A Descriptive, Phase IV, Open-label, Single-arm Multi-center Study to Assess the Immunogenicity and Safety of MenQuadfi® as a Booster Vaccine in Healthy Toddlers 12 to 23 Months of Age Who Had Been Primed With at Least 1 Dose of Another Quadrivalent Meningococcal Conjugate Vaccine, ie, Nimenrix® (MCV4-TT) or Menveo® (MCV4-CRM), in Infancy.
Phase: PHASE4
Conditions: Meningococcal Immunisation, Healthy Volunteers
Sponsor: Sanofi Pasteur, a Sanofi Company

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Clinical Study Protocol 
Protocol Title: 
A descriptive, Phase IV, open-label, single-arm multi-center study to assess the immunogenicity 
and safety of MenQuadfi® as a booster vaccine in healthy toddlers 12 to 23 months of age who 
had been primed with at least 1 dose of another quadrivalent meningococcal conjugate vaccine, ie, 
Nimenrix® (MCV4-TT) or Menveo® (MCV4-CRM), in infancy.  
Study Code: MEQ00086 
Amendment Number: Not applicable 
Compound: MenQuadfi® 
Brief Title: 
Study of immunogenicity and safety of MenQuadfi® as a booster vaccine in toddlers 12 to 23 
months, regardless of the quadrivalent meningococcal conjugate vaccine used for priming in 
infancy. 
Study Phase: Phase IV 
Sponsor Name and Legal Registered Address: 
Sanofi Pasteur  
14 Espace Henry Vallée, 69007 Lyon, France 
Manufacturer: 
Sanofi Pasteur Inc. 
Discovery Drive, Swiftwater, PA 18370-0187, USA 
Regulatory Agency Identifier Number: 
WHO UTN: U1111-1277-6838 
Protocol Version Number: 2.0 
Approval Date: 03 February 2023 
Responsible medical officer (RMO), and designee(s), and pharmacovigilance (PV) representative 
names and contact information will be provided separately. 
The study center(s), the investigators at each center, and the coordinating investigator(s) are also 
listed in a separate document. 
NCT Number: NCT05929651
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Document History   
 
Previous 
Version 
Date 
Comments 
1.0 
27 September 2022 
 Version submitted to IRB/IEC and was updated (to 
version 2.0) per review comments. Version 1.0 was not 
used in the study  
 
 
 
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Table of Contents 
DOCUMENT HISTORY ................................................................................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 3 
LIST OF TABLES ........................................................................................................................................... 7 
LIST OF FIGURES .......................................................................................................................................... 7 
1 
PROTOCOL SUMMARY ................................................................................................................. 8 
1.1 
SYNOPSIS ....................................................................................................................................... 8 
1.2 
SCHEMA ........................................................................................................................................ 13 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 15 
2 
INTRODUCTION ............................................................................................................................ 17 
2.1 
STUDY RATIONALE ...................................................................................................................... 17 
2.2 
BACKGROUND ............................................................................................................................. 18 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 18 
2.3.1 
Risks from Study Participation ....................................................................................................... 18 
2.3.2 
Benefits from Study Participation ................................................................................................... 21 
2.3.3 
COVID-19 Risk Assessment .......................................................................................................... 21 
2.3.4 
Overall Benefit-Risk Conclusion .................................................................................................... 21 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 22 
4 
STUDY DESIGN ............................................................................................................................ 24 
4.1 
OVERALL DESIGN ........................................................................................................................ 24 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 25 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 26 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 26 
5 
STUDY POPULATION .................................................................................................................. 27 
5.1 
INCLUSION CRITERIA .................................................................................................................. 27 
5.2 
EXCLUSION CRITERIA................................................................................................................. 27 
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5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 29 
5.4 
SCREEN FAILURES ...................................................................................................................... 29 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT / ADMINISTRATION OF 
STUDY INTERVENTION] .............................................................................................................. 30 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 31 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 31 
6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY ........................................... 32 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 33 
6.3.1 
Randomization and Allocation Procedures .................................................................................... 33 
6.3.2 
Blinding and Code-breaking Procedures ....................................................................................... 33 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 33 
6.5 
DOSE MODIFICATION .................................................................................................................. 33 
6.6 
CONTINUED ACCESS TO STUDY INTERVENTION AFTER THE END OF THE STUDY ......... 34 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 34 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 34 
6.8.1 
Rescue Medicine ............................................................................................................................ 35 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 36 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 36 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 36 
7.3 
LOST TO FOLLOW-UP ................................................................................................................. 37 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 38 
8.1 
EFFICACY AND IMMUNOGENICITY ASSESSMENTS ............................................................... 39 
8.1.1 
Efficacy Assessments .................................................................................................................... 39 
8.1.2 
Immunogenicity Assessments ....................................................................................................... 39 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 40 
8.2.1 
Medical History ............................................................................................................................... 40 
8.2.2 
Physical Examinations ................................................................................................................... 41 
8.2.3 
Vital Signs ...................................................................................................................................... 41 
8.2.4 
Clinical Safety Laboratory Tests .................................................................................................... 41 
8.2.5 
Pregnancy Testing ......................................................................................................................... 41 
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8.2.6 
Viremia/Vaccinemia ....................................................................................................................... 41 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS, AND OTHER SAFETY 
REPORTING .................................................................................................................................. 41 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ............................................ 42 
8.3.2 
Method of Detecting AEs and SAEs .............................................................................................. 43 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 43 
8.3.4 
Regulatory Reporting Requirements for SAEs .............................................................................. 43 
8.3.5 
Pregnancy ...................................................................................................................................... 44 
8.3.6 
Adverse Events of Special Interest ................................................................................................ 44 
8.4 
PHARMACOKINETICS .................................................................................................................. 44 
8.5 
GENETICS ..................................................................................................................................... 44 
8.6 
BIOMARKERS ............................................................................................................................... 45 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 45 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ........................................... 45 
8.9 
LEFTOVER BIOLOGICAL SAMPLES ........................................................................................... 45 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 45 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 47 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 47 
9.2 
ANALYSIS SETS ........................................................................................................................... 47 
9.3 
STATISTICAL ANALYSES ............................................................................................................ 48 
9.3.1 
General Considerations ................................................................................................................. 48 
9.3.2 
Immunogenicity Endpoints ............................................................................................................. 48 
9.3.3 
Safety Endpoints ............................................................................................................................ 49 
9.3.4 
Other Endpoints ............................................................................................................................. 49 
9.4 
INTERIM ANALYSES .................................................................................................................... 50 
9.5 
SAMPLE SIZE DETERMINATION ................................................................................................. 50 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 51 
10.1 
APPENDIX: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS .......... 51 
10.1.1 
Regulatory and Ethical Considerations .......................................................................................... 51 
10.1.2 
Financial Disclosure ....................................................................................................................... 52 
10.1.3 
Informed Consent Process ............................................................................................................ 52 
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10.1.4 
Data Protection .............................................................................................................................. 54 
10.1.5 
Committees Structure .................................................................................................................... 56 
10.1.6 
Dissemination of Clinical Study Data ............................................................................................. 57 
10.1.7 
Data Quality Assurance ................................................................................................................. 57 
10.1.8 
Source Documents ......................................................................................................................... 58 
10.1.9 
Study and Site Start and Closure ................................................................................................... 59 
10.1.10 Publication Policy ........................................................................................................................... 60 
10.2 
APPENDIX: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 61 
10.2.1 
Definition of SAE ............................................................................................................................ 61 
10.2.2 
Definition of AE .............................................................................................................................. 62 
10.2.3 
Recording and Follow-Up of AE and/or SAE ................................................................................. 65 
10.2.4 
Reporting of SAEs .......................................................................................................................... 67 
10.2.5 
Assessment of Intensity ................................................................................................................. 68 
10.2.5.1 Tables for Clinical Abnormalities .................................................................................................... 68 
10.2.5.1.1 
Solicited AR Intensity Grading Scale......................................................................................... 68 
10.2.5.1.2 
Serious and Non-serious Unsolicited AE Intensity Grading Scale ............................................ 71 
10.3 
APPENDIX: MEASURES FOR A REGIONAL OR NATIONAL EMERGENCY THAT IS 
DECLARED BY A GOVERNMENTAL AGENCY ........................................................................... 72 
10.4 
APPENDIX: RISK-BASED APPROACH ........................................................................................ 72 
10.5 
APPENDIX: ABBREVIATIONS ...................................................................................................... 73 
11 
REFERENCES ............................................................................................................................... 75 
12 
SPONSOR SIGNATURE PAGE .................................................................................................... 77 
 
 
 
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List of Tables  
Table 1.1: Schedule of activities .................................................................................................................... 15 
Table 2.1: Potential risks of clinical significance and risk management ....................................................... 19 
Table 3.1: Objectives and endpoints ............................................................................................................. 22 
Table 4.1: Overall design............................................................................................................................... 25 
Table 6.1: Study Intervention(s) Administered .............................................................................................. 31 
Table 10.1: Solicited injection site reactions: terminology, definitions, and intensity scales – Infants and 
toddlers aged ≤ 23 months ............................................................................................................................ 69 
Table 10.2: Solicited systemic reactions: terminology, definitions, and intensity scales – Infants and 
toddlers aged ≤ 23 months ............................................................................................................................ 70 
 
 
 
List of Figures  
Figure 1 – Graphical study design ................................................................................................................. 14 
 
 
 
 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol Title: 
A descriptive, Phase IV, open-label, single-arm multi-center study to assess the immunogenicity 
and safety of MenQuadfi® as a booster vaccine in healthy toddlers 12 to 23 months of age who 
had been primed with at least 1 dose of another quadrivalent meningococcal conjugate vaccine, ie, 
Nimenrix® (MCV4-TT) or Menveo® (MCV4-CRM), in infancy. 
Brief Title: 
Study of immunogenicity and safety of MenQuadfi® as a booster vaccine in healthy toddlers 12 to 
23 months, regardless of the quadrivalent meningococcal conjugate vaccine used for priming in 
infancy. 
Rationale: 
The objective of MEQ00086 study is to describe the immunogenicity and safety of MenQuadfi® 
(Meningococcal Polysaccharide [Serogroups A, C, Y, and W] Tetanus Toxoid (TT) Conjugate 
Vaccine, also identified as MenACYW conjugate vaccine or as MenACYW-TT) when 
administered as a booster dose in healthy toddlers 12 – 23 months of age who had been primed 
during the first year of life with at least 1 dose of another licensed quadrivalent meningococcal 
conjugate vaccine, either Nimenrix® (MCV4-TT) or Menveo® (MCV4 - CRM). The evidence 
generated from this study will provide reassurance that MenQuadfi® used as a booster dose in 
toddlers who had been primed with another licensed MCV4 vaccine will provide an adequate 
immune response and protection against invasive meningococcal disease (IMD). 
Objectives, Endpoints: 
 
Objectives 
Endpoints 
Immunogenicity 
Immunogenicity 
1) To describe the immune response to a booster 
dose of MenQuadfi® as measured by the 
serum bactericidal assay using human 
complement (hSBA) in toddlers aged 12-23 
months, who had been primed with at least 1 
dose of another MCV4 vaccine during 
infancy 
2) To describe the antibody responses to 
meningococcal serogroups A, C, W, and Y 
before and 1 month after a booster dose of 
1) 
hSBA antibody titers ≥ 1:8 (seroprotection) 
against meningococcal serogroups A, C, W 
and Y at D31 (+14 days) after booster 
vaccination with MenQuadfi®  
2) 
At Day (D)01 (baseline) before vaccination 
and at D31 [+14 days] after the 
administration of a booster dose of 
MenQuadfi® the following will be assessed 
for meningococcal serogroups A, C, W and Y 
as measured by hSBA: 
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MenQuadfi® as measured by hSBA and rSBA 
in toddlers 12-23 months of age who had been 
primed with at least 1 dose of another MCV4 
vaccine during infancy 
3) To describe the antibody responses to 
meningococcal serogroups A, C, W, and Y 
before and 1 month after a booster dose of 
MenQuadfi® as measured by hSBA and rSBA 
in toddlers 12-23 months of age who had been 
primed with 2 doses of another MCV4 
vaccine during infancy 
4) To describe the antibody responses to 
meningococcal serogroups A, C, W, and Y 
before and 1 month after a booster dose of 
MenQuadfi® as measured by hSBA and rSBA 
in toddlers 12-23 months of age who had been 
primed with 1 dose of another MCV4 vaccine 
during infancy 
5) To describe the antibody responses to tetanus 
toxoid before and 1 month after a booster 
dose of MenQuadfi® in toddlers 12-23 months 
of age who had been primed with at least 1 
dose of another MCV4 vaccine during 
infancy 
• 
Antibody titers against meningococcal 
serogroups A, C, W, and Y 
• 
Antibody titers ≥ 1:4 and ≥ 1:8 
• 
≥ 4-fold rise from pre-vaccination to 
post-vaccination  
• 
Vaccine seroresponse, defined as 
follows: 
• 
For a participant with a pre-
vaccination titer < 1:8, a 
post-vaccination titer ≥ 1:16 
• 
For a participant with a pre-
vaccination titer ≥ 1:8, a 
post-vaccination titer at least 4-fold 
greater that the pre-vaccination titer 
At Day (D)01 (baseline) before vaccination 
and at D31 [+14 days] after the administration 
of a booster dose of MenQuadfi® the 
following will be assessed for meningococcal 
serogroups A, C, W and Y as measured by 
rSBA: 
• 
Antibody titers against meningococcal 
serogroups A, C, W, and Y 
• 
Antibody titers ≥ 1:8 and ≥ 1:128  
• 
≥ 4-fold rise from pre-vaccination to 
post-vaccination  
• 
Vaccine seroresponse defined as follows: 
• 
For a participant with a pre-
vaccination titer < 1:8, a 
post-vaccination titer ≥ 1:32 
• 
For a participant with a pre-
vaccination titer ≥ 1:8, a 
post-vaccination titer at least 
4-fold greater that the 
pre-vaccination titer 
3) 
Same endpoints as described for endpoint #2 
4) 
Same endpoints as described for endpoint #2 
5) 
Antibody concentrations against tetanus 
toxoid at D01 (baseline) and at D31 
(+14 days) after the administration of a 
booster dose of MenQuadfi® 
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Safety 
Safety 
• 
To describe the safety profile of a booster 
dose of MenQuadfi® administered to 
toddlers 12-23 months of age who had 
been primed with at least 1 dose of another 
MCV4 vaccine during infancy 
• 
Presence of any unsolicited systemic 
adverse events (AEs) reported in the 
30 minutes after vaccination. 
• 
Presence of solicited (pre-listed in the 
participant’s diary card [DC] and case 
report form [CRF]) injection site reactions 
up to 7 days after vaccination. 
• 
Presence of solicited systemic reactions 
(pre-listed in the participant’s DC and 
CRF) up to 7 days after vaccination. 
• 
Presence of unsolicited AEs up to 30 days 
after vaccination. 
• 
Presence of serious adverse events (SAEs) 
[including AESIs], throughout the trial 
from Visit 1 to 30 days after study 
vaccination. 
Depending on the items, the endpoints recorded or 
derived could include: 
• 
Nature (Medical Dictionary for Regulatory 
Activities [MedDRA] preferred term), 
time of onset, duration/number of days of 
occurrence, intensity, relationship to the 
vaccine, whether the AE led to early 
termination from the study, outcome, and 
seriousness criterion 
 
Overall Design: 
This is a descriptive, Phase IV, open-label, single-arm, un-controlled, multi-center study to 
describe the immunogenicity and safety of a single dose of MenQuadfi® administrated as a 
booster vaccine in healthy toddlers 12 – 23 months of age who had been primed before study 
participation with at least 1 dose of another quadrivalent meningococcal conjugate vaccine, ie, 
Nimenrix® (MCV4-TT) or Menveo® (MCV4-CRM), in infancy.  
The eligible participant population for this booster vaccine administration will be recruited in 
Argentina from the general population who have received at least one of the 2 infant doses of 
quadrivalent meningococcal conjugate vaccine (Nimenrix® or Menveo®) recommended at 3-
months or at 5-months of age. 
All participants will receive a single booster dose of MenQuadfi® at Visit 1 on Day (D)01. 
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All participants will provide a 5 mL blood sample for immunogenicity assessments at D01, pre-
vaccination (baseline) and 1-month post booster vaccination at D31 (+14 days). 
Solicited AE information will be collected for 7 days after booster vaccination; unsolicited AE 
information will be collected from Visit 1 (D01) to Visit 2 (D31 [+14 days]), and SAE 
information (including AESIs), will be collected throughout the study period from D01 to D31 
(+14 days) after booster vaccination. 
 
Type of design 
Open-label, single-group, multi-center 
Phase 
IV 
Control method 
Un-controlled 
Study population 
Healthy toddlers aged 12 months to 23 months 
Countries 
Argentina 
Level and method of blinding 
open-label 
Study intervention assignment method 
No randomization 
Brief Summary: 
This study will evaluate the immunogenicity and safety of a single dose of MenQuadfi® 
administered as a booster vaccine in toddlers 12 – 23 months of age in Argentina who had been 
primed with at least 1 dose of the quadrivalent meningococcal conjugate vaccines Nimenrix® or 
Menveo® during infancy to protect against IMD.  
Study Duration: Approximately 1 month per participant.  
Treatment Duration: Participants will receive a single dose of MenQuadfi® at Visit 1. Participants 
will provide 2 blood samples, one at D01 (Visit 1) pre-vaccination and another at D31 (Visit 2) 
post-vaccination for the immunogenicity assessments. 
Visit Frequency: Study will include 2 visits at D01 (Visit 1) and at D31 (Visit 2), and 1 Telephone 
call (TC) for safety follow-up at D09 post study vaccination. 
Number of Participants: 
A total of approximately 180 participants (minimum of 30 evaluable participants from the 
low - enrolling of the 2 priming vaccines) are expected to be enrolled with the aim to obtain a total 
of 150 evaluable participants. 
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Intervention Groups and Duration: 
Eligible participants (12 – 23-month-old toddlers who had received at least one of two priming 
doses of either Nimenrix® or Menveo® vaccine during infancy as part of their routine 
immunization, before 12 months of age) will be assigned in an open-label design to receive a 
single booster dose of MenQuadfi® vaccine with an interval of at least 2 months after the last 
vaccination with Nimenrix® or Menveo®, as an intramuscular (IM) injection at D01. 
The duration of participation will be approximately 1 month for each participant. 
Study Intervention: 
Investigational medicinal product: MenACYW conjugate vaccine (MenQuadfi®): 
Meningococcal Polysaccharide (Serogroups A, C, W, and Y) Tetanus Toxoid Conjugate Vaccine 
(Sanofi Pasteur Inc., Swiftwater, PA, USA) 
• 
Form: Liquid solution 
• 
Composition: Each 0.5 milliliter (mL) dose of MenACYW conjugate vaccine was 
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 55 µg* 
*Tetanus toxoid protein quantity is approximate and dependent on the polysaccharide-to-protein ratio for the 
conjugates used in each formulation  
• 
Route of administration: Intramuscular (IM) injection 
Statistical Considerations: 
All analyses will be descriptive; no hypotheses will be tested.  
In general, categorical variables will be summarized and presented by frequency counts, 
proportion percentages, and CIs. The 95% CIs of point estimates will be calculated using the 
normal approximation for quantitative data and the Exact binomial distribution (Clopper-Pearson 
method) for percentages. For geometric mean titers (GMTs), 95% CIs of point estimates will be 
calculated using normal approximation assuming they are log-normally distributed. 
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For immunogenicity data, assuming that log10 transformation of the titers / concentrations follows 
a normal distribution, first, the mean and 95% confidence intervals (CIs) will be calculated on 
log10 (titers / concentrations) using the usual calculation for normal distribution, then antilog 
transformations will be applied to the results of calculations, to compute geometric mean titers / 
concentrations (GMTs / GMCs) and their 95% CIs. 
All immunogenicity analyses will be performed on the Per-Protocol Analysis Set (PPAS) and 
presented overall and by priming vaccine. Additional immunogenicity analyses will be performed 
on the full analysis set (FAS). Descriptive statistics will be provided for the hSBA and rSBA 
antibody titers against meningococcal serogroups (A, C, W, and Y) and for antibody 
concentrations against tetanus toxoid contained in MenACYW conjugate vaccine as a carrier 
protein. 
Safety analyses will be performed on the Safety Analysis Set (SafAS) and presented overall and 
by priming vaccine. The main parameters for the safety endpoints will be described by 95% CIs 
using the Exact binomial method (Clopper-Pearson method). 
Data Monitoring/Other Committee:  
No 
1.2 
SCHEMA  
The graphical design of MEQ00086 study is presented in Figure 1. 
 
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Figure 1 – Graphical study design  
 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
Table 1.1: Schedule of activities  
Phase IV Study, 2 Visits, 1 Vaccination, 2 Blood Samples, ~1 Month Duration Per Participant 
Visit/Contact 
Collection of 
information in the 
CRF 
Visit 1 
TC1§ 
Visit 2** 
Study timelines (days) 
 
D01 
D09 
D31 
Time windows (days) 
 
NA 
[+2 D] 
[+14 D] 
Visit procedures: 
 
 
 
 
Informed consent  
X 
X 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
Collection of demographic data 
X 
X 
 
 
Collection of Medical history 
X 
Significant  
Medical History 
X 
 
 
Collection of vaccination history 
X 
X 
 
 
Physical examination 
 
X 
 
X 
Pre-vaccination temperature 
 
X 
 
 
Review of temporary 
contraindications for blood 
sampling* 
X 
X 
 
X 
Allocation of participant number 
X 
X 
 
 
Blood sampling (BL)† [5 mL] 
X 
BL0001 
Pre-vac 
 
BL0002 
Vaccination (vac) 
X 
X 
 
 
Immediate surveillance (30 min) 
X 
X 
 
 
Diary card provided 
 
X 
 
 
Collection of solicited injection 
site and systemic reactions 
X 
X 
X 
 
Collection of unsolicited adverse 
events (AEs) 
X 
X 
X 
X 
Diary card collected 
 
 
 
X 
Collection of concomitant 
medications 
X 
Reportable 
concomitant 
medication 
X 
X 
X 
Collection of SAEs, including 
adverse events of special interest 
(AESIs) 
X 
To be reported at any time during the study from D01 
to D31 (+14 days) after study vaccination 
End of Active Phase participation 
record‡ 
X 
 
 
X 
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AESI: Adverse Events of Special Interest; CRF: case report form; SAE: Serious Adverse Events 
* Should a participant receive oral or injectable antibiotic therapy within 3 days prior to each blood draw, the Investigator will 
postpone that blood draw until it has been 3 days since the participant last received oral or injectable antibiotic therapy. 
Postponement is still to be within the timeframe for blood draw (30 to 44 days after vaccination at D01). If postponement will 
result in the sample collection falling outside of the appropriate timeframe, the blood sample should be collected without 
postponement, and it should be documented appropriately that the sample was taken less than 3 days after stopping antibiotic 
treatment 
† Blood sample at D01 will be drawn before administration of the vaccine  
‡In case of participant discontinuation at a visit, the entire visit will be completed. Active Phase is from Visit 1 to Visit 2 
completion. 
§ The Investigator or an authorized designee will remind the parents, guardians, or legally acceptable representatives to bring back 
the diary card (DC) at the next visit and will answer any questions. If D09 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 
SAEs (including AESIs) not yet reported and will remind the subject's parent/guardian to continue using the diary card, to bring 
the diary card to the study center at the next visit and confirm the date and time of the next visit. 
**The Investigator or an authorized designee will interview the parents, guardians, or legally acceptable representatives to collect 
the information recorded in the DC and will attempt to clarify anything that is incomplete or unclear. 
 
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2 
INTRODUCTION  
The investigational quadrivalent Meningococcal Polysaccharide (serogroups A, C, W, and Y) 
Tetanus Toxoid Conjugate Vaccine (also known as MenQuadfi®) was designed for the 
immunization of individuals of all ages (infants 6 weeks of age and older through and including 
older adults ≥ 56 years of age) against invasive meningococcal disease (IMD). The purpose of the 
vaccine is to provide broad coverage against circulating meningococcal strains from serogroups 
A, C, W, and Y. Compared to a previous Sanofi Pasteur meningococcal conjugate vaccine, 
Menactra®, MenACYW conjugate vaccine is prepared using tetanus toxoid as the carrier protein. 
Conjugation of polysaccharide antigens to a protein carrier can induce T-cell-dependent immune 
responses, which are anticipated to give rise to higher antibody titers, longer duration of the 
immune response, and enhanced immunologic memory that allows for a booster response. 
The goal for the MenACYW conjugate vaccine is to provide broad protection against IMD caused 
by serogroups A, C, W, and Y in all age groups including children as young as 6 weeks of age, 
adolescents, and adults, including those 56 years of age and older. Clinical studies are ongoing to 
support an extension of the licensure in individuals from 6 weeks of age and older. 
The clinical development program targets licensure of the MenACYW conjugate vaccine in many 
countries in North America, Europe, Latin America, Africa, the Middle East, and Asia Pacific. It 
has been licensed for active immunization of individuals from 2 years of age in the United States 
(US) since April 2020, and for active immunization of individuals from 12 months of age in in the 
European Union (EU) since November 2020. The MenACYW conjugate vaccine has also been 
approved in Argentina (May 2021) in individuals from 12 months of age. 
MenACYW conjugate vaccine has been evaluated in over 7500 participants (infants, toddlers, 
adolescents, and adults, including those > 56 years of age) in completed Phase II and Phase III 
studies. In these studies, the MenACYW conjugate vaccine was found to be well tolerated and did 
not reveal any apparent safety concerns. Phase III studies are ongoing to investigate the vaccine in 
infants from 6 weeks of age. 
2.1 
STUDY RATIONALE  
The objective of MEQ00086 study is to describe the immunogenicity and safety of the 
MenACYW conjugate vaccine when administered as a booster dose in healthy toddlers 12 – 23 
months of age who had been primed during the first year of life with at least 1 dose of another 
licensed quadrivalent meningococcal conjugate vaccine, either Nimenrix® (MCV4-TT) or 
Menveo® (MCV4-CRM), according to the immunization practices in Argentina. The purpose is to 
demonstrate that the MenACYW conjugate vaccine booster vaccination will elicit a strong 
immune response in toddlers who had been primed with either Nimenrix® or Menveo®. The 
evidence generated from this study may provide assurance that the MenACYW conjugate vaccine 
used as a booster dose in toddlers primed with another licensed MCV4 may provide adequate 
immune response and protection against IMD. 
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2.2 
BACKGROUND  
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). Some age groups are disproportionately affected by IMD, with major peaks of IMD 
incidence occurring in infants, adolescents and young adults. 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. Worldwide, most cases of 
meningococcal disease are caused by serogroups A, B, C, X, Y, and W (2) (3) (4).  
The epidemiology of N. meningitidis can be described as complex, unpredictable, geographically 
variable, and changing over time. IMD occurs worldwide in both endemic and epidemic forms 
with seasonal variation. 
A retrospective observational study based on four Argentinean national databases (National 
Surveillance system, hospital, vital statistics, and laboratory network) reported an average number 
of IMD cases of up to 450 per year between 2007 to 2016, after adjusting by improved bacterial 
culture methods and PCR, and a mean mortality rate of 0.098 per 100 000 habitants. The 
percentage of the two most common serogroups, B and W represented together an average of 89% 
of all cases of N. meningitidis infections characterized by the National Reference Laboratory 
between 2008 and 2016. The peak number and incidence rates of estimated IMD cases occurred in 
the age group <1 year, followed by the age group 1 to 4 years (5). It is estimated that the incidence 
declined from 0.75/100,000 in 2012 to 0.28/100,000 in 2016. There has not been new data 
published since 2017, when the MenACWY conjugate vaccine was introduced in the National 
Immunization Program (NIP) for infants at 3, 5 and 15 months, with a dose for adolescents at 11 
years of age (6). 
2.3 
BENEFIT/RISK ASSESSMENT  
More detailed information about the known and expected benefits and risks, reasonably expected 
adverse events (AEs), the potential risks, and uncertainties of MenACYW conjugate vaccine may 
be found in the Investigator’s Brochure (IB), Participant Information Leaflet, Package Insert, or 
Summary of Product Characteristics. 
2.3.1 Risks from Study Participation  
The potential risks of clinical significance and risk management are summarized in Table 2.1. 
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Table 2.1: Potential risks of clinical significance and risk management  
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Risk Management 
Investigated Vaccine: MenACYW conjugate vaccine  
Anaphylaxis 
Known important risk occurring 
at a low frequency (very rare) 
based on what would be 
common for any vaccine. 
 
One case of anaphylaxis was 
reported 10 minutes after 
receiving the second dose of 
MenQuadfi® given alone in 
study MET52. While temporal 
relationship was consistent with 
causal association to MenACYW 
conjugate vaccine and 
anaphylaxis has been reported 
with association to immunization 
in general, causality was 
assessed as related. 
Observation period after 
vaccination for early detection 
and treatment. 
 
Exclusion criteria: Known 
systemic hypersensitivity to any 
of the study intervention 
components, or history of a life-
threatening reaction to the study 
intervention used in the study or 
to a product containing any of 
the same substances. 
Guillain-Barré syndrome 
Important potential risk-based on 
post-marketing experience for 
other quadrivalent 
meningococcal conjugate 
vaccines occurring with a low 
frequency (very rare) with no 
definite evidence of excess risk 
identified in population based 
study (7) (8) (9). A review by 
the Institute of Medicine found 
inadequate evidence to accept or 
reject a causal relationship 
between tetanus toxoid-
containing vaccines and 
Guillain-Barré syndrome (10). 
No cases with MenACYW 
conjugate vaccine in the 
completed studies. 
Exclusion criteria: Personal 
history of Guillain-Barré 
syndrome 
Bell’s palsy 
 
Refer to IB Section 6 for more 
information regarding potential 
risks 
Important potential risk-based on 
post-marketing experience for 
other quadrivalent 
meningococcal conjugate 
No risk mitigation actions 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Risk Management 
vaccines occurring at a low 
frequency (very rare).  
A post-marketing observational 
safety study conducted in a US 
health maintenance organization 
found a statistically significant 
association with Bell’s palsy 
when a licensed quadrivalent 
meningococcal conjugate 
vaccine (MCV4-CRM 
[Menveo®]) was administered 
concomitantly with other 
vaccines (tetanus, diphtheria, and 
acellular pertussis [Tdap], 
human papillomavirus [HPV], 
and/or influenza vaccine), while 
no association was found when 
the vaccine was administered 
alone (11). This study used a 
longer risk interval than used in 
previous studies, beyond the 
biologically plausible and widely 
accepted risk interval of 42 days. 
No cases with MenACYW 
conjugate vaccine within 42 days 
of vaccination in the completed 
studies. 
Study Procedures 
Vasovagal reactions (fainting) 
Syncope can occur following, or 
even before, any vaccination or 
blood draw as a psychogenic 
response to the needle injection, 
most commonly in the 
adolescent age group (12). 
Cases of vasovagal-like response 
(eg, dizziness) or syncope have 
been observed infrequently in 
adolescent or young adult study 
participants within 30 minutes of 
vaccination with MenACYW 
conjugate vaccine. 
Observation period after 
vaccination for early detection 
and treatment. Procedures should 
be in place to prevent falling 
injury and manage syncopal 
reactions. 
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2.3.2 Benefits from Study Participation  
There might be no direct benefit from receiving MenACYW conjugate vaccine. 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 participants 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. 
As with any vaccine, MenACYW conjugate vaccine may not protect 100% of individuals against 
the disease they are designed to prevent. 
2.3.3 COVID-19 Risk Assessment  
MenACYW conjugate vaccine is a vaccine against IMD. MenACYW conjugate vaccine would 
not cause immune suppression. Therefore, the risk that a participant in this trial will contract 
COVID solely due to the administration of the study intervention(s) will be similar to the risk that 
a person not participating in this trial will contract COVID. However, the risk of exposure to 
infected people cannot be completely excluded as the participants may need to be exposed to 
public areas (eg, commute to/from the site and at the site).  
Risk Mitigation:  
• Not start the study until the local confinement measures or other safety restrictions linked 
to the COVID-19 pandemic are lifted by the local Authorities.  
• Continued risk assessment by the investigator and Sponsor before deciding to start the 
trial.  
• Reduce the public exposure while ambulatory when possible. 
2.3.4 Overall Benefit-Risk Conclusion  
Considering the measures taken to minimize risk to participants enrolled in this study, the 
potential risks that may result from study participation are balanced by the anticipated benefits 
that may be afforded to participants.  
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3 
OBJECTIVES AND ENDPOINTS  
The study objectives and the corresponding endpoints are described in Table 3.1. 
Table 3.1: Objectives and endpoints  
Objectives 
Endpoints 
 
 
Immunogenicity 
1) 
To describe the immune response 
to a booster dose of MenQuadfi® 
as measured by the serum 
bactericidal assay using human 
complement (hSBA) in toddlers 
aged 12-23 months, who had been 
primed with at least 1 dose of 
another MCV4 vaccine during 
infancy 
2) 
To describe the antibody responses 
to meningococcal serogroups A, C, 
W, and Y before and 1 month after 
a booster dose of MenQuadfi® as 
measured by hSBA and rSBA in 
toddlers 12-23 months of age who 
had been primed with at least 1 
dose of another MCV4 vaccine 
during infancy 
3) 
To describe the antibody responses 
to meningococcal serogroups A, C, 
W, and Y before and 1 month after 
a booster dose of MenQuadfi® as 
measured by hSBA and rSBA in 
toddlers 12-23 months of age who 
had been primed with 2 doses of 
another MCV4 vaccine during 
infancy 
4) 
To describe the antibody responses 
to meningococcal serogroups A, C, 
W, and Y before and 1 month after 
a booster dose of MenQuadfi® as 
measured by hSBA and rSBA in 
toddlers 12-23 months of age who 
had been primed with 1 dose of 
Immunogenicity 
1) 
hSBA antibody titers ≥ 1:8 (seroprotection) against 
meningococcal serogroups A, C, W and Y at D31 
(+14 days) after booster vaccination with 
MenQuadfi®  
2) 
At Day (D)01 (baseline) before vaccination and at 
D31 [+14 days] after the administration of a 
booster dose of MenQuadfi® the following will be 
assessed for meningococcal serogroups A, C, W 
and Y as measured by hSBA: 
• 
Antibody titers against meningococcal 
serogroups A, C, W, and Y 
• 
Antibody titers ≥ 1:4 and ≥ 1:8 
• 
≥ 4-fold rise from pre-vaccination to post-
vaccination  
• 
Vaccine seroresponse, defined as follows: 
• 
For a participant with a pre-vaccination 
titer < 1:8, a post-vaccination titer ≥ 1:16 
• 
For a participant with a pre-vaccination 
titer ≥ 1:8, a post-vaccination titer at 
least 4-fold greater that the 
pre-vaccination titer 
At Day (D)01 (baseline) before vaccination and at 
D31 [+14 days] after the administration of a 
booster dose of MenQuadfi® the following will be 
assessed for meningococcal serogroups A, C, W 
and Y as measured by rSBA: 
• 
Antibody titers against meningococcal 
serogroups A, C, W, and Y 
• 
Antibody titers ≥ 1:8 and ≥ 1:128  
• 
≥ 4-fold rise from pre-vaccination to post-
vaccination  
• 
Vaccine seroresponse defined as follows: 
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Objectives 
Endpoints 
another MCV4 vaccine during 
infancy 
5) 
To describe the antibody responses 
to tetanus toxoid before and 1 
month after a booster dose of 
MenQuadfi® in toddlers 12-23 
months of age who had been 
primed with at least 1 dose of 
another MCV4 vaccine during 
infancy 
 
• 
For a participant with a pre-vaccination 
titer < 1:8, a post-vaccination titer ≥ 1:32 
• 
For a participant with a pre-vaccination 
titer ≥ 1:8, a post-vaccination titer at 
least 4-fold greater that the 
pre-vaccination titer 
3) 
Same endpoints as described for endpoint #2 
4) 
Same endpoints as described for endpoint #2 
5) 
Antibody concentrations against tetanus toxoid at 
D01 (baseline) and at D31 (+14 days) after the 
administration of a booster dose of MenQuadfi® 
 
 
Safety 
• 
To describe the safety profile of a 
booster dose of MenQuadfi® 
administered to toddlers 12-23 
months of age who had been 
primed with at least 1 dose of 
another MCV4 vaccine during 
infancy 
Safety 
• 
Presence of any unsolicited systemic adverse 
events (AEs) reported in the 30 minutes after 
vaccination. 
• 
Presence of solicited (pre-listed in the participant’s 
diary card [DC] and case report form [CRF]) 
injection site reactions up to 7 days after 
vaccination. 
• 
Presence of solicited systemic reactions (pre-listed 
in the participant’s DC and CRF) up to 7 days after 
vaccination. 
• 
Presence of unsolicited AEs up to 30 days after 
vaccination. 
• 
Presence of SAEs [including AESIs], throughout 
the trial from Visit 1 to 30 days after study 
vaccination. 
Depending on the items, the endpoints recorded or 
derived could include: 
Nature (Medical Dictionary for Regulatory Activities 
[MedDRA] preferred term), time of onset, 
duration/number of days of occurrence, intensity, 
relationship to the vaccine, whether the AE led to early 
termination from the study, outcome, and seriousness 
criterion 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a descriptive, Phase IV, open-label, single-arm, un-controlled, multi-center study to 
describe the immunogenicity and safety of a single dose of the MenACYW conjugate vaccine 
administrated as a booster vaccine in healthy toddlers 12 – 23 months of age who had been primed 
before study participation with at least 1 dose of another quadrivalent meningococcal conjugate 
vaccine, ie, Nimenrix® (MCV4-TT) or Menveo® (MCV4-CRM), in infancy.  
The eligible participant population for this booster vaccine administration will be recruited in 
Argentina from the general population who have received at least one of the 2 infant doses of 
quadrivalent meningococcal conjugate vaccine (Nimenrix® or Menveo®) recommended at 3-
months or at 5-months of age. 
All participants will receive a single booster dose of the MenACYW conjugate vaccine at Visit 1 
on Day (D)01. 
All participants will provide a 5 mL blood sample for immunogenicity assessments at D01, pre-
vaccination (baseline) and 1-month post booster vaccination at D31 (+14 days). 
Solicited AE information will be collected for 7 days after booster vaccination; unsolicited AE 
information will be collected from Visit 1 (D01) to Visit 2 (D31 [+14 days]), and SAE 
information (including AESIs), will be collected throughout the study period from D01 to D31 
(+14 days) after study vaccination. 
The design of the study is summarized in Table 4.1. 
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Table 4.1: Overall design  
Type of design 
Open-label, single-group, multi-center 
Phase 
IV 
Control method 
Un-controlled 
Study population 
Healthy toddlers aged 12 months to 23 months 
Level and method of blinding 
Open-label 
Study intervention assignment method 
No randomization 
Number of participants 
A total of approximately 180 participants (minimum of 
30 evaluable participants from the low - enrolling of the 
2 priming vaccines) are expected to be enrolled with the 
aim to obtain a total of 150 evaluable participants. 
Intervention groups 
All eligible participants (12 – 23-month-old toddlers 
who had received at least one of two priming doses of 
either Nimenrix® or Menveo® vaccine during infancy as 
part of their recommended immunization, before 12 
months of age) will be assigned in an open-label design 
to receive a single booster dose of the MenACYW 
conjugate vaccine with an interval of at least 2 months 
after the last vaccination with Nimenrix® or Menveo®, as 
an intramuscular (IM) injection at D01. 
Total duration of study participation 
The duration of each participation will be approximately 
1 month for each participant 
Countries 
Argentina 
Use of an Independent Data Monitoring 
Committee, Dose Escalation Committee, or 
similar review group 
No 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
The clinical development of MenACYW conjugate vaccine started in 2006 with the objective to 
provide protection against 4 serogroups (A, C, Y, and W) that cause IMD, in all population age 
groups, including infant as young as 6 weeks of age and including adults 56 years of age and 
older. 
The MenACYW conjugate vaccine is prepared using tetanus toxoid as the carrier protein. 
Conjugation of polysaccharide antigens to a protein carrier can induce T cell-dependent immune 
responses, which are anticipated to give rise to higher antibody titers, longer duration of the 
immune response, and enhanced immunologic memory that allows for a booster response. 
The first marketing authorization for MenACYW conjugate vaccine was obtained in the US on 
23 April 2020 (international birth date) and is currently licensed in more than 40 countries 
including the EU, under centralized procedure. The initial licensures of this vaccine cover age 2 
years and above in the US and age 12 months and above in Europe, Canada, Australia and 
Argentina, with a single injection. Studies are ongoing to support the extension of indication from 
6 weeks of age. 
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In the private vaccination clinics and NIP, MenACWY vaccination is included in the 
immunization calendar with a 2+1 schedule (at 3-, 5-, and 15-months) and a single dose at 11 
years of age. 
In Argentina, Menveo® and Nimenrix® are approved for use from 2-months of age and 6-weeks of 
age, respectively, and therefore can be used for the MenACWY vaccination schedule at 3-, 5-, and 
15-18 months of age. While clinical studies are currently ongoing at Sanofi Pasteur to extend the 
indication of MenQuadfi® from 6 weeks of age, the current approval is for use in individuals 12 
months of age and older. In this context, it is interesting to generate evidence that the MenACYW 
conjugate vaccine can be used as a booster dose in toddlers primed with Menveo® or Nimenrix®. 
Mixing vaccines or vaccine interchangeability is when similar vaccines from different 
manufacturers authorized with the same indications are used for a vaccination series to complete a 
vaccination course (13). This can be in circumstances such as vaccine shortages, or when the 
details of initial vaccination are not known.  
Different MenACWY vaccines are licensed, and even if it is preferable to use the same brand of 
MenACWY vaccine when giving subsequent doses, especially for completing a primary 
vaccination course for young children, any of the licensed quadrivalent meningococcal vaccine 
may be used regardless of which meningococcal vaccine was used for initial vaccination, 
according to the US recommendations of the Advisory Committee on Immunization Practices 
(ACIP) (14), or the Meningococcal vaccines – FAQ | NCIRS Fact sheet issued by the Australian 
National Centre for Immunization Research and Surveillance (15), or the Meningococcal vaccine: 
Canadian Immunization Guide (13). 
It should be noted that current vaccines offering protection from meningococcal serogroup B 
disease are not interchangeable as these vaccines contain different antigens, and the same vaccine 
product is required for all priming and booster doses (13).  
4.3 
JUSTIFICATION FOR DOSE  
All participants will receive a single dose of MenACYW conjugate vaccine on D01 as per the 
current/intended recommendation of booster dose in this age group for quadrivalent 
meningococcal conjugate vaccination. 
4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed the last visit 
planned in the SoA. 
The end of the study is defined as the date of the last visit of the last participant in the study. 
However, for periodic safety reports, the study is considered completed when the clinical study 
report is finalized. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
There are no screening criteria other than the inclusion and exclusion criteria. 
5.1 
INCLUSION CRITERIA  
Participants are eligible for the study only if all of the following criteria are met: 
Age 
I01: 
Aged 12 to 23 months on the day of inclusiona 
Type Of Participant And Disease Characteristics 
I02: 
Participants who are healthy as determined by medical evaluation including medical 
history, physical examination, and judgment of the Investigator 
I03: 
Received at least one priming dose of licensed Nimenrix® or Menveo® vaccine during 
infancy before 12 months of age with an interval of at least 2 months between the last 
vaccination with Nimenrix® or Menveo® and the MenQuadfi® booster dose 
Informed Consent 
I04: 
Informed consent form has been signed and dated by the parent(s) or other legally 
acceptable representative and by an independent witness, if required by local regulations 
Other Inclusions 
I05: 
Participant and parent/legally acceptable representative(s) are able to attend all scheduled 
visits and to comply with all study procedures 
I06: 
Covered by health insurance, if required by local regulations 
5.2 
EXCLUSION CRITERIA  
Participants are not eligible for the study if any of the following criteria are met: 
                                                 
a  “12 to 23 months” means from the day of the 12th month after birth to the day before the 24th month after 
birth  
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Medical Conditions 
E01: 
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) 
E02: 
History of meningococcal infection, confirmed either clinically, serologically, or 
microbiologically 
E03: 
At high risk for meningococcal infection during the study (specifically but not limited to 
participants with persistent complement deficiency, with anatomic or functional asplenia, 
or participants traveling to countries with high endemic or epidemic disease) 
E04: 
Personal history of Guillain-Barré syndrome 
E05: 
Personal history of an Arthus-like reaction after vaccination with a tetanus toxoid-
containing vaccine 
E06: 
Known systemic hypersensitivity to any of the study intervention components, or history 
of a life-threatening reaction to the study intervention used in the study or to a product 
containing any of the same substancesb  
E07: 
Laboratory-confirmed thrombocytopenia, or known suspected thrombocytopenia, as 
reported by the parent/legally acceptable representative, contraindicating intramuscular 
injection  
E08: 
Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, 
contraindicating intramuscular injection 
E09: 
Chronic illness that, in the opinion of the investigator, is at a stage where it might 
interfere with study conduct or completionc 
E10: 
Moderate or severe acute illness/infection (according to investigator judgment) or febrile 
illness (temperature ≥ 38.0°C [≥ 100.4°F]) on the day of study intervention 
administration. A prospective participant should not be included in the study until the 
condition has resolved or the febrile event has subsided 
                                                 
b  
The components of study intervention are listed in Section 6.1 of the protocol and in the 
Investigator’s Brochure.  
c  Chronic illness may include, but is not limited to, cardiac disorders, renal disorders, auto-immune 
disorders, diabetes, psychiatric disorders or chronic infection 
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Prior/Concomitant Therapy 
E11: 
Receipt of any vaccine (including COVID-19 vaccines) in the 4 weeks preceding the 
study intervention administration or planned receipt of any vaccine (including COVID-
19 vaccines) in the 4 weeks following the study intervention administration except for 
influenza vaccination, which may be received at least 2 weeks before or 2 weeks after the 
study intervention. This exception includes monovalent pandemic influenza vaccines 
and multivalent influenza vaccines. 
E12: 
Previous vaccination with a Meningococcal C vaccine or Meningococcal B (MenB) 
vaccine 
E13: 
Receipt of immunoglobulins, blood or blood-derived products in the past 3 months 
E14: 
Receipt of oral or injectable antibiotic therapy within 72 hours prior to the first blood 
draw 
Prior/Concurrent Clinical Study Experience 
E15: 
Participation at the time of study enrollment (or in the 4 weeks preceding the study 
intervention administration) or planned participation during the present study period in 
another clinical study investigating a vaccine, drug, medical device, or medical procedure 
Other Exclusions 
E16: 
Participant is in an emergency setting, or hospitalized involuntarily 
E17: 
Identified as a natural or adopted child of the Investigator or employee with direct 
involvement in the proposed study 
If the participant has a primary physician who is not the Investigator, the site should contact this 
physician with the participant’s consent to inform him / her of the participant’s participation in the 
study. In addition, the site should ask this primary physician to verify exclusion criteria relating to 
previous therapies, such as receipt of blood products or previous vaccines. 
5.3 
LIFESTYLE CONSIDERATIONS  
No other restrictions than the ones listed in the exclusion criteria or in the contraindications for 
subsequent vaccinations are required. 
5.4 
SCREEN FAILURES  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently assigned to study intervention. Screening information is recorded in the source 
documents. 
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Individuals who do not meet the criteria for participation in this study (screen failure) can be 
rescreened when the condition excluding them from participation is resolved (eg, fever, antibiotics 
received within 72 hours, etc). 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT / ADMINISTRATION OF 
STUDY INTERVENTION]  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures proposed in 
Appendix 10.3: Contingency measures for a regional or national emergency that is declared by a 
governmental agency should be considered for enrollment/randomization/administration of study 
intervention. 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
Note: Vaccines or products administered outside of study protocol are not considered as study 
interventions and are reported in the CRF as reportable medications (see Section 6.8). Study 
procedures (eg, blood sampling) are also not considered as study interventions. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Study interventions are described in Table 6.1. 
Table 6.1: Study Intervention(s) Administered  
Intervention Name 
MenACYW conjugate vaccine: Meningococcal Polysaccharide 
(Serogroups A, C, W, and Y) Tetanus Toxoid Conjugate Vaccine 
(Sanofi Pasteur Inc., Swiftwater, PA, USA) 
Use 
Investigational 
IMP and NIMP 
IMP 
Type  
Vaccine 
Dose Form 
Liquid solution 
Unit Dose 
Strength(s) 
Each dose of MenACYW conjugate vaccine contains the following 
components: 
Meningococcal capsular polysaccharides: 
• 
Serogroup A*: 10 µg 
• 
Serogroup C*: 10 µg 
• 
Serogroup Y*: 10 µg 
• 
Serogroup W*: 10 µg 
* Conjugated to tetanus toxoid protein carrier: 55 µg** 
**Tetanus toxoid protein quantity is approximate and dependent on the 
polysaccharide-to-protein ratio for the conjugates used in each 
formulation 
Excipients/Diluent 
Sodium acetate buffered saline solution 
Dosage Level(s) 
0.5 mL per dose 
Number of Doses / 
Dosing Interval 
1 dose  
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Route of 
Administration 
Intramuscular injection  
Site of 
Administration 
Anterolateral area of the thigh or deltoid muscle  
Sourcing 
Provided by the Sponsor 
Packaging and 
Labeling 
MenACYW conjugate vaccine (single-dose vial) will be supplied 
with investigational labeling and packaging according to national 
regulations. Each single dose of study interventions will be 
identified by a unique number on the detachable label and on the 
outer carton label. The detachable label is for the sites to attach to 
the source documents. See the Operating Guidelines for additional 
label detail. 
Current/Former 
Name(s) or Alias(es) 
MenQuadfi® 
Batch Number 
TBD 
Storage Conditions 
Study interventions will be stored in a refrigerator at a temperature 
ranging from +2°C to +8°C. The study interventions must not be 
frozen. 
IMP: Investigational Medicinal Product; NIMP: Non-Investigational Medicinal Product; TBD: to be determined 
6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY  
MenACYW conjugate vaccine is supplied in single-dose (0.5 mL) vials. 
It will be administered intramuscularly in the deltoid muscle of the upper arm according to 
country-specific recommendations.  
The site of injection should be prepared with a suitable antiseptic. After administration of the 
vaccine, the used syringe and needles will be disposed of in accordance with currently established 
guidelines.  
Prior to administration, all study products must be inspected visually for cracks, broken seals, 
correct label content, and extraneous particulate matter and/or discoloration, whenever solution 
and container permit. If any of these conditions exist, the vaccine must not be administered. A 
replacement dose is to be used, and the event is to be reported to the Sponsor. The rubber stopper 
should not be removed from any of the vaccine vials. 
1) The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
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2) Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. 
3) The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
4) Further guidance and information for the final disposition of unused study interventions will 
be provided to the study personnel. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
6.3.1 Randomization and Allocation Procedures  
Participants will not be randomized. 
6.3.2 Blinding and Code-breaking Procedures  
This is an open-label study. 
6.4 
STUDY INTERVENTION COMPLIANCE  
The following measures will ensure that the study intervention is administered as planned (see 
Table 6.1), and that any noncompliance is documented so that it can be accounted for in the data 
analyses: 
• All study interventions will be administered by qualified and trained study personnel 
• The person in charge of study intervention management at the site will maintain 
accountability records of study intervention delivery to the study site, study intervention 
inventory at the site, dose(s) given to each participant, and unused or wasted doses 
For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, contingency measures are included in 
Appendix 10.3: Contingency Measures for a regional or national emergency that is declared by a 
governmental agency.  
6.5 
DOSE MODIFICATION  
Not applicable. 
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6.6 
CONTINUED ACCESS TO STUDY INTERVENTION AFTER THE END OF THE STUDY  
Not applicable. 
6.7 
TREATMENT OF OVERDOSE  
Since the study intervention is administered by a health care professional, it is unlikely that 
overdose by injection occurs. 
However, in the event of an overdose, the investigator should: 
1) Contact the RMO immediately. 
2) Closely monitor the participant for any AE/SAE. 
3) Document the quantity of the excess of the overdose in the source documents. 
6.8 
CONCOMITANT THERAPY  
Reportable medications include medications that may affect the interpretation of safety data (eg, an 
antipyretic or analgesic that could have reduced the intensity or frequency of an adverse event) or 
may interfere with the development or measurement of the immune response (eg, the use of 
immune-suppressors, immune-modulators, or some antibiotics that can affect certain bioassays). 
Some medications such as steroids can affect both the evaluation of the safety and the immune 
response to a vaccine. 
This may include medications of interest that were started prior to the day of vaccination, and 
even stopped prior to enrollment if there is a reasonable possibility that they may have an impact 
on safety and / or immune assessment during study participation.  
Three standard categories of reportable medications are defined: 
• Category 1: medications impacting or that may have an impact on the evaluation of the safety 
(eg, antipyretics, analgesics, and non-steroidal anti-inflammatory drugs [NSAIDs], systemic 
steroids/corticosteroids [therapy duration less than 2 weeks] and other immune-modulators). 
Category 1 medications do not define the PPAS. 
Note: Topical steroids (inhaled, optic, ophthalmic, nasal, etc.) should not be captured or 
reported. 
• Category 2: medications impacting or that may have an impact on the immune response and 
used to define the PPAS; for example: 
• 
Flu vaccines administered within 14 days pre or post each trial vaccination, 
including the day of the study vaccination visit and up to the last blood draw. 
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• 
Any vaccine other than study vaccines (vaccines non-described in the Protocol) 
within the 28 days (4 weeks) preceding or after the trial vaccination, including the 
day of the study vaccination visit and up to the last blood draw. 
• 
Immune globulins, blood or blood-derived products: used in the 3 months preceding 
the first blood draw and up to the last blood draw. 
• 
Immunosuppressive therapy such as immune-suppressors, immune-modulators with 
immunosuppressive properties, long-term systemic corticosteroids therapy 
(prednisone or equivalent for more than 2 consecutive weeks) used in the 3 months 
preceding the study vaccination, anti-cancer chemotherapy, anti-proliferative drugs 
such as deoxyribonucleic acid (DNA) synthesis inhibitors, or radiation therapy: used 
in the 6 months preceding the study vaccination, and up to the last blood draw. 
• Category 3: systemic (oral or injectable) antibiotics, received within 72 hours preceding each 
visit for blood draw related to IMP assessment (meningococcal vaccines) and used to define 
the PPAS, as they may interfere with bioassays used for antibody testing when taken before a 
blood draw. 
Note: Topical antibiotics (inhaled, optic, ophthalmic, nasal, etc.) should not be captured or 
reported. 
Reportable medications will be collected in the CRF until the end of the solicited and unsolicited 
follow-up period. 
Dosage and administration route, homeopathic medication, topical and inhaled steroids, as well as 
topical, ophthalmic, and ear treatments will not be recorded (except topical analgesics applied at the 
injection site of study intervention). 
Medications given in response to an AE will be captured in the “Action Taken” section of the AE 
CRF only. No details will be recorded in the concomitant medication Form of the CRF unless the 
medication(s) received belong(s) to the reportable medications list. Medications will be coded 
using the WHODrug dictionary. 
6.8.1 Rescue Medicine  
Appropriate medical equipment and emergency medications, including epinephrine (1:1000), 
must be available at the study site in the event of an anaphylactic, vasovagal, or other immediate 
allergic reaction. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 10.1. 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
Not applicable as there is only one vaccination. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• 
A participant may withdraw from the study at any time at the request of his/her 
parents/legally acceptable representatives, or may be withdrawn at any time at the discretion 
of the investigator for safety, behavioral, or compliance reasons. This is expected to be 
uncommon. 
• 
The reason for withdrawal should be clearly documented in the source documents and in the 
CRF.  
• 
The participant will be permanently discontinued from the study intervention and the study at 
that time. However, the site should attempt to contact them and complete all scheduled safety 
follow-ups, except if they specified that they do not want to be contacted again and it is 
documented in the source document. 
• 
If the participants’ parents/ legally acceptable representatives withdraw consent for disclosure 
of future information, the Sponsor will retain and continue to use any data collected before 
such a withdrawal of consent. 
• 
If a participants’ parents/ legally acceptable representatives withdraw consent, they may 
request destruction of any biological samples taken (unless local law requires not to destroy 
them), and the investigator must document this in the site study records. 
• 
Withdrawn participants will not be replaced. However, in specific situations, if judged 
necessary and according to the number of withdrawn participants, the sample size may be 
increased to maintain the statistical power or the minimum number of evaluable participants 
of the study. Participants’ numbers will not be reassigned. 
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7.3 
LOST TO FOLLOW-UP  
A participant will be considered lost to follow-up if he/she fails to return for Visit 2 and if 
participants’ parents/legally acceptable representatives are unable to be contacted by the study 
site. 
The following actions must be taken if a participant fails to return to the site for a required study 
visit or if participants’ parents/legally acceptable representatives cannot be contacted as planned 
in the SoA: 
• 
The site must attempt to contact the participants’ parents/legally acceptable 
representatives and reschedule the missed visit as soon as possible, counsel the 
participants’ parents/legally acceptable representatives on the importance of maintaining 
the assigned visit schedule, and ascertain whether the participants’ parents/legally 
acceptable representatives wish to and/or should let their child continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participants’ parents/legally acceptable 
representatives (where possible, 3 telephone calls and, if necessary, a certified letter to 
the participant’s last known mailing address or local equivalent methods). These contact 
attempts should be documented in the participant’s medical record. 
• 
Should the participants’ parents/legally acceptable representatives continue to be 
unreachable, the participant will be considered lost to follow-up. 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
 
• 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness. 
• 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• 
Exceptional situations (eg, COVID-19) may prevent access to the clinical trial sites. In these 
situations, site visits may be replaced by home visits where blood draw, physical examination 
and safety assessments will be performed by home nurses. 
Blood samples will be collected as described in the SoA table (Section 1.3).  
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 5 mL (at Visit 1 [BL0001] 
and Visit 2 [BL0002]) in total. Repeat or unscheduled samples may be taken for safety reasons or 
for technical issues with the samples. 
Temporary contraindications for blood sampling 
Should a participant receive oral or injectable antibiotic therapy within 3 days (72 hours) prior to a 
blood draw, the Investigator will postpone that blood draw until it has been 3 days since the 
participant last received oral or injectable antibiotic therapy. Postponement must still be within the 
timeframe for blood draw. If postponement will result in the sample collection falling outside of 
the appropriate timeframe, the blood sample should be collected without postponement, and it 
should be documented appropriately that the sample was taken less than 3 days after stopping 
antibiotic treatment. 
Guidance and information for the sample collection, preparation, storage, and shipment will be 
provided to the study personnel. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 10.3: Contingency Measures for a regional or national emergency that is 
declared by a governmental agency. 
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8.1 
EFFICACY AND IMMUNOGENICITY ASSESSMENTS  
Planned timepoints for all immunogenicity assessments are provided in the SoA. 
8.1.1 Efficacy Assessments  
No clinical efficacy data will be obtained in the study. 
8.1.2 Immunogenicity Assessments  
Functional meningococcal antibody activity against serogroups A, C, Y, and W will be measured 
in a serum bactericidal assay utilizing hSBA and rSBA. The results will be expressed as vaccine 
seroresponse, seroprotection, and GMTs. 
Antibodies to Meningococcal Antigens (hSBA Method) 
Functional meningococcal antibody activity against serogroups A, C, Y, and W will be measured 
in a serum bactericidal assay utilizing human complement. Two-fold dilutions of test sera are 
prepared in sterile 96-well microtiter plates. Serogroup-specific meningococcal bacteria along 
with human complement are added to the serum dilutions and allowed to incubate. After this 
incubation period, an agar overlay medium is added to the serum/complement/bacteria mixture, 
allowed to harden, and then incubated overnight at 37°C with 5% carbon dioxide (CO2). Bacterial 
colonies present in the wells are then counted. The endpoint titer is determined by the reciprocal 
serum dilution yielding ≥ 50% killing as compared to the mean of the complement control wells. 
The lower limit of quantification (LLOQ) of the hSBA assay is a titer of 1:4. 
The hSBA testing will be performed at Global Clinical Immunology (GCI), Swiftwater, 
Pennsylvania or at qualified contract laboratories for GCI.  
Antibodies to Meningococcal Antigens (rSBA Method) 
Functional meningococcal antibody activity against serogroups A, C, Y, and W will be measured 
in a SBA using a rabbit complement. Two-fold dilutions of test sera are prepared in sterile 96-well 
microtiter plates. Serogroup-specific meningococcal bacteria along with baby rabbit complement 
are added to the serum dilutions and allowed to incubate. After this incubation period, 10 µL of 
the serum/complement/bacteria mixture is removed and added to a blood agar plate using the tilt 
method, and then incubated overnight at 37°C with 5% CO2. Bacterial colonies present on the 
blood agar plate are then counted. The bactericidal titer of each sample is expressed as the final 
reciprocal dilution yielding ≥ 50% killing as compared to the T60 (average number of bacteria in 
each control well after incubation) colony-forming unit (CFU). To report a titer greater than 1:4, 
clear bactericidal activity must be noted and the next dilution must have a CFU count less than the 
calculated 20% T60. The LLOQ of the rSBA assay is a titer of 1:4.  
The rSBA testing will be performed at Vaccine Evaluation Unit, Public Health Laboratory, 
Manchester 
, United Kingdom. 
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Antibody concentrations against tetanus toxoid contained in MenACYW conjugate vaccine as a 
carrier protein will be determined in toddlers 12 – 23 months of age who received meningococcal 
conjugate vaccine (ie, Nimenrix or Menveo), in infancy. The results will be expressed as 
percentage of participants with antibody concentrations to tetanus toxoid ≥ 0.01 international units 
(IU)/mL and ≥ 0.1 IU/mL, and geometric mean concentrations (GMCs). 
Tetanus (diphtheria, tetanus, pertussis multiplexed electrochemiluminescent [DTP-ECL] assay) 
Anti-tetanus antibodies will be measured by DTP-ECL assay, a multiplexed serological assay 
which allows for the simultaneous quantification of human antibodies to 6 specific antigens 
including diphtheria toxoid, tetanus toxoid, and 4 pertussis antigens: pertussis toxin, filamentous 
haemagglutinin, fimbriae and pertactin. 
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 immunoglobulin (Ig)G 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. 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. For this 
study, only tetanus results will be calculated. 
The tetanus antibody testing will be performed at Global Clinical Immunology (GCI), Swiftwater, 
Pennsylvania or at qualified contract laboratories for GCI. 
8.2 
SAFETY ASSESSMENTS  
This section presents safety assessments other than AEs which are presented in Section 8.3. 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Medical History  
Prior to enrollment, participants will be assessed for pre-existing conditions and illnesses, both 
past and ongoing. Any such conditions will be documented in the source document. Significant 
(clinically relevant) medical history (reported as diagnosis) including conditions/illnesses for 
which the participant is or has been followed by a physician or conditions/illnesses that could 
resume during the course of the study or lead to an SAE or to a repetitive outpatient care will be 
collected in the CRF. Collected information will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA).  
For each condition, the data collected will be limited to  
• Diagnosis (this is preferable to reporting signs and symptoms) 
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The reporting of signs and symptoms in lieu of a diagnosis is strongly discouraged. 
Dates, medications, and body systems are not to be recorded, and the information collected will 
not be coded. Its purpose is to assist in the later interpretation of safety data collected during the 
study. 
8.2.2 Physical Examinations  
At Visit 1 and Visit 2, the investigator or a designee will perform a clinical or medically-driven 
physical examination. Information will be recorded in the source document. 
8.2.3 Vital Signs  
Oral, rectal, or axillary route (axillary preferred) pre-vaccination temperature using a certified 
standard digital thermometer will be systematically collected by the Investigator on the source 
document (including the route of measurement). Other types of thermometer (tympanic scan, 
temporal artery scan and infrared skin scan) must not be used. 
8.2.4 Clinical Safety Laboratory Tests  
Not applicable. 
8.2.5 Pregnancy Testing  
Not applicable. 
8.2.6 Viremia/Vaccinemia  
Not applicable. 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS, AND OTHER SAFETY 
REPORTING  
The definitions of an AE, SAE, and the different categories of AEs can be found in 
Appendix 10.2. 
AEs will be reported by the parents / legally acceptable representatives to the investigator, then by 
the Investigator to the Sponsor. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study (see Section 7). 
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The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 10.2. 
8.3.1 Time Period and Frequency for Collecting AE and SAE Information  
Immediate Post-vaccination Observation Period 
Participants will be kept under observation for 30 minutes after vaccination to ensure their safety. 
The post-vaccination observation should be documented in the source document. 
Reactogenicity 
Solicited injection site reactions will be collected from the day of vaccination until 7 days after 
vaccination (D01 to D08). 
Solicited systemic reactions will be collected from the day of vaccination until 7 days after 
vaccination (D01 to D08). 
The solicited injection site reactions and systemic reactions that are pre-listed in the diary cards 
and CRF, together with the intensity scales, are presented in Appendix 10.2.5.1.1. 
Unsolicited Non-serious Adverse Events 
Unsolicited non-serious adverse events will be collected from the day of vaccination until 30 days 
after vaccination (D01 to D31 [+ 14 days]). 
The intensity grading scale for unsolicited non-serious adverse events is presented in 
Appendix 10.2.5.1.2. 
Adverse Events of Special Interest (AESIs) 
AESIs will be collected throughout the study period from D01 to D31 (+14 days) post study 
vaccination.  
See Section 8.3.6 for the list of AESIs. 
SAEs 
Information on SAEs will be collected and assessed throughout the study, from D01 to D31 (+14 
days) post study vaccination. However, before the first study intervention administration, only 
SAEs related to study procedures are to be collected in the case report form (CRF) (eg, SAEs 
related to blood sampling). 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 10.2. The investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
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Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must promptly 
notify the Sponsor. 
8.3.2 Method of Detecting AEs and SAEs  
Individual diary cards, specifically designed for this study by the Sponsor and provided to the 
study sites, will be given to study participants’ parents/legally acceptable representatives for the 
recording of daily safety information. These diary cards will include pre-listed terms and intensity 
scales as well as areas for free text to capture additional safety information or other relevant 
details. Participants’ parents / legally acceptable representatives will also be provided with rulers 
for measuring the size of injection site reactions, and with standard digital thermometers for 
measuring daily temperatures. To ensure consistency of reporting, the study sites will instruct 
participants’ parents / legally acceptable representatives on how to correctly use these tools. 
At specified intervals, the investigator or a designee will interview the participants’ parents / 
legally acceptable representatives to collect the information recorded in the diary card, and will 
attempt to clarify anything that is incomplete or unclear. All clinical study information gathered 
by the study site will be reported electronically by the investigator or 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. 
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts, unless a participants’ parents / legally acceptable representatives 
refuses further contact. All AEs that are considered by the investigator as serious, or related to the 
study intervention administered, or that led to study or vaccination discontinuation, [or AEs of 
special interest (as defined in Section 8.3.6)], will be followed during the conduct of the study 
until resolution, stabilization, or the participant is lost to follow-up (as defined in Section 7.3). For 
related SAEs ongoing at last study visit, such follow-up may need to continue after the end of the 
study.  
Further information on follow-up procedures is provided in Appendix 10.2. 
8.3.4 Regulatory Reporting Requirements for SAEs  
• 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
• 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
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reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators. 
• 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then 
file it and will notify the IRB/IEC, if appropriate according to local requirements. 
• 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary. 
8.3.5 Pregnancy  
Not applicable as the study does not include women of childbearing potential. 
8.3.6 Adverse Events of Special Interest  
An AESI is an event for which ongoing monitoring and rapid communication by the Investigator 
to the Sponsor must be done. The following SAEs will be captured as serious AESIs throughout 
the study: 
• Generalized seizures (febrile and non-febrile) (16) 
• Kawasaki disease (17) (18) (19) 
• Guillain-Barré syndrome (20) 
• Idiopathic thrombocytopenic purpura (ITP) (21) 
These events have been listed as AESIs based on the feedback received from the EU regulators 
for the MenACYW conjugate vaccine. 
No safety concerns relating to these AESIs have been identified with the use of MenACYW 
conjugate vaccine in the completed clinical trials. 
Because of their medical importance and to ensure expedited communication to the Sponsor, these 
AESIs are to be considered as SAEs and reported to the Sponsor according to the procedure 
described in Appendix 10.2.4.  
8.4 
PHARMACOKINETICS  
Pharmacokinetics parameters are not evaluated in this study. 
8.5 
GENETICS  
Genetics are not evaluated in this study. 
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8.6 
BIOMARKERS  
No other biomarkers than those described in the immunogenicity assessments section 
(Section 8.1.2) are evaluated in this study. 
8.7 
IMMUNOGENICITY ASSESSMENTS  
See Section 8.1.2. 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS  
Medical Resource Utilization and Health Economics parameters are not evaluated in this study. 
8.9 
LEFTOVER BIOLOGICAL SAMPLES  
Any unused part of the biological samples collected for this study (blood samples) are being 
retained in long-term storage (for up to 25 years after the end of the study) to support answers to 
regulatory questions related to the product’s licensure and the potential revalidation of the study 
results. The biological samples will be securely stored at the Sponsor’s laboratory. 
The other biological samples collected to qualify the participant for inclusion in the study or to 
monitor his/her health during the study are dedicated for immediate use. If any of these biological 
samples are not completely used up, they will be destroyed at the latest at the end of the study or 
after the time requested by local law. 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease and the development of new 
vaccines/medicines. Reuse of coded data and biological samples (leftover) will be limited to 
future scientific research conducted under a research plan for the purpose of diagnosing, 
preventing or treating diseases. The future research projects will be conducted under the 
Sponsor’s and/or its affiliates’ and/or, if applicable, the partner of the Sponsor which has licensed 
the study intervention to the Sponsor or which is co-developing the study intervention with the 
Sponsor’s control, acting alone or in collaboration with research partners such as universities, 
research institutions or industrial partners with whom the coded data may be shared.  
Data and biological samples will be stored and used for future research only when consented to by 
participants (see Section 10.1.3) and, when applicable, further information on the future research 
has been provided to the study participants, unless prohibited by local laws or IRBs/IECs (in such 
case, consent for future use of samples will not be included in the local informed consent form 
[ICF]). The conditions for reuse will be adapted locally with the appropriate language in the ICF.  
In any case, a specific consent will be collected for the performance of genetic analyses on 
leftover samples. 
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Data Protection – Processing of Coded Clinical Data  
The study participants will be provided with all mandatory details of the data processing in Part 2 
of the ICF. The Sponsor adopts safeguards for protecting participant confidentiality and personal 
data (see Section 10.1.4). 
Use of Leftover Samples for Future Research 
Remaining leftover samples will be used only after the study ends, ie end of study as defined in 
the study protocol.  
The study participants will be provided with all mandatory details of the use of their biological 
samples (leftover) in Part 2 of the ICF.  
Relating data and biological samples for future research will be stored for up to 25 years after the 
end of the study. 
Any samples remaining at the end of the retention period will be destroyed. If a participant 
requests destruction of his/her samples before the end of the retention period, the investigator 
must notify the Sponsor (or its contract organization) in writing. In such case, samples will be 
destroyed and related coded data will be anonymized unless otherwise required by applicable 
laws. 
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9 
STATISTICAL CONSIDERATIONS  
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. 
9.1 
STATISTICAL HYPOTHESES  
No hypotheses will be tested. The analyses will be descriptive.  
Details on statistical methods are provided in Section 9.3. 
9.2 
ANALYSIS SETS  
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis 
Set 
Description 
Safety Analysis Set (SafAS) 
Participants who have received the study vaccine. All participants will 
have their safety analyzed according to the vaccine they actually 
received. 
Safety data recorded for a vaccine received out of the protocol design 
will be excluded from the analysis (and listed separately). 
Full analysis set (FAS) 
Subset of SafAS.  
Participants who received the study vaccine and had a valid post-
vaccination serology result. Participants will be analyzed 
according to the intervention they received. 
Per-protocol analysis set 
(PPAS) 
Subset of FAS. 
 
Participants presenting with at least 1 of the following relevant 
protocol deviations will be excluded from the PPAS: 
• Participant did not meet all protocol-specified inclusion 
criteria or met at least 1 of the protocol-specified exclusion 
criteria 
• Participant did not receive the study vaccine 
• Preparation and/or administration of vaccine was not done as 
per-protocol 
• Participant did not provide a post-dose serology sample in the 
proper time window or a post-dose serology sample was not 
drawn Blood sampling 2 (BL0002) / Visit 2: Visit 1+ 30 day 
(+14 days) 
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Participant Analysis 
Set 
Description 
• Participant’s serology sample did not produce a valid test 
result (ie, results for all meningococcal antigens are missing) 
• 
Participant had other protocol violations that affected the 
participant’s immune response, as determined by the clinical 
team before locking the database 
• 
Participant received a protocol-prohibited Category 2 or 
Category 3 therapy/medication/vaccine 
9.3 
STATISTICAL ANALYSES  
The SAP will be finalized prior to database lock and it will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of the 
planned statistical analyses of all the endpoints. 
9.3.1 General Considerations  
Immunogenicity analyses will be performed on the PPAS and FAS. Safety analysis will be 
performed on the SafAS.  
9.3.2 Immunogenicity Endpoints  
Descriptive statistics will be provided for the hSBA and rSBA antibody titers against 
meningococcal serogroups (A, C, W, and Y) and for antibody concentrations against tetanus 
toxoid contained in MenQuadfi® as a carrier protein. 
In general, categorical variables will be summarized and presented by frequency counts, 
proportion percentages, and CIs. The 95% CIs of point estimates will be calculated using the 
normal approximation for quantitative data and the Exact binomial distribution (Clopper-Pearson 
method) for percentages. For GMTs, 95% CIs of point estimates will be calculated using normal 
approximation assuming they are log-normally distributed.  
 
For immunogenicity data, assuming that log10 transformation of the titers / concentrations follows 
a normal distribution, first, the mean and 95% CIs will be calculated on log10 (titers / 
concentrations) using the usual calculation for normal distribution, then antilog transformations 
will be applied to the results of calculations, to compute GMTs / GMCs and their 95% CIs. 
Reverse cumulative distribution curve (RCDC) figures will be provided for the antibody titers 
against meningococcal serogroups and the antibody concentrations against tetanus toxoid 
contained in MenQuadfi®. 
In summary, descriptive analyses on A, C, Y, and W serogroups on D01 and D31 after 
vaccination with MenACYW conjugate vaccine will include but not be limited to: 
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• hSBA and rSBA GMTs and 95% CI 
• hSBA and rSBA titer distribution and RCDC 
• Percentage of participants with hSBA titer ≥ 1:4 and ≥ 1:8 and 95% CI 
• Percentage of participants with rSBA titer ≥ 1:8 and ≥ 1:128 and 95% CI 
• Percentage of participants with hSBA and rSBA titer ≥4-fold rise from pre-vaccination to 
post-vaccination, and 95% CI 
• Percentage of participants with hSBA and rSBA vaccine seroresponse rate and 95% CI 
hSBA vaccine seroresponse for serogroups A, C, Y, and W defined as: 
o For a participant with a pre-vaccination titer < 1:8, the post-vaccination titer must 
be ≥ 1:16 
o For a participant with a pre-vaccination titer ≥ 1:8, the post-vaccination titer must 
be at least 4-fold greater than the pre-vaccination titer 
rSBA vaccine seroresponse defined as: 
o a post-vaccination rSBA titer ≥ 1:32 for participants with pre-vaccination rSBA 
titer < 1:8, or  
o a post-vaccination titer ≥ 4 times the pre-vaccination titer for participants with pre-
vaccination rSBA titer ≥ 1:8 
In addition, descriptive analyses on anti-tetanus antibody concentrations will include but not be 
limited to: 
• GMCs and 95% CI 
• The percentage of participants with antibody concentrations to tetanus toxoid 
≥ 0.01 international units (IU)/mL and ≥ 0.1 IU/mL and 95% CI 
All immunogenicity analyses will be performed on the PPAS (evaluable participants) and 
presented overall and by priming vaccine.  
9.3.3 Safety Endpoints  
Safety 
Safety analyses will be performed on the SafAS and presented overall and by priming vaccine. 
The main parameters for the safety endpoints will be described by 95% CIs using the Exact 
binomial method (Clopper-Pearson method). 
9.3.4 Other Endpoints  
Same statistical analyses will be applied as described above for the description of the other 
immunogenicity endpoints. 
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9.4 
INTERIM ANALYSES  
An interim report may be generated with hSBA analysis of all immunogenicity endpoints and 
safety endpoints depending on the timelines regarding the availability of the rSBA data. Final 
report will be generated with the analyses of rSBA immunogenicity endpoints.  
This study will not include an early safety data review. No additional analyses are planned to be 
performed prior to the formal completion of the study. 
9.5 
SAMPLE SIZE DETERMINATION  
There are no statistically powered hypotheses in this study thus no formal sample size 
computation. All analyses will be descriptive. 
The sample size was set to approximatively 180 participants (minimum of 30 evaluable 
participants from the low - enrolling of the 2 priming vaccines) to have at least 150 evaluable 
participants assuming a drop-out rate of approximatively 15%. 
In terms of immunogenicity for any of the 4 serogroups, considering a sample size of 150 
evaluable subjects, the expected precision of the 95% CI using the Exact binomial method will be 
as follow: 
Seroprotection rates (titer >= 1:8) Precision* 
85% 
13.77 
90% 
11.62 
95% 
8.96 
100% 
2.88 
*Difference between the upper and lower bounds of the 95%CI 
In terms of safety, the planned sample size will allow for identification of common AEs. One 
hundred and fifty evaluable subjects will allow with 95% probability, the detection of an AE 
occurring with a frequency of 2% or more, using the rule of threes. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS  
Note: The term “participant” is used throughout this protocol. However, the term “subject” will be 
used in the CRF in order to comply with the Clinical Data Interchange Standards Consortium 
(CDISC) requirements. Similarly, “legally acceptable representative” is used in the protocol 
whereas “guardian” is used in the CRF. 
10.1.1 Regulatory and Ethical Considerations  
• 
This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines 
• 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
guidelines 
• 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation [GDPR]) 
• 
The protocol, ICF, Investigator’s Brochure (IB), and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator or the Sponsor (according to 
local regulations) and reviewed and approved by the IRB/IEC before the study is initiated 
• 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate hazard 
to study participants 
• 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants 
• 
The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC (in addition to summaries required from the Sponsor) 
• 
Determining whether an incidental finding (as per Sanofi policy) should be returned to a 
participant and, if it meets the appropriate criteria, to ensure the finding is returned (an 
incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
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performed). The following should be considered when determining the return of an 
incidental finding: 
• The return of such information to the study participants’ parents/legally acceptable 
representatives (and/or his/her designated healthcare professional, if so designated by 
the participants’ parents/legally acceptable representatives) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
• The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity.  
• The participants’ parents/legally acceptable representatives in a clinical study have 
the right to opt out of being notified by the investigator of such incidental findings. In 
the event that the participants’ parents/legally acceptable representatives have opted 
out of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, investigators should seek independent 
ethical advice before determining next steps. 
• In case the participants’ parents/legally acceptable representatives have decided to 
opt out, the investigator must record in the site medical files that she/he does not want 
to know about such findings. 
• 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• 
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), European Medical Device Regulation 2017/745 for clinical device 
research (if applicable), and all other applicable local regulations 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial Disclosure  
Information related to financial disclosure is described in the investigator’s contract. 
10.1.3 Informed Consent Process  
• The investigator or his/her representative will explain the nature of the study, including the 
risks and benefits, to the participants’ parents / legally acceptable representatives and 
answer all questions regarding the study, including what happens to the participant when 
his/her participation ends (post-trial access strategy for the study). 
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• Parents / legally acceptable representatives must be informed that their child’s 
participation is voluntary. Participants’ parents / legally acceptable representative will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, privacy and data protection requirements including 
those of the Global Data Protection Regulation (GDPR) and of the French law, where 
applicable, and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• The actual ICF used at each center may differ, depending on local regulations and IEC / 
IRB requirements. However, all versions must contain the standard information found in 
the sample ICF provided by the Sponsor. Any change to the content of the ICF must be 
approved by the Sponsor and the IEC / IRB prior to the form being used. 
• If new information becomes available that may be relevant to the participants’ parents’ / 
legally acceptable representatives’ willingness to continue their child’s participation in the 
study, this will be communicated to the participants’ parents/legally acceptable 
representatives in a timely manner. Such information will be provided via a revised ICF or 
an addendum to the original ICF. 
• Participants’ parents/legally acceptable representatives must be reconsented to the most 
current version of the ICF(s) during their participation in the study. Where participants are 
not in the study anymore, the Sponsor must define if those participants must or not re-
consent or be informed of the revision (eg, if the processing of personal data is modified, if 
the Sponsor changes). 
• A copy of the ICF(s) must be provided to the participant’s parents / legally acceptable 
representatives. 
The ICF will contain a separate section that addresses the use of remaining mandatory for research 
of participants’ data and/or samples (remaining mandatory ones for optional research). Each 
option is subject to an independent consent and must be confirmed by ticking checkboxes in ICF 
Part 3, each checkbox corresponding to a specific use: consent for the performance of an optional 
exploratory research; consent for storage and use of coded data for future research; consent for use 
of leftover samples and associated coded data for future research; consent for collection of 
additional biological samples for storage and use for future research. The investigator or 
authorized designee will explain to each participant’s parent/ legally acceptable representative the 
objectives of the exploratory research and why data and samples are important for future research. 
Participant’s parent/ legally acceptable representative will be told that they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during the storage 
period. 
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Rationale for Including Participants Unable to Give Consent 
MEQ00086 is a study to be conducted to describe the immunogenicity and safety of the 
MenACYW conjugate vaccine when administered as a booster dose in healthy toddlers 12 – 23 
months of age who had been primed during the first year of life with at least 1 dose of another 
licensed quadrivalent meningococcal conjugate vaccine, either Nimenrix® (MCV4-TT) or 
Menveo® (MCV4 - CRM). 
Since these participants are unable to give their consent, written informed consent must be 
obtained from the parent or legally acceptable representative in accordance with local practices 
before participation in the study and before any study-related procedure is done. The signature on 
the ICF must be dated by the parent/ legally acceptable representative in accordance with local 
practices. The parent/ legally acceptable representative should be able to consent for their child. 
The child of minor parents must not be included in the study. 
Recruitment Procedures 
Before the start of the study, the Investigator or sub-investigator will contact an appropriate pool 
of potential participants (independent of the Investigator and investigational team) and invite them 
to participate in the study. The site will ensure that any advertisements used to recruit participants 
(eg, letters, pamphlets, posters) are submitted to Sanofi Pasteur prior to submission to the 
IEC/IRB for approval. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 10.3: Contingency Measures for a regional or national emergency that is 
declared by a governmental agency.  
10.1.4 Data Protection  
All personal data collected and/or processed in relation to this study will be handled in compliance 
with all applicable Privacy & Data Protection laws and regulations, including the GDPR (General 
Data Protection Regulation). The study Sponsor is the Sanofi company responsible for ensuring 
compliance with this matter, when processing data from any individual who may be included in 
the Sanofi databases, including investigators, nurses, experts, service providers, Ethics Committee 
members, etc.  
When archiving or processing personal data pertaining to the investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
Protection of participant personal data 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
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Participants’ race and ethnicity will be collected in this study because these data are required by 
regulatory agencies (eg, on African-American population for the FDA or on Japanese population 
for the Pharmaceuticals and Medical Devices Agency in Japan). 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only 
by the unique identifier; participant names or any information which would make the 
participant identifiable will not be transferred to the Sponsor. 
• The participants’ parents/legally acceptable representatives must be informed that their 
child’s personal study-related data will be used by the Sponsor in accordance with 
applicable data protection laws. The level of disclosure must also be explained to the 
participants’ parents/legally acceptable representatives as described in the informed 
consent. 
• The participants’ parents/legally acceptable representatives must be informed that their 
child’s medical records may be examined by Clinical Quality Assurance auditors or other 
authorized personnel appointed by the Sponsor, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities. 
• Participants’ parents/legally acceptable representatives must be informed that their child’s 
study-related data will be used for the whole “product development program”, ie, for this 
study as well as for the following steps necessary for the development of the 
investigational product, including to support negotiations with payers and publication of 
results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or pre-
contractual relationship. They may be communicated to any company of the Sanofi group 
(“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com). 
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients:  
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• Personnel within Sanofi or partners or service providers involved in the study  
• Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity 
may also be published on public websites in the interest of scientific research 
transparency 
• 
Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance with 
the requirement of European law including, notably:  
• The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
• Sanofi’s Binding Corporate Rules for intra-group transfers.  
• 
Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• 
Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• 
In order to facilitate the maintenance of investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the Transcelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the Transcelerate project. This sharing allows investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the Transcelerate project.  
• 
Professionals have the right to object to the processing, to request for access to and the 
rectification of their personal data, as well as their erasure (where applicable) by 
contacting the Sanofi Data Protection Officer: Sanofi DPO - 54 rue La Boétie - 75008 
PARIS - France (to contact Sanofi by email, visit https://www.sanofi.com/en/our-
responsibility/sanofi-global-privacy-policy/contact). 
10.1.5 Committees Structure  
Participant safety will be continuously monitored by the Sponsor’s internal safety review 
committee which includes safety signal detection at any time during the study. The Sponsor’s 
internal safety review committee, led by the PV representative and the RMO, will be responsible 
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for the review, assessment, and evaluation of safety data generated from this study. This 
committee is empowered to recommend a pause in recruitment and/or further vaccination while it 
investigates any potential signal or concern. 
10.1.6 Dissemination of Clinical Study Data  
Study Participants 
At the end of the clinical study, the Sponsor may publish the study results in scientific journal(s). 
As part of the review for publication, independent scientists may need to use “coded” data of all 
the study participants to independently verify the study’s results. 
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance, and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to https://vivli.org. 
Individual participant data and supporting clinical documents are available for request at 
https://vivli.org. While making information available we continue to protect the privacy of 
participants in our clinical trials. Details on data sharing criteria and process for requesting access 
can be found at this web address: https://vivli.org. 
Professionals involved in the study or in the drug development program 
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “EFPIA Code on 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
Healthcare Organizations”. 
10.1.7 Data Quality Assurance  
• 
All participant data relating to the study will be recorded on electronic CRFs unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
• 
Guidance on completion of CRFs will be provided in CRF Completion Instructions.  
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
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• 
Quality tolerance limits (QTLs) will be predefined to identify systematic issues that can 
impact patient safety and/or reliability of study results. These predefined parameters will 
be monitored during the study, and important deviations from the QTLs and remedial 
actions taken will be summarized in the clinical study report. 
• 
Monitoring details describing strategy including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or onsite monitoring) are provided in the monitoring plan. 
• 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
The Sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations). 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
• 
The protocol will be signed by the RMO, and a Protocol Investigator Agreement Form 
(PIAF) will be signed by all investigators. The clinical study report will be signed by the 
RMO and the coordinating investigator. In case no coordinating investigator has been 
designated, it will be the responsibility of the RMO or designee(s) to identify the signatory 
investigator. 
10.1.8 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. 
• 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• 
Data entered in the CRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
• 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
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source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9 Study and Site Start and Closure  
Study personnel will be informed of which clinical supplies will be provided by the Sponsor or 
the site. 
The study start date is considered the date of the first visit planned in the SoA of the first 
participant. 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been either destroyed or returned to the Sponsor, all samples are shipped to the appropriate 
laboratories, the center study site has all the documents necessary for archiving and a study site 
closure visit has been performed along with a Site Close Out Form submitted to the IRB, as 
required. 
The investigator may initiate study site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include but are not 
limited to: 
For study termination: 
• Discontinuation of further study intervention development 
• Information on the study intervention leads to doubt as to the benefit/risk ratio 
• For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor’s procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants 
by the investigator 
• Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
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10.1.10 Publication Policy  
Information related to publication policy is described in the investigator’s contract. 
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10.2 
APPENDIX: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING  
10.2.1 Definition of SAE  
 
An SAE is defined as any adverse event that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether hospitalization occurred or was necessary, the AE 
should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) that may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
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f. 
Is other medically important event 
• The term "Other medically important events" refers to events which do not meet any of 
the above seriousness criteria, but which are considered as serious based on investigator 
medical judgment.  
• Medical or scientific judgment should be exercised by the investigator in deciding 
whether expedited reporting is appropriate in other situations such as significant medical 
events that may jeopardize the health of the participant or may require intervention to 
prevent one of the other outcomes listed in the above definition. These important 
medical events should also usually be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, 
convulsions, or development of intervention dependency or intervention abuse, new-
onset diabetes or autoimmune disease, or suspected transmission of any infectious agent 
via an authorized medicinal product. 
Note: Serious and severe are not synonymous. The term severe is often used to describe the 
intensity of a specific event as corresponding to Grade 3. This is not the same as serious, which is 
based on participant / event outcome or action criteria usually associated with events that pose a 
threat to a participant’s life or functioning. 
10.2.2 Definition of AE  
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
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• 
New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention 
interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
 
Events NOT Meeting the AE Definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads 
to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
Other Definitions 
Adverse Reaction: 
An adverse reaction (AR) is any noxious and unintended response to a study intervention 
related to any dose. 
Immediate Event/Reaction: 
Immediate events are recorded to capture medically relevant unsolicited systemic AEs which 
occur within the first 30 minutes after vaccination. 
Reactogenicity / Solicited Reactions: 
The reactogenicity of a vaccine refers to the property of such vaccine to be able to produce 
common "expected" adverse reactions (either systemic or at the injection site) and its associated 
signs and symptoms. 
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A solicited reaction is an “expected” adverse reaction (sign or symptom) observed and reported 
under the conditions (nature and onset) pre-listed in the protocol and CRF ([eg, injection site 
pain or headache occurring between the day of vaccination and the next 7 days]).  
By definition, solicited reactions are considered as being related to the corresponding IMP 
administered. 
For injectable vaccines, solicited reactions can either be solicited injection/administration site 
reactions or solicited systemic reactions  
Injection / Administration Site Reactions: 
An injection/administration site reaction is an AR at and around the injection/administration site 
of the IMP. Injection/administration site reactions are commonly inflammatory reactions. 
Solicited injection / administration site reactions are reactions at and around the 
injection / administration site of the IMP observed and reported under the conditions (nature 
and onset) pre-listed in the protocol and CRF. It is considered by default as being related to the 
IMP administered at that site. 
Note: « Administration site reaction » term is only to be used for vaccines that are not intended 
to be administered by injection. 
Systemic AR: 
Systemic ARs are all ARs that are not injection or administration site reactions. They therefore 
include systemic manifestations such as headache, fever, as well as localized or topical 
manifestations that are not associated with the injection or administration site (eg, erythema that 
is localized but that is not occurring at the injection site).  
Solicited systemic reactions are systemic AEs observed and reported under the conditions 
(nature and onset) pre-listed in the protocol and CRF. Solicited systemic reactions occurring 
during the specified collection period are always considered related to the IMP even if there is 
evidence of alternative etiology. 
Unsolicited AE/AR: 
An unsolicited AE is an observed AE that does not fulfill the conditions of solicited reactions, 
ie, pre-listed in the CRF in terms of diagnosis and onset window post-vaccination. For example, 
varicella or a solicited term such as headache starting after the solicited observation period (eg, 
headache starting on Day 10 post-vaccination in the case where headache occurring between the 
day of vaccination and the next 7 days is pre-listed in the protocol and CRF as a solicited 
reaction). 
An unsolicited AR is an unsolicited AE that is considered related to an IMP.  
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Unsolicited AEs includes both serious (SAEs) and non-serious unsolicited AEs. 
All unsolicited AEs occurring at and around the IMP injection/administration site are to be 
considered by default as related to the IMP administered at that site and are therefore referred as 
unsolicited injection/administration site ARs. 
All unsolicited AEs which are not at and around the IMP injection/administration site, are 
referred as systemic unsolicited AE. For each unsolicited systemic AE, the investigator assesses 
the relationship to the IMP. Systemic AEs assessed as related to IMP are referred as systemic 
ARs. 
Adverse Event of Special Interest (AESI): 
An adverse event of special interest (serious or non-serious) is one of scientific and medical 
concern specific to the Sponsor’s study intervention or program, for which ongoing monitoring 
and rapid communication by the Investigator to the Sponsor can be appropriate. Such an event 
might warrant further investigation in order to characterize and understand it. Depending on the 
nature of the event, rapid communication by the study Sponsor to other parties (eg, regulators) 
might also be warranted. 
10.2.3 Recording and Follow-Up of AE and/or SAE  
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the CRF pages. 
• 
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
 
 
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Assessment of Causal Relationship 
By convention, all AEs reported at the injection site (either solicited or unsolicited) and all 
solicited systemic AEs are considered to be related to the IMP (see definition in Section 6) and 
therefore are referred to as reactions and do not require the investigator’s opinion on 
relatedness. 
• 
Causal relationship of unsolicited systemic AEs and SAEs will be recorded as follows: 
• 
For non-serious unsolicited systemic AEs (except for non-serious AESIs), relationship 
to study intervention will usually be assessed by the investigator only.  
• 
For SAEs and non-serious AESIs, relationship to study intervention will be assessed 
by both the investigator and the Sponsor (except for injection site reactions which will 
be related by default). Sponsor assessment is entered in the Global Pharmacovigilance 
(GPV) database only.  
• 
For SAEs only, the causal relationship to study procedures (related/not related to study 
procedures) will be assessed by both the investigator and the Sponsor. Sponsor 
assessment is entered in the GPV database only. 
• 
The investigator will assess the causal relationship between each unsolicited systemic 
AE and the study intervention administered as either not related or related, based on the 
following definitions: 
• 
Not related – The AE is clearly / most probably caused by other etiologies such as 
participants’ underlying condition, therapeutic intervention, or concomitant therapy; or 
the delay between vaccination and the onset of the AE is incompatible with a causal 
relationship; or the AE started before the vaccination (screening phase, if applicable) 
• 
Related – There is a “reasonable possibility” that the AE was caused by the study 
intervention administered, meaning that there are facts (evidence) or arguments to 
suggest a causal relationship 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causal relationship. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always makes an assessment of causal relationship for every event 
before the initial transmission of the SAE data to the Sponsor. 
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• 
The investigator may change his/her opinion of causal relationship in light of follow-up 
information and send an SAE follow-up report with the updated causal relationship 
assessment. 
• 
The causal relationship assessment is one of the criteria used when determining 
regulatory reporting requirements. 
 
Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor 
to elucidate the nature and/or causal relationship of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-up 
period, when available the investigator will provide the Sponsor with a copy of any 
post-mortem findings including histopathology. 
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
• 
Serious adverse events likely to be related to the study intervention, that persist at the 
end of the study will be followed up by the investigator until their complete 
disappearance or the stabilization of the participant’s condition. The investigator will 
inform the Sponsor of the date of final disappearance of the event or the date of 
“chronicity” establishment. 
10.2.4 Reporting of SAEs  
SAE Reporting to the Sponsor via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to the Sponsor will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. The site will enter 
the SAE data into the electronic system as soon as it becomes available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section). 
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SAE Reporting to the Sponsor via Paper CRF 
• 
The SAE paper CRF can be sent to the Sponsor by one of the following means: 
• 
By fax, to the following number: (570) 957 - 2782 
• 
In PDF format to the following email address, using a method of transmission that 
includes password protection: PV.outsourcing@sanofipasteur.com 
• By express mail, to the following address:  Sanofi Pasteur Inc. 
                                                                     Reception and Triage – Case Management 
                                                                     Global Pharmacovigilance 
                                                                     Mail Drop: 45D38 
                                                                     Discovery Drive 
                                                                     Swiftwater, PA 18370 
 
Safety Emergency Call 
If, as per the investigator's judgment, a participant experiences a medical emergency, the 
investigator may contact the Sponsor's RMO for advice on how to address any study-related 
medical question or problem. If the RMO is not available, then the investigator may contact the 
Call Center—available 24 hours a day, 7 days a week—that will forward all safety emergency 
calls to the appropriate primary or back-up Sponsor contact, as needed. The toll-free contact 
information for the Call Center will be provided separately. 
This process does not replace the need to report an SAE. The investigator is still required to 
follow the protocol-defined process for reporting SAEs to the GPV Department. 
In case of emergency code-breaking, the investigator is required to follow the code-breaking 
procedures described in Section 6.3.2. 
10.2.5 Assessment of Intensity  
The investigator will make an assessment of intensity for each AE reported during the study. An 
intensity grade will be assigned to each AE. The intensity grading scales used in this study are 
adapted from the “FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September 2007”. 
10.2.5.1 Tables for Clinical Abnormalities  
10.2.5.1.1 Solicited AR Intensity Grading Scale  
 
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Table 10.1: Solicited injection site reactions: terminology, definitions, and intensity scales 
– Infants and toddlers aged ≤ 23 months  
CRF term 
(MedDRA 
lowest level 
term 
[LLT]) 
Injection site tenderness 
Injection site 
erythema 
Injection site swelling 
Diary card 
term 
Tenderness 
Redness 
Swelling 
Definition 
Pain when the injection site is 
touched or injected limb 
mobilized 
Presence of a redness 
including the 
approximate point of 
needle entry 
Swelling at or near the injection 
site 
Swelling or edema is caused by a 
fluid infiltration in tissue or cavity 
and, depending on the space 
available for the fluid to disperse, 
swelling may be either soft 
(typically) or firm (less typical) to 
touch and thus can be best 
described by looking at the size of 
the swelling 
Intensity 
scale* 
 
Grade 1:  
CRF and DC: Minor reaction 
when injection site is touched 
Grade 2:  
CRF and DC: Cries or 
protests when injection site is 
touched 
Grade 3:  
CRF: Cries when injected 
limb is mobilized, or the 
movement of the injected 
limb is reduced 
DC: 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 tenderness, the scale will be provided in the CRF and the intensity will be transcribed from the diary 
card. For other injection site reactions (erythema and swelling), the classification as Grade 1, 2, or 3 will be 
applied at the time of statistical analysis; the scale is provided for information purposes only. The actual 
size of the reaction will be reported in the CRF. 
 
 
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Table 10.2: Solicited systemic reactions: terminology, definitions, and intensity scales – Infants and 
toddlers aged ≤ 23 months  
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 
(≥ 100.4°F) 
Vomiting does 
not include 
spitting up 
Inconsolable crying 
without a 
determined 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 
or ≥ 100.4°F to 
≤ 101.3°F 
Grade 1: 
CRF and DC: 
1 episode per 
24 hours 
Grade 1:  
CRF and DC: 
< 1 hour 
Grade 1:  
CRF and DC: 
Sleepier than 
usual or less 
interested in 
surroundings 
Grade 1:  
CRF and DC: 
Eating less 
than normal 
Grade 1:  
CRF and DC: Easily 
consolable 
 
Grade 2: 
> 38.5°C to 
≤ 39.5°C 
or > 101.3°F to 
≤ 103.1°F 
Grade 2:  
CRF and DC: 2–
5 episodes per 
24 hours 
Grade 2:  
CRF and DC: 1–
3 hours  
Grade 2: 
CRF and DC: 
Not interested 
in 
surroundings 
or did not 
wake up for a 
feed / meal 
Grade 2:  
CRF and DC: 
Missed 1 or 2 
feeds / meals 
completely 
Grade 2:  
CRF and DC: 
Requiring increased 
attention 
 
Grade 3:  
> 39.5°C 
or > 103.1°F 
Grade 3  
CRF: 
≥ 6 episodes per 
24 hours or 
requiring 
parenteral 
hydration 
DC: at least 6 
episodes per 24 
hours or 
requiring 
intravenous 
hydration (fluids 
administered in 
the arm or leg) 
Grade 3:  
CRF and DC: 
> 3 hours 
Grade 3:  
CRF and DC: 
Sleeping most 
of the time or 
difficult to 
wake up 
Grade 3:  
CRF and DC: 
Refuses ≥ 3 
feeds / meals 
or refuses 
most feeds / 
meals 
Grade 3:  
CRF: Inconsolable 
DC: Inconsolable 
(cannot be 
comforted) 
* For all reactions (except fever), the scale will be provided in the CRF and the intensity will be transcribed 
from the diary card. For fever, the body temperature will be recorded, and the classification as Grade 1, 2, or 
3 will be assigned at the time of the statistical analysis based on the unit used to measure the temperature and 
the intensity scale. 
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Important Notes for the Accurate Assessment of Temperature: 
Participants or parents / legally acceptable representatives are to measure body temperature once 
per day, preferably always at the same time, and using the same standard unit of the considered 
country (Celsius or Fahrenheit) consistently. The optimal time for measurement is the evening, 
when body temperature is the highest. Temperature is also to be measured at the time of any 
apparent fever. The observed daily temperature and the route of measurement are to be recorded 
in the diary card, and the highest temperature will be recorded by the site in the CRF. The 
preferred route for this study is axillary. 
10.2.5.1.2 Serious and Non-serious Unsolicited AE Intensity Grading Scale  
For measurable unsolicited AEs that are part of the list of solicited reactions, the corresponding 
scale for solicited reactions will be used (see Section 10.2.5.1.1). 
All other unsolicited AEs, including SAEs, will be classified according to the following intensity 
scale: 
• 
Grade 1 
• 
CRF: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
• 
Diary card: No interference with activity. 
• 
Grade 2 
• 
CRF: A type of adverse event that is usually alleviated with additional therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the research participant. 
• 
Diary card: Some interference with activity. 
• 
Grade 3 
• 
CRF: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention. 
• 
Diary card: Significant; prevents daily activity. 
 
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10.3 
APPENDIX: MEASURES FOR A REGIONAL OR NATIONAL EMERGENCY THAT IS 
DECLARED BY A GOVERNMENTAL AGENCY  
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, terrorist attack) may prevent access to the clinical study 
site. 
Contingency procedures are suggested below and in Section 5.5, Section 6.4, Section 8, and 
Section 10.1.3 for an emergency that prevents access to the study site, to ensure the safety of the 
participants, to consider continuity of the clinical study conduct, protect study integrity, and assist 
in maintaining compliance with GCP in Conduct of Clinical Trials Guidance. Sponsor agreement 
must be obtained prior to the implementation of these procedures for the duration of the 
emergency. 
During the emergency, if the site is unable to adequately follow protocol mandated procedures, 
alternative treatment outside the clinical study should be proposed, and enrollment administration 
of study intervention, and blood sampling may be temporarily delayed/halted. 
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible. In case this is not possible due to a temporary disruption caused by an 
emergency, focus should be given to assessments necessary to ensure the safety of participants 
and those important to preserving the main scientific value of the study. 
Procedures to be considered in the event of a regional or national emergency declared by a 
governmental agency: 
• If onsite visits are not possible visit windows may be extended for assessment of safety 
data that cannot be obtained remotely. 
Contingencies implemented due to emergency will be documented. 
10.4 
APPENDIX: RISK-BASED APPROACH  
ICH E6-R2 guideline for GCP is introducing the « risk-based approach » concept which permits 
to focus efforts on what is critical for a study and most specifically on Critical Data and Critical 
Processes. Critical data and processes are defined for the study with associated risks in the Study 
Risk Management Plan. 
 
 
 
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10.5 
APPENDIX: ABBREVIATIONS  
AE 
 
adverse event 
AESI  
adverse event of special interest 
AR 
 
adverse reaction 
BL 
 
blood sampling 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CRF 
 
case report form 
D 
 
day 
DC 
 
diary card 
DNA  
deoxyribonucleic acid 
EU 
 
European Union 
FAS 
 
full analysis set 
GCP  
Good Clinical Practice 
GMC  
geometric mean concentration 
GMT  
geometric mean titer 
GPV  
Global Pharmacovigilance 
hSBA  
serum bactericidal assay using human complement 
IB 
 
Investigator’s Brochure 
ICF 
 
informed consent form 
ICH 
 
International Council for Harmonisation 
IEC 
 
Independent Ethics Committees 
IM 
 
intramuscular 
IMD  
invasive meningococcal disease 
IMP 
 
investigational medicinal product 
IRB 
 
Institutional Review Boards 
MCV4  
quadrivalent meningococcal conjugate vaccine 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
 
milliliter 
NIMP  
non-investigational medicinal product 
PIAF  
Protocol Investigator Agreement Form 
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PPAS  
per-protocol analysis set 
PV 
 
pharmacovigilance 
RCDC  
reverse cumulative distribution curve 
RMO  
Responsible Medical Officer 
rSBA  
serum bactericidal antibody assay using baby rabbit complemen 
SAE 
 
serious adverse event 
SafAS  
safety analysis set 
SAP 
 
statistical analysis plan 
SoA 
 
schedule of activities 
SUSARs 
suspected unexpected serious adverse reactions 
TBD  
to be determined 
TC 
 
telephone call 
TT 
 
tetanus toxoid 
US 
 
United States 
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11 
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