saccharides; 34 µg CRM197 carrier protein, 100 µg polysorbate 80, 295 µg succinate buffer, 
and 125 µg aluminum as aluminum phosphate adjuvant. 
6.1.5.2 
Preparation and Administration 
Prevenar 13® is supplied as a suspension for IM injection in 0.5 mL single-dose prefilled syringes. 
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. Another dose is to be used, and the event is to be reported to the Sponsor. 
One dose (0.5 mL) of Prevenar 13® will be administered IM into the anterolateral area of the thigh 
or the deltoid muscle of the arm, as per local country preferences, the Investigator’s criteria, and 
depending upon the number of vaccinations received. The site of injection should be documented. 
The site of injection should be prepared with a suitable antiseptic. After administration of the 
vaccine, 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 under the supervision of 
a responsible healthcare professional at each study site to ensure their safety, and any reactions 
during this period will be documented in the CRF. Appropriate medical equipment and emergency 
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medications, including epinephrine (1:1000), must be available on site in the event of an 
anaphylactic or other immediate allergic reaction. 
The procedures for preparing and administering the Prevenar 13® are detailed in the SPC (45). 
6.1.5.3 
Dose Selection and Timing 
All subjects in Groups 7 and 9 will receive 1 dose of Prevenar 13® on D0. 
6.1.6 
Identity of Control Products 
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 by the Sponsor in single-dose vials in cartons, 
both with investigational labeling and packaging according to national regulations. The content of 
the labeling will also be in accordance with the local regulatory specifications and requirements. 
Each vial will have 1 fixed multilingual booklet label (in Korean, Russian, Spanish, and Thai) 
with room to view the product and each carton will have 1 fixed multilingual booklet label and 
2 detachable labels enabling identification and providing information on the study. The detachable 
carton labels are for the sites to attach to source documents and the subject’s vaccination card. See 
the Operating Guidelines for additional label detail. 
Commercial lots of the licensed pediatric vaccines (M-M-RII®, VARIVAX®, Prevenar 13®, and 
Hexaxim®) will be supplied by Sanofi Pasteur, Inc. 
For some countries, where acceptable and in accordance with local regulations, primary labels are 
in English with information in local language on the carton; for other countries primary and 
secondary labels are in local language in accordance with local 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 in order 
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 
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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 trial 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 trial site, product inventory at the site, the dose(s) given to each subject, and the disposal of 
or return to the Sponsor of unused doses.  
The necessary information on the product labels is to be entered into the source document and the 
CRF. If applicable, information may also be entered into the subject’s vaccination card. 
The Sponsor’s monitoring staff will verify the trial site’s product accountability records against 
the record of administered doses in the CRFs and the communication from the IWRS (if 
applicable). 
In case of any expected or potential shortage of product during the trial, 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 syringe broke or particulate matter was 
observed in the syringe), the site personnel must either contact the IWRS 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 trial period. 
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Dosage and administration route will not be recorded. Homeopathic medication will not be 
recorded. Topical treatment will not be recorded. 
The fact that a medication was given in response to an AE will be captured in the “Action Taken” 
column of the AE only. No details will be recorded in the concomitant medication module of the 
CRF unless the medication received belongs to one of the prelisted categories. Medications will 
not be coded. 
7 
Management of Samples 
Blood samples for the assessment of antibody responses, CBC, and blood chemistry, as well as 
urine samples, will be collected at Visits 0 (the Russian Federation only), 1, and 2. See the Tables 
of Study Procedures and Section 5.1.3 for details of the sampling schedule. 
7.1 
Sample Collection 
7.1.1 
Blood Samples 
For Immunogenicity: 
At Visit 0 (the Russian Federation only), Visit 1 (Mexico, South Korea, and Thailand), and 
Visit 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 verify 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.  
If feasible, blood is to be taken from the limb opposite to the one that will be used for vaccination. 
If injection(s) and blood sampling are done in the same limb, the injection site(s) and blood 
sampling site should be at least 2.5 cm (1 inch) apart or can be done according to local clinical 
practice as per the Investigator’s judgment. 
For CBC and Blood Chemistry (Sites in the Russian Federation Only) 
Blood samples for CBC and blood chemistry will be collected in a separate tube from the sample 
for immunogenicity. If only a limited volume of blood is available, the safety blood sample takes 
precedence over the blood sample for immunogenicity assessments. For blood samples of subjects 
enrolled at sites in the Russian Federation, tubes, labels, and other materials required for testing 
will be provided locally. Sample labeling and processing will be done according to the hospital’s 
standard practice. See Operating Guidelines for further details. 
7.1.2 
Urine Samples for Urine Chemistry (Sites in the Russian Federation Only) 
Approximately 8 mL of first-stream urine will be collected at the following times: Visit 0, and 
Visit 2. For urine samples of subjects enrolled at sites in the Russian Federation, tubes, labels, and 
other materials required for testing will be provided locally. Labeling procedures will be done the 
same way as for blood samples. 
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7.2 
Sample Preparation 
Detailed instructions on how to prepare blood samples for assessment of antibody response are 
contained in the Operating Guidelines provided to the site. An overview of the procedures is 
provided here. 
7.2.1 
Serum Samples 
For Immunogenicity 
After the blood draw, the sampling 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 by pipetting; samples are handled 1 subject at a time to avoid the mix-
up of the subjects’ blood tubes. At least 1.5 mL of serum should be placed in the primary 
cryotube, and the remaining serum should be placed in the retention cryotubes. If less than 1.5 mL 
of serum is available, all of the sera should be placed in the primary cryotube, and no retention 
cryotubes should be used. 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 subject’s consent for future use of his / her 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. 
For CBC and Blood Chemistry (Sites in the Russian Federation Only): 
Blood samples for CBC and blood chemistry will be prepared at ambient temperature and sent to 
the site’s local laboratory for testing. The testing will be done according to the site’s routine 
practice and standard procedures. 
7.2.2 
Urine Samples for Urine Chemistry (Sites in the Russian Federation Only) 
Samples will be prepared at ambient temperature and analyzed locally. The testing will be done 
according to the site’s routine practice and standard procedures. 
7.3 
Sample Storage and Shipment 
7.3.1 
Serum Samples 
For Immunogenicity 
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 
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during the entire trial. 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. 
In case a subject is found not eligible to participate by the study staff after the blood samples have 
been obtained but before the subject has been vaccinated, the subject’s blood sample will be 
discarded as per local standard practices and not stored.  
Shipments to the laboratories 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 International Air 
Transport Association (IATA) 602 regulations. 
Samples will be shipped to Global Clinical Immunology (GCI) at Sanofi Pasteur. The address is 
provided in the Operating Guidelines. Samples will be shipped outside the country only after 
approval from the relevant authorities. 
For CBC and Blood Chemistry (Sites in the Russian Federation Only) 
Blood samples for CBC and blood chemistry will be stored at ambient temperature and sent to the 
site’s local laboratory for testing. The testing will be done according to the site’s routine practice 
and standard procedures. 
7.3.2 
Urine Samples for Urine Chemistry (Sites in the Russian Federation Only) 
Samples will be prepared at ambient temperature and analyzed locally. The testing will be done 
according to the site’s routine practice and standard procedures. 
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. 
For Mexico, South Korea, and Thailand only: Depending on local regulations, subjects’ parents 
/ guardians will be asked to indicate in the ICF or country specific consent form 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 laboratory methods. Genetic tests will never be performed on these 
samples without individual informed consent.  
This does not apply to the Russian Federation. The unused stored serum samples from subjects in 
the Russian Federation will not be used for any testing other than that directly related to this 
study.  
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8 
Clinical Supplies 
Sanofi Pasteur will supply the trial sites with protocols, ICFs, CRFs, SAE reporting forms, diary 
cards, and other trial documents, as well as with the following trial materials: all study vaccines 
and injection materials, 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 trial. 
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, 
indicating the quantity required. Contact information is provided in the Operating Guidelines. 
They must allow approximately 1 week for an order to be filled and to have the supplies sent to 
their site. 
9 
Endpoints and Assessment Methods 
9.1 
Primary Endpoints and Assessment Methods 
9.1.1 
Immunogenicity 
9.1.1.1 
Immunogenicity Endpoints 
The primary endpoints for the evaluation of immunogenicity are: 
Antibody (Ab) titers against meningococcal serogroups A, C, Y, and W measured by serum 
bactericidal assay using human complement (hSBA) for Groups 1, 2, 4, 5, 7, 8, 10, and 11 at 
Visit 0 (for subjects in the Russian Federation) or Visit 1 (for subjects in Mexico, South Korea, 
and Thailand) (before vaccination[s]) and 30 days (+14 days) after vaccination(s) (all subjects). 
9.1.1.2 
Immunogenicity Assessment Methods 
 
 
 
 
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9.2.1.2 
Immunogenicity Assessment Methods 
The assay methods to be used are summarized below. Laboratory technicians conducting the 
immunogenicity assays will be blinded to the group to which each subject was assigned. 
Anti-Diphtheria, Tetanus and Pertussis Antibodies  
The assay for measuring anti-diphtheria, tetanus, and pertussis antibodies will be performed at 
GCI, Sanofi Pasteur, Swiftwater, PA, USA. 
The DTP (Diphtheria , Tetanus, and Pertussis) ECL (electrochemiluminescent) is a multiplexed 
serological assay which allows for the simultaneous quantification of human antibodies to 
6 specific antigens including diphtheria toxoid (DT), tetanus toxoid (TT), and four pertussis 
antigens: pertussis toxin, filamentous hemagglutinin (FHA), fimbriae types 2 and 3 (FIM2,3) and 
pertactin (PRN).  
In this assay, each well of a 96-well microtiter plate is pre-coated in precise positions with the 
6 different antigens in a multi-spot fashion. Following incubation with serum samples, antigen-
specific antibodies bind to the respective antigens. The captured antibodies are then detected using 
a sulfotag conjugated anti-human IgG conjugate. Electrical stimulation of the conjugate in the 
presence of a chemiluminescent substrate results in the generation of a light signal from each 
specific spot that is captured by a camera in relative light units (RLU). The signal generated is 
directly proportional to the amount of antibodies present in the sample, which is quantified using 
software and based on an established reference standard sample curve. 
The anti-diphtheria method will be performed only on BL2 samples collected from Groups 4 and 
6 only. 
The anti-tetanus method will be performed on BL1 and BL2 samples collected from Groups 4 and 
6 only. 
The anti-pertussis method will be performed on BL1 and BL2 samples collected from Groups 4 
and 6 only. 
Anti-Polio Antibodies 
The assay for measuring anti-polio antibodies will be performed at GCI, Sanofi Pasteur, 
Swiftwater, PA, USA. 
Anti-poliovirus types 1, 2, and 3 will be measured by neutralization assay. Serial dilutions of sera 
are mixed with challenge poliovirus and incubated with cultured Vero cells that are sensitive to 
poliovirus. Specific neutralizing Ab contained in the sera bind to and neutralize the challenge 
poliovirus. The neutralized poliovirus does not affect cellular viability and these cells continue to 
metabolize and release CO2, reducing the pH of the culture medium. Cell survival correlates with 
the change in the pH indicator (phenol red to yellow at pH ≤ 7.0) contained in the medium. In the 
absence of neutralizing Ab, the challenge poliovirus reduces cellular metabolism and CO2 
production. Therefore, the pH does not decrease and a color change is not detected. The poliovirus 
MIT measures the functional serum Ab response to poliovirus by utilizing Vero cells (African 
green monkey kidney cells) and wild type poliovirus strains 1, 2, and 3 (Mahoney, MEF-1, and 
Saukett, respectively) as the challenge virus. The Karber method is used to determine the serum 
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dilution that neutralized 50% of the challenge virus. Results are expressed as titers (1/dilution). 
The LLOQ of the anti-poliovirus types 1, 2, and 3 assays is 4 (1/dil). 
This method will be performed only on BL2 samples collected from Groups 4 and 6. 
Anti-Hepatitis B Antibodies 
The assay for measuring anti-hepatitis B antibodies will be performed at GCI, Sanofi Pasteur, 
Swiftwater, PA, USA. 
Anti-hepatitis B Ab will be measured by the commercially available VITROS ECi/ECiQ 
Immunodiagnostic System using chemiluminescence detection technology. The VITROS ECi 
Immunodiagnostic system uses an Ab mediated antigen sandwich formation to detect the presence 
of anti-hepatitis B surface antigen (HBsAg) total immunoglobulin in human serum. This involves 
the reaction of anti-HBsAg in the sample with plasma-derived HBsAg (ad and ay subtypes) 
coated onto the wells. A horseradish peroxidase (HRP)-labeled HBsAg conjugate (ad and ay 
subtypes) then complexes with the bound anti-hepatitis Bs (HepBs), forming an antigen sandwich. 
Substrate is then added which catalyzes HRP, producing light. The light signals are read by the 
VITROS ECi/ECiQ. Immunodiagnostic System and the amount of HRP conjugate bound is 
directly proportional to the concentration of anti-HepBs antibodies present in the sample. Results 
are reported in milli-international units (mIU)/mL by comparison to a calibrator provided by the 
manufacturer that has been calibrated according to the WHO First International Reference 
Preparation for Antibody to HBsAg (1977). The LLOQ is 5 mIU/mL. 
This method will be performed only on BL2 samples collected from Groups 4 and 6. 
Anti-Haemophilus influenza type b (Anti-PRP) Antibodies 
The assay for measuring anti-PRP antibodies will be performed at GCI, Sanofi Pasteur, 
Swiftwater, PA, USA. 
Anti-PRP concentrations will be measured using a Farr-type radioimmunoassay (RIA). Serum 
levels of anti-Haemophilus influenzae type b (Hib) Capsular Polysaccharide (PRP) Ab are 
determined by RIA, in which serum samples are incubated with radiolabeled PRP (3H-PRP) in the 
presence of 36Cl (volume marker). Specific Ab bind to tritiated capsular PS to form antigen-Ab 
complexes. These complexes are precipitated with ammonium sulfate and collected by 
centrifugation. The radioactivity is measured in the precipitated pellet, in counts per minute 
(CPM) and is proportional to the amount of anti-Hib capsular PS Ab present in the serum sample. 
The concentration of anti-PRP antibody in the serum sample is determined from the concentration 
response curve generated by the titration results of dilutions of the reference standard analyzed in 
the assay. Results are reported in µg/mL by comparison to the Center for Biologics Evaluation 
and Research (CBER), Lot No. 1983 reference standard. The LLOQ of the anti-PRP RIA is 
0.06 µg/mL. 
This method will be performed only on BL2 samples collected from Groups 4 and 6. 
Anti-Pneumococcal Antibodies 
The assay for measuring anti-pneumococcal antibodies will be performed at GCI, Sanofi Pasteur, 
Swiftwater, PA, USA. 
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The pneumococcal capsular PS (PnPS) IgG Electrochemiluminescent (ECL) assay is used to 
quantitate the amount of anti-Streptococcus pneumoniae PS (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 
9N, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F and 33F) antibodies in human serum. 
In this method, purified antigen of 8 PnPS are coated into defined spots within the wells of a 96-
well microtiter plate by MesoScale Discovery (MSD) using 3 types of plates to cover all 21 PnPS. 
Diluted serum samples (test samples, reference standard, and quality controls), pre-treated with 
pneumococcal cell wall absorbents (to reduce the interference of non-specific antibodies in the 
assay), are incubated in the wells. Specific antibodies in the serum samples bind to the 
immobilized antigen. Unbound antibodies are washed from the wells, and SULFO-TAG-
conjugated anti-human immunoglobulin is added. The antibody conjugate binds to the antigen-
antibody complex. Excess conjugate is washed away, and read buffer is added. The plate is read 
using electrochemiluminescence on an MSD imager. The intensity of the generated light is 
proportional to the amount of specific antibody bound to the antigen-coated spots. An 
international reference standard assayed on each plate is used to calculate the amount of anti-
pneumococcal IgG antibodies (µg/mL) in human serum. 
This method will be performed on BL1 and BL2 samples collected from Groups 7 and 9 only. 
Anti-Measles Antibodies 
The assay for measuring anti-measles antibodies will be performed by Merck, Richmond VA, 
USA. 
The measles EIA (enzyme immunoassay) detects total IgG antibody to measles virus. Plates are 
coated using inactivated measles antigen that is bound to solid phase microtiter plates. The 
antigen is derived from measles Edmonston strain-infected Vero cells. Serum or plasma is added 
to the coated plates and samples positive for measles antibodies will bind to the measles antigen-
coated plates, forming antibody-antigen complexes. The bound antibody-antigen complexes can 
then be detected using an alkaline phosphatase labeled anti-human IgG. Color development 
occurs as a result of the addition of an enzyme-specific substrate phenolphthalein monophosphate. 
The color intensity is then measured spectrophotometrically with the highest intensity of color 
correlating to a high level of measles antibody and lowest color intensity correlating to low levels 
of measles antibody. Measles specific titers (antibody concentration in mIU/mL) in the samples 
are determined by interpolation from a standard curve that is run on each assay plate. The 
serostatus cutoff for the measles assay is 120 mIU/mL. 
Anti-Mumps Antibodies 
The assay for measuring anti-mumps antibodies will be performed by Merck, Richmond, VA, 
USA. 
The mumps enzyme-linked immunosorbent assay (ELISA) detects IgG antibodies to mumps 
virus. The assay uses an earlier passage of the Jeryl Lynn® mumps virus (Jeryl Lynn® 135 
[JL135], < 12 passages) and is considered to be a wild-type (WT)-like strain. The reactivity of the 
sera to the mumps antigens prepared from JL135-infected Vero cells is subtracted from that of 
uninfected Vero cells (denoted as tissue culture control [TCC] wells). JL135 mumps virus antigen 
or TCC is bound to solid phase microtiter plates and serum containing mumps antibody is added. 
The mumps antibody bound to the WT mumps antigen-coated plates forms an antibody-antigen 
complex. The bound antibody-antigen complex is then detected using an enzyme-labeled anti-
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human IgG. Color development occurs with the addition of a substrate and color intensity is 
measured spectrophotometrically. Results are obtained as a difference of the average duplicate of 
each optical density (OD) of JL135 mumps antigen wells and the average duplicate OD of TCC 
wells for each serum sample (noted as delta optical density [DOD]). Quantitation of the human 
IgG antibody to mumps virus, or antibody concentration, is determined by comparison of the 
resulting test DOD to a standard curve. The serostatus cutoff for the mumps assay is 10 Mumps 
Ab units/mL. 
Anti-Rubella Antibodies 
The assay for measuring anti-rubella antibodies will be performed by Merck, Richmond, VA, 
USA. 
The rubella IgG EIA detects total IgG antibody to rubella virus. Plates are coated using 
inactivated rubella antigen that is bound to solid phase microtiter plates. The antigen is derived 
from Rubella HPV-77 infected Vero cells. Serum is added to the coated plate and samples 
positive for rubella antibodies will bind to the rubella antigen-coated plates, forming antibody-
antigen complexes. The bound antibody-antigen complexes can then be detected using an alkaline 
phosphatase labeled anti-human IgG. Color development occurs as a result of the addition of an 
enzyme-specific substrate, phenolphthalein monophosphate. The color intensity is then measured 
spectrophotometrically with the highest intensity of color correlating to a high level of rubella 
antibody and lowest color intensity correlating to low levels of rubella antibody. Rubella specific 
titers (antibody concentration in IU/mL) in the samples are determined by interpolation from a 
standard curve that is run on each assay plate. The serostatus cutoff for the rubella assay is 
10 IU/mL. 
Anti-Varicella Antibodies 
The assay for measuring anti-varicella antibodies will be performed by Merck, Richmond, VA, 
USA. 
The glycoprotein enzyme-linked immunosorbent assay (gpELISA) detects antibodies to varicella 
zoster virus (VZV). The assay detects antibodies to VZV glycoprotein (gp), which have been 
purified from MRC-5 cells infected with the KMcC strain of VZV by lectin affinity 
chromatography. The reactivity of the sera to the gp antigens from uninfected MRC-5 cells 
(denoted as TCC wells]) is subtracted from the reactivity of the sera to the gp antigens purified 
from VZV-infected MRC-5 cells. The concentration of serum antibody to the VZV gp antigen as 
determined by gpELISA is shown to correlate with neutralizing antibody concentrations. The 
assay uses the “second antibody” format with varicella glycoprotein (gp) antigen and MRC-5 
TCC glycoprotein coated on the solid phase microtiter plate. Diluted sera are dispensed into 
2 VZV gp antigen coated wells and 2 MRC5 gp coated wells for each standard curve point, 
control, and sample. Antibody to the varicella virus in a test sample binds to the antigen coated 
plate. Antibody to varicella glycoprotein in a test sample, bound to the antigen on the solid phase 
microtiter plate, is subsequently detected using goat anti-human IgG alkaline phosphatase 
conjugate. After substrate addition for color development, quantitation is obtained by comparison 
of sample DOD to a standard curve. The DOD is determined by subtracting the average OD of the 
TCC coated wells from its corresponding VZV gp average OD. Results for the assay are reported 
as concentration of antibody in gpELISA units/mL. The serostatus cutoff for the varicella assay is 
1.25 gpELISA Ab units/mL. 
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These anti-measles, mumps, rubella, and varicella methods will be performed on BL1 and BL2 
samples collected from Groups 1, 3, 10, and 12 only. 
9.2.2 
Safety 
There are no secondary objectives for safety. 
9.2.3 
Efficacy 
No clinical efficacy data will be obtained in the trial. 
9.3 
Observational Endpoints and Assessment Methods 
9.3.1 
Immunogenicity 
9.3.1.1 
Immunogenicity Endpoints 
Ab titers against meningococcal serogroups A, C, Y, and W measured by rSBA before and 
30 days (+14 days) after vaccination with MenACYW conjugate vaccine in 100 subjects from 
each of Groups 1, 4, and 7, and in 50 subjects from each of Groups 2, 5, and 8. 
9.3.1.2 
Immunogenicity Assessment Methods 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                 
a  T60: Time of incubation duration of 60 minutes 
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Sanofi Pasteur 
MET57 
395 – MenACYW Conjugate Vaccine 
Confidential/Proprietary Information 
Page 83 of 105 
Table 9.1: Solicited injection site reactions: terminology, definitions, and intensity scales 
 
CRF term 
(MedDRA lowest 
level term [LLT]) 
Injection site tenderness 
Injection site erythema 
Injection site swelling 
Diary card term 
Tenderness 
Redness 
Swelling 
Definition 
 
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: Minor reaction when injection site is 
touched 
Grade 2: Cries or protests when injection site is 
touched 
Grade 3: Cries when injected limb is moved, or 
the movement of the injected limb is reduced 
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 tenderness, parents / guardians will record the intensity level (Grade 1, 2, or 3) in the diary card. 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. 
Sanofi Pasteur 
 
 
Confidential/Proprietary Information 
                
 
MET57
395 – MenACYW Conjugate Vaccine
Protocol Version 4.0
Page 83 of 106

Sanofi Pasteur 
MET57 
395 – MenACYW Conjugate Vaccine 
Confidential/Proprietary Information 
Page 84 of 105 
 
Table 9.2: Solicited systemic reactions: terminology, definitions, and intensity scales 
CRF term 
(MedDRA lowest 
level term [LLT]) 
Fever 
Vomiting 
Crying abnormal  
Drowsiness 
Appetite lost 
Irritability 
Diary card term 
Temperature 
Vomiting 
Abnormal crying 
Drowsiness 
Loss of appetite 
Irritability 
Definition 
Elevation of 
temperature to 
≥ 38.0°C  
Vomiting does not include 
spitting up 
Inconsolable crying 
without a reason 
Reduced interest in 
surroundings, or 
increased sleeping 
See intensity scale 
An excessive response to 
stimuli: increased fussiness, 
whining, and fretfulness 
despite attempts to comfort 
the infant and despite 
caregiver responses that 
would normally be 
soothing 
Intensity scale* 
Grade 1:  
≥ 38.0°C to 
≤ 38.5°C 
 
Grade 1: 1 episode per 
24 hours 
Grade 1: < 1 hour 
Grade 1: Sleepier than 
usual or less interested in 
surroundings 
Grade 1: Eating less 
than normal 
Grade 1: Easily consolable 
 
Grade 2: 
> 38.5°C to 
≤ 39.5°C 
 
Grade 2: 2–5 episodes per 
24 hours 
Grade 2: 1–3 hours  
Grade 2: Not interested 
in surroundings or did 
not wake up for a feed / 
meal 
Grade 2: Missed 1 or 2 
feeds / meals completely 
Grade 2: Requiring 
increased attention 
 
Grade 3: > 39.5°C 
 
Grade 3: ≥ 6 episodes per 
24 hours or requiring 
parenteral hydration 
Grade 3: > 3 hours 
Grade 3: Sleeping most 
of the time or difficult to 
wake up 
Grade 3: Refuses ≥ 3 
feeds / meals or refuses 
most feeds / meals 
Grade 3: Inconsolable 
*  For all reactions but fever, parents / guardians will record the intensity level (Grade 1, 2, or 3) in the diary card. 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. 
Sanofi Pasteur 
 
 
Confidential/Proprietary Information 
                
 
MET57
395 – MenACYW Conjugate Vaccine
Protocol Version 4.0
Page 84 of 106

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Sanofi Pasteur 
MET57 
395 – MenACYW Conjugate Vaccine 
Confidential/Proprietary Information 
Page 90 of 105 
vaccination and the onset of the SAE is incompatible with a causal relationship; or the SAE 
started before the vaccination(s) (screening phase, if applicable). 
1 - Related: There is a “reasonable possibility” that the SAE was caused by the vaccination, 
meaning that there is evidence or arguments to suggest a causal relationship. 
(ICH Guidelines, Clinical Safety Data Management E2A) 
Following this, the Sponsor’s Product Safety Officer (PSO) will also assess the causal relationship 
to the product, based on the available information and current medical knowledge. 
The decision to modify or discontinue the trial 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 trial protocol. 
11 Data Collection and Management 
11.1 Data Collection and CRF Completion 
Individual safety diary cards, specifically designed for this trial by the Sponsor and provided to 
the study sites, will be given to study participants for the recording of daily safety information as 
described in Section 9.3.2.3. These diary cards 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 or guardians 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 / guardians 
on how to correctly use these tools. 
At specified intervals, the Investigator or an authorized designee will interview the parents / 
guardians to collect the information recorded in the diary card, and will attempt to clarify anything 
that is incomplete or unclear. All clinical trial information gathered by the study site will be 
reported electronically by the Investigator or authorized designee using a web-based CRF. (Any 
information that was not documented in the diary card will first be captured in the source 
document and then reported electronically.) The CRF has been designed specifically for this trial 
under the responsibility of the Sponsor, using a validated Electronic Records / Electronic 
Signature-compliant platform (21 CFR Part 11). 
Sanofi Pasteur 
 
Confidential/Proprietary Information 
                
MET57
395 – MenACYW Conjugate Vaccine
Protocol Version 4.0
Page 90 of 106

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Sanofi Pasteur 
MET57 
395 – MenACYW Conjugate Vaccine 
Confidential/Proprietary Information 
Page 92 of 105 
SAE Data Management  
During the trial, data pertaining to SAEs reported on eSAE Forms will be integrated into the 
Sponsor’s centralized GPV database. 
Upon receipt of an eSAE Form, the data will be entered into the GPV database after a duplicate 
check. Each SAE case will be assigned a case identification number. Each case will be entered in 
the GPV database and assessed by the case management platform or its delegate before being 
reported to the relevant authorities as necessary. Assessment of related cases will be done in 
collaboration with the PSO 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 pertaining to SAEs in the GPV database will be reconciled with that in the 
clinical database. 
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 Safety Management 
Team (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. 
In general, categorical variables will be summarized and presented by frequency counts, 
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 (49). For GMTs or geometric mean concentrations (GMCs), 
95% CIs of point estimates will be calculated using normal approximation assuming they are log-
normally distributed. 
12.1.1 Hypotheses and Statistical Methods for Primary Objective 
12.1.1.1 Hypotheses 
No hypotheses will be tested. Descriptive statistics will be presented. 
Sanofi Pasteur 
 
Confidential/Proprietary Information 
                
MET57
395 – MenACYW Conjugate Vaccine
Protocol Version 4.0
Page 92 of 106

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Sanofi Pasteur 
MET57 
395 – MenACYW Conjugate Vaccine 
Confidential/Proprietary Information 
Page 97 of 105 
13 Ethical and Legal Issues and Investigator / Sponsor Responsibilities 
13.1 Ethical Conduct of the Trial / Good Clinical Practice 
The conduct of this trial 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, medical and 
hospital records, screening logs, informed consent / assent forms, telephone contact logs, and 
worksheets. The purpose of trial source documents is to document the existence of subjects and to 
substantiate the integrity of the trial 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, the study coordinator will obtain verbal clarification 
from the subject, enter the response into the “investigator’s comment” page of the diary card, and 
transfer the information to the CRF. 
The subject pre-screening log should list all individuals contacted by the Investigators to 
participate in the trial, 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 later 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. 
13.3 Confidentiality of Data and Access to Subject Records 
Prior to initiation of the trial, the Investigator will sign a fully executed confidentiality agreement 
with Sanofi Pasteur. 
Sanofi Pasteur personnel (or designates), the IECs / IRBs, and regulatory agencies, including the 
US Food and Drug Administration (FDA), the Korean Ministry of Food and Drug Safety 
(MFDS), the Mexican Health Authority (Federal Commission for Protection against Sanitary 
Risks [COFEPRIS]), the Ministry of Health of the Russian Federation, and the Thai Food and 
Drug Administration require direct access to all study records, and will treat these documents in a 
confidential manner. 
                                                 
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. 
Sanofi Pasteur 
 
Confidential/Proprietary Information 
                
MET57
395 – MenACYW Conjugate Vaccine
Protocol Version 4.0
Page 97 of 106

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13.4.2 Audits and Inspections 
A quality assurance audit may be performed at any time by the Sponsor’s Clinical and Medical 
Quality Operations department (C&MQO) or by independent auditors to verify that the trial 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 trial documents during these inspections and audits. 
13.4.3 Archiving 
The Investigator must keep all trial documents after the completion or discontinuation of the trial, 
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, trial 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 trial documents upon less than 90 days advance written notification to the Sponsor. In 
addition, trial 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 trial 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 trial, including certificates attesting that satisfactory audit and inspection 
procedures have been carried out, 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 trial’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. 
13.6 Stipends for Participation 
The subject’s parent / guardian may be provided with a stipend or transportation aid according to 
local practice and regulations to compensate for the time and/or travel required for study visits 
and procedures. 
13.7 Publication Policy 
Data derived from this trial are the exclusive property of Sanofi Pasteur. Any publication or 
presentation related to the trial must be submitted to Sanofi Pasteur for review before submission 
of the manuscript. After publication of the results of the trial, any participating center may publish 
or otherwise use its own data provided that any publication of data from the trial gives recognition 
Sanofi Pasteur 
 
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to the trial 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 trial 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 trial are not to be considered confidential. 
Sanofi Pasteur’s review can be expedited to meet publication guidelines. 
 
Sanofi Pasteur 
 
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14 References List 
 
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WA, Offit PA, editors. Vaccines. 6th ed. Philadelphia (PA): Saunders (Elsevier); 2013:388-
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Harrison LH, Trotter CL, Ramsay ME. Global epidemiology of meningococcal disease. 
Vaccine. 2009;27(Suppl 2):B51-63. 
3 
Harrison OB, Claus H, Jiang Y, et al. Description and nomenclature of Neisseria 
meningitidis capsule locus. Emerg Infect Dis. 2013;19(4):566-73. 
4 
Pollard AJ. Global epidemiology of meningococcal disease and vaccine efficacy. Pediatr 
Infect Dis J. 2004;23(12 Supp):S274-9. 
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Kvalsvig AJ, Unsworth DJ. The immunopathogenesis of meningococcal disease. J Clin 
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Sidikou F, Djibo S, Taha MK, et al. Polymerase chain reaction assay and bacterial 
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Ibarz-Pavon AB, Gabastou J-M. Improving surveillance and characterization of 
meningococcal disease in Latin America and the Caribbean region: a collaborative research 
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meningitidis. Final Report 2010-2013. Available at URL: 
https://partners.sanofi.com/global/menactra/Documents/PAHO%20SIREVA%202%20Meni
ngococcal%20Surveillance%20Final%20Report.pdf. Accessed 18 May 2015. 
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Ceyhan M, Yildirim I, Balmer P, et al. A prospective study of etiology of childhood acute 
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16 
Boisier P, Nicolas P, Djibo S, et al. Meningococcal meningitis: unprecedented incidence of 
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Broker M, Jacobsson S, Kuusi M, et al. Meningococcal serogroup Y emergence in Europe: 
update 2011. Hum Vaccin Immunother. 2012;8(12):1907-11. 
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Cohn AC, MacNeil JR, Harrison LH, et al. Changes in Neisseria meningitidis disease 
epidemiology in the United States, 1998-2007: implications for prevention of 
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National Foundation for Infectious Diseases. Addressing the challenges of Serogroup B 
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2014.pdf. Accessed 11 June 2015. 
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complex associated with severe invasive disease in England and Wales. Health Protection 
Weekly Report. Vol 8 No 41 Published on: 24 October 2014. Available online: 
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Törös B, Thulin Hedberg S, Jacobsson S, Fredlund H, Olcén P, Mölling P. Surveillance of 
invasive Neisseria meningitidis with a serogroup Y update, Sweden 2010 to 2012. Euro 
Surveill. 2014;19(42):pii=20940. Available online: 
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2015. 
26 
Thulin Hedberg S, Törös B, Fredlund H, Olcén P, Mölling P. Genetic characterisation of the 
emerging invasive Neisseria meningitidis serogroup Y in Sweden, 2000 to 2010. Euro 
Surveill. 2011;16(23):pii=19885. Available online: 
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2015. 
27 
The European Meningococcal Disease Society (EMGM). 11th EMGM Meeting, 18-20 May 
2011. Ljubljana Slovenia. Poster P035, 037-040. 
Sanofi Pasteur 
 
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28 
Mustapha MM, Marsh JW, Harrison, LH. Global epidemiology of capsular group W 
meningococcal disease (1970-2015): Multifocal emergence and persistence of hypervirulent 
sequence type (ST)-11 clonal complex. Vaccine. 2016;34(13):1515-23. 
29 
Wilder-Smith A, Chow A, Goh KT. Emergence and disappearance of W135 meningococcal 
disease. Epidemiol Infect. 2010;138(7):976-8. 
30 
Zhou H, Liu W, Xu L, Deng L, Deng Q, Zhuo J, Shao Z. Spread of Neisseria meningitidis 
serogroup W clone, China. Emerg Infect Dis. 2013;19(9):1496-9. 
31 
Chiou CS, Liao JC, Liao TL, et al. Molecular epidemiology and emergence of worldwide 
epidemic clones of Neisseria meningitidis in Taiwan. BMC Infec Dis. 2006;6:25. 
32 
Raja NS, Parasakthi N, Puthucheary SD, Kamarulzaman A. Invasive meningococcal disease 
in the University of Malay Medical Centre, Kuala Lumpur, Malaysia. J Postgrad Med. 
2006;52(1):23-9. 
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Poovazhagi V, Devasena N. Neiserria Meningitis due to W135 strain from South India. J 
Infect Dis Ther. 2014;2(5):165. 
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Hayakawa K, Itoda I, Shimuta K, Takahashi H, Ohnishi M. Urethritis caused by novel 
Niesseria meningitidis serogroup W in man who has sex with men, Japan. Emerg Infect Dis. 
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Abad R, Lopez EL, Debbaq R, Vazquez JA. Serogroup W meningococcal disease: global 
spread and current affect on the Southern Cone in Latin America. Epidemiol Infect. 
2014;142(12):2461-70. 
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Safadi MA, O'Ryan M, Valenzuela Bravo MT, et al. The current situation of meningococcal 
disease in Latin America and updated Global Meningococcal Initiative (GMI) 
recommendations. Vaccine. 2015;33(48):6529-36. 
37 
Broker M, Jacobsson S, DeTora L, Pace D, Taha MK. Increase of meningococcal serogroup 
Y cases in Europe: a reason for concern? Hum Vaccin Immunother. 2012;8(5):685-8. 
38 
Centers for Disease Control and Prevention. Update: Guillain-Barré syndrome among 
recipients of Menactra meningococcal conjugate vaccine--United States, June 2005-
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Velentgas P, Amato AA, Bohn RL, et al. Risk of Guillain-Barré syndrome after 
meningococcal conjugate vaccination. Pharmacoepidemiol Drug Saf. 2012;21(12):1350-8. 
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43 
MMRII [package insert]. Whitehouse Station (NJ): Merck & Co., Inc. 
http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM
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VARIVAX [Summary of Product Characteristics] Maidenhead, (England): Sanofi Pasteur 
SA. https://www.medicines.org.uk/emc/medicine/15264 
45 
Prevenar 13 [Summary of Product Characteristics]. Manufacturer of biological active 
substance: Wyeth Pharmaceuticals Division of Pfizer Ireland Pharmaceuticals (Ireland). 
http://www.ema.europa.eu/ema/index.jsp%3Fcurl=pages/medicines/human/medicines/0011
04/human_med_001220.jsp%26murl=menus/medicines/index.jsp?curl=search.jsp&q=Preve
nar+13+SmPC&btnG=Search&mid=WC0b01ac058001d125 
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f 
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https://www.medicines.org.uk/emc/medicine/17494 
48 
Bonhoeffer J, Menkes J, Gold MS, de Souza-Brito G, Fisher MC, Halsey N, Vermeer P and 
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seven methods. Stat Med. 1998;17:857-72. 
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