A Phase 3 Trial to Evaluate the Safety, Immunogenicity, and Non-Interference With Concomitant Routine Vaccines, of a Meningococcal Serogroup ACYWX Conjugate Vaccine (NmCV-5) in Comparison With MenACWY-TT Conjugate Vaccine in Healthy Malian Infants
Phase: PHASE3
Conditions: Meningitis
Sponsor: Emory University

DMID Protocol 20-0024 
 
Version 4.0 
NmCV-5 EPI Study 
 
23 May 2023 
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 A Phase 3 Trial to Evaluate the Safety, Immunogenicity, and Non-
Interference with Concomitant Routine Vaccines, of a 
Meningococcal Serogroup ACYWX Conjugate Vaccine (NmCV-5) 
in Comparison with MenACWY-TT Conjugate Vaccine in Healthy 
Malian Infants 
 
 
DMID Protocol Number: 20-0024 
DMID Funding Mechanism:  
Infectious Diseases Clinical Research Consortium (IDCRC) cooperative agreement 
 
Product Sponsor:  
SIIPL (Serum Institute of India Pvt. Ltd.) 
Pune, India 
 
Protocol Chair: Wilbur Chen, MD, MS 
 
 
Draft or Version Number:  4.0 
23 May 2023 
 
 
 

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STATEMENT OF ASSURANCE 
Each Institution will hold a current Federal Wide Assurance (FWA) issued by the Office of 
Human Research Protections (OHRP) for federally funded human subjects research.  Each FWA 
will designate at least one Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) registered with OHRP, for which the research will be reviewed and approved by the 
IRB/IEC and will be subject to continuing review [45 CFR 46.103(b)]. The IRB/IEC designated 
under an FWA may include an institution’s IRB/IEC, an independent IRB/IEC, or an IRB/IEC of 
another institution after establishing a written agreement with that other institution. 
 

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STATEMENT OF COMPLIANCE 
The study trial will be carried out in accordance with Good Clinical Practice (GCP) and as 
required by the following: 
• 
United States Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of Human 
Subjects 
• 
Food and Drug Administration (FDA) Regulations, as applicable: 21 CFR Part 50 (Protection 
of Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical Investigators), 21 
CFR Part 56 (Institutional Review Boards), 21 CFR Part 11, and 21 CFR Part 312 
(Investigational New Drug Application), 21 CFR 812 (Investigational Device Exemptions) 
• 
International Conference on Harmonisation: Good Clinical Practice (ICH E6); 62 Federal 
Register 25691 (1997); and future revisions 
• 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research 
• 
National Institutes of Health (NIH) Office of Extramural Research, Research Involving 
Human Subjects, as applicable 
• 
National Institute of Allergy and Infectious Diseases (NIAID) Clinical Terms of Award, as 
applicable 
• 
Applicable Federal, State, and Local Regulations and Guidance 

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SIGNATURE PAGE 
The signature below provides the necessary assurance that this trial will be conducted according 
to all stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal regulations and 
ICH E6 Good Clinical Practice (GCP) guidelines. 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements. 
I agree to conduct the study in accordance with the current protocol and will not make changes to 
the protocol without obtaining the sponsor’s approval and IRB/IEC approval, except when 
necessary, to protect the safety, rights, or welfare of subjects. 
Site Investigator Signature: 
 
Signed: 
 
Date: 
 
 
Samba Sow, MD 
University of Maryland School of Medicine/Center for  
Vaccine Development – Bamako, Mali 
 
 
 
Signed: 
 
Date: 
 
 
Wilbur H. Chen, MD, MS, FACP, FIDSA 
Protocol Chair 
University of Maryland School of Medicine/Center for  
Vaccine Development and Global Health – Baltimore, 
MD 
 
 
 
 
 

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TABLE OF CONTENTS 
STATEMENT OF ASSURANCE ...................................................................................................2 
STATEMENT OF COMPLIANCE .................................................................................................3 
SIGNATURE PAGE .......................................................................................................................4 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES ...........................................................................................................................9 
LIST OF FIGURES .......................................................................................................................10 
LIST OF ABBREVIATIONS ........................................................................................................11 
PROTOCOL SUMMARY .............................................................................................................14 
Schedule of Events................................................................................................................21 
 
BACKGROUND AND SCIENTIFIC RATIONALE ..........................................................23 
 
Background .................................................................................................................23 
1.1.1 Summary of Pre-Clinical Studies with NmCV-5 ...........................................24 
1.1.2 Summary of Clinical Studies of NmCV-5 .....................................................25 
 
Scientific Rationale .....................................................................................................28 
1.2.1 Purpose of Study ............................................................................................28 
1.2.2 Study Population ............................................................................................28 
 
Potential Risks and Benefits .......................................................................................29 
1.3.1 Potential Risks ...............................................................................................29 
1.3.2 Potential Benefits ...........................................................................................31 
 
STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR OUTCOME MEASURES .....32 
 
Study Design Description ...........................................................................................32 
 
Study Objectives .........................................................................................................33 
2.2.1 Primary ...........................................................................................................33 
2.2.2 Secondary .......................................................................................................34 
2.2.3 Tertiary ...........................................................................................................34 
2.2.4 Exploratory ....................................................................................................34 
 
Study Endpoints or Outcome Measures .....................................................................34 
2.3.1 Primary ...........................................................................................................34 
2.3.2 Secondary .......................................................................................................34 

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2.3.3 Tertiary ...........................................................................................................35 
2.3.4 Exploratory ....................................................................................................36 
 
STUDY INVERVENTION/INVESTIGATIONAL PRODUCT .........................................37 
 
Study Product Description ..........................................................................................37 
3.1.1 Formulation, Packaging, and Labeling ..........................................................37 
3.1.2 Product Storage and Stability .........................................................................38 
 
Acquisition/Distribution .............................................................................................38 
 
Dosage/Regimen, Preparation, Dispensing and Administration of Study 
Intervention/Investigational Product.........................................................................39 
 
Pre-determined Modification of Study Intervention/Investigational Product for an 
Individual Subject .....................................................................................................39 
 
Accountability Procedures for the Study Intervention/Investigational Product(s) .....39 
 
SELECTION OF SUBJECTS AND STUDY ENROLLMENT AND WITHDRAWAL ....41 
 
Eligibility Criteria .......................................................................................................41 
4.1.1 Subject Inclusion Criteria...............................................................................41 
4.1.2 Subject Exclusion Criteria .............................................................................41 
 
Withdrawal from the Study, Discontinuation of Study Product, or Study Termination
 ..................................................................................................................................43 
4.2.1 Withdrawal from the Study or Discontinuation of the Study Product ...........43 
4.2.2 Subject Replacement ......................................................................................43 
4.2.3 Participants who are randomized into Group 2 (15-month) but are not 
vaccinated with a randomized meningococcal vaccine .................................44 
4.2.4 Study Termination .........................................................................................44 
 
STUDY PROCEDURES ......................................................................................................45 
 
Screening ....................................................................................................................45 
 
Enrollment ..................................................................................................................47 
 
Planned Study Visits ...................................................................................................50 
5.3.1 Follow-up .......................................................................................................50 
5.3.2 Final Study Visit ............................................................................................51 
5.3.3 Early Termination Visit .................................................................................51 
 
Field Worker Home or Community Visits .................................................................52 
 
Unscheduled Study Visits ...........................................................................................52 

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Protocol Deviations ....................................................................................................52 
 
DESCRIPTION OF CLINICAL AND LABORATORY EVALUATIONS .......................54 
 
Clinical Evaluations ....................................................................................................54 
 
Laboratory Evaluations ...............................................................................................55 
6.2.1 Clinical Laboratory Evaluations ....................................................................55 
6.2.2 Research Assays .............................................................................................55 
 
ASSESSMENT OF SAFETY ...............................................................................................56 
 
Assessing and Recording Safety Parameters ..............................................................56 
7.1.1 Adverse Events (AEs) ....................................................................................56 
7.1.2 Reactogenicity ................................................................................................57 
7.1.3 Serious Adverse Events (SAEs) .....................................................................59 
 
Specification of Safety Parameters .............................................................................59 
7.2.1 Unsolicited Events .........................................................................................59 
7.2.2 Medically-Attended Adverse Events (MAAEs) ............................................59 
 
Reporting Procedures ..................................................................................................60 
7.3.1 Reporting Serious Adverse Events ................................................................60 
7.3.2 Regulatory Reporting for Studies Not Conducted Under DMID-Sponsored 
IND ................................................................................................................61 
7.3.3 Reporting of Pregnancy .................................................................................61 
 
Type and Duration of Follow-up of Subjects after Adverse Events ...........................61 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings......................................................................................62 
 
Halting Rules ..............................................................................................................62 
7.6.1 Study Halting Criteria ....................................................................................62 
 
Safety Oversight .........................................................................................................62 
 
HUMAN SUBJECTS PROTECTION .................................................................................65 
 
Institutional Review Board/Independent Ethics Committee ......................................65 
 
STATISTICAL CONSIDERATIONS .................................................................................68 
 
Overview and Study Design .......................................................................................68 
 
Study Hypotheses .......................................................................................................68 
 
Sample Size Considerations .......................................................................................69 
 
Treatment Assignment Procedures .............................................................................71 

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9.4.1 Randomization Procedures ............................................................................71 
9.4.2 Masking Procedures .......................................................................................71 
 
Planned Interim Analyses ...........................................................................................72 
9.5.1 Interim Safety Review ...................................................................................72 
9.5.2 Interim Immunogenicity or Efficacy Review ................................................73 
 
Analysis Plan ..............................................................................................................73 
 
ELECTRONIC CASE REPORT FORMS, SOURCE DOCUMENTS AND ACCESS TO 
SOURCE DATA...................................................................................................................77 
 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................78 
 
DATA HANDLING AND RECORD KEEPING ................................................................79 
 Data Collection and Management Responsibilities ....................................................79 
 Data Coordinating Center/Biostatistician Responsibilities ........................................79 
 Data Capture Methods ................................................................................................80 
 Types of Data ..............................................................................................................80 
 Study Records Retention ............................................................................................80 
 
CLINICAL MONITORING .................................................................................................82 
 
PUBLICATION POLICY ....................................................................................................83 
 
LITERATURE REFERENCES ............................................................................................84 
 
APPENDICES ......................................................................................................................86 
 
Schedule of Events............................................................................86 
 
TOXICITY TABLE ..........................................................................88 
 
 

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LIST OF TABLES 
Table 1: Completed pre-clinical studies of NmCV-5 candidates ..................................................24 
Table 2: Percentage of subjects with seroresponse at 28-days following first dose in 
Malian Children ..........................................................................................................26 
Table 3: Current EPI Schedule in Mali ..........................................................................................27 
Table 4: “Enhanced” EPI Schedule for study participants ............................................................28 
Table 5: Study Group Design ........................................................................................................33 
Table 6. Toxicity Grading Scale – Solicited Local Reactions .......................................................58 
Table 7. Subjective Solicited Systemic Reactogenicity Grading ...................................................58 
Table 8. Power to test non-inferiority of the proportion of participant with seroprotective 
response at Day 29 for serogroup A, C, W and Y, for a non-inferiority 
margin of -10% (-0.1) and a sample size of at least 183 and 366 evaluable 
participants in MenACWY-TT and NmCV-5 arms, respectively. .............................70 
Table 9. Power to test non-inferiority of the proportion of participant with seroprotective 
response at Day 29 for serogroup X, when compared to lowest 
seroprotective response rate among A, C, W, Y serogroups, with a non-
inferiority margin of -10% (-0.1) and a sample size of at least 183 and 366 
evaluable participants in MenACWY-TT and NmCV-5 arms, respectively. .............70 
 
 
 

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LIST OF FIGURES 
Figure 1: 
 Schematic of Study Design ........................................................................................21 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
BCG 
Bacillus Calmette–Guérin vaccine, for tuberculosis 
CDSCO 
Central Drugs Standard Control Organisation, DCGI 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CMC 
Chemistry, Manufacturing and Control 
COI  
Conflict of Interest  
CRF 
Case Report Form 
CRM197 
Cross reactive material, detoxified mutant diphtheria toxin 
CROMS 
Clinical Research Operations and Management Support 
CSR  
Clinical Study Report 
CVD 
Center for Vaccine Development and Global Heath, Baltimore 
CVD-Mali 
Centre pour le Développement des Vaccines du Mali 
DCC 
Data Coordinating Center 
DCF 
Data Collection Form 
DCGI 
Drugs Controller General of India 
DDE 
Direct Data Entry 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID 
DPM 
Departement de Pharmacie et Medicaments 
DTwP 
Diphtheria, Tetanus, and Pertussis vaccine 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-Linked Immunosorbent Assay 
EPI 
Expanded Program on Immunization 
FDA 
Food and Drug Administration 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMT  
Geometric Mean Titer   
HepB 
Hepatitis B virus vaccine 
Hib 
Haemophilus influenzae type b conjugate vaccine 
IATA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ID 
Identification  
IDCRC 
Infectious Disease Clinical Research Consortium 
IDE 
Investigational Device Exemption 
 

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IEC 
Independent or Institutional Ethics Committee 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IPV 
Inactivated Polio Vaccine, parenteral 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
MAAE 
Medically-Attended Adverse Event 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MenA 
Monovalent meningococcal serogroup A conjugate vaccine, 
MenAfriVac® 
MenACYW-TT 
Quadrivalent meningococcal conjugate vaccine, Nimenrix® 
MM 
Medical Monitor 
MO 
Medical Officer 
MOP 
Manual of Procedures 
MR 
Measles-Rubella Vaccine 
MVP 
Meningitis Vaccine Project 
N 
Number (typically refers to subjects) 
NDA 
New Drug Application 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH 
NIBSC 
National Institute for Biological Standards and Control 
NIH 
National Institutes of Health, DHHS 
NmC 
Serogroup C 
NmCV-5 
Meningococcal (A,C,Y,W,X) polysaccharide conjugate vaccine 
NmW 
Serogroup W 
NmX 
Serogroup X 
NRA 
National Regulatory Agency 
OER 
Office of Extramural Research 
OHRP 
Office for Human Research Protections 
OPV 
Oral Polio Vaccine 
PCV 
Pneumococcal Conjugate Vaccine 
PEI 
Paul Ehrlich Institute 
PHE 
Public Health England  
PHI 
Protected Health Information 
PI 
Principal Investigator 
PP 
Per Protocol  
PQ 
Pre-Qualification 
PS 
Polysaccharides 
QA 
Quality Assurance 
QC 
Quality Control 
rSBA 
Rabbit complement serum bactericidal antibody 
SA 
Secondary Aims 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAGE 
WHO’s Strategic Advisory Working Group of Experts 
SAP 
Statistical Analysis Plan 

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SCHARP 
Statistical Center for HIV/AIDS Research & Prevention, at Fred 
Hutchinson Cancer Research Center 
SDCC 
Statistical and Data Coordinating Center 
SDSU 
Statistical and Data Science Unit  
SIIPL 
Serum Institute of India Pvt Ltd. 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Event 
TT 
Tetanus Toxoid 
UKHSA 
UK Health Security Agency 
US 
United States 
VTEU 
Vaccine and Treatment Evaluation Unit 
WHO 
World Health Organization 
YF 
Yellow Fever vaccine 
 

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PROTOCOL SUMMARY 
Title: 
A Phase 3 Trial to Evaluate the Safety, Immunogenicity, and 
Non-Interference with Concomitant Routine Vaccines, of a 
Meningococcal Serogroup ACYWX Conjugate Vaccine 
(NmCV-5) in Comparison with  MenACWY-TT Conjugate 
Vaccine in Healthy Malian Infants 
 
Design of the Study: 
 
 
This trial will evaluate a single dose of NmCV-5 administered at 
either 9 months or 15 months of age, time points in the 
Expanded Program on Immunization (EPI) schedule when 
meningococcal vaccine is most likely to be administered. Infants 
aged 9 months will be consented and randomized to the assigned 
age group to receive vaccine at 9 months or 15 months. Infants 
aged 9 months (eligibility 9-11 months) and randomized to the 9-
month age group will be randomized in a 2:1 ratio to receive a 
single dose of NmCV-5 or a single dose of MenACWY-TT. 
Prospectively identified and consented infants randomized to the 
15-month age group will return when aged 15 months (eligibility 
15-17 months) and will be randomized in a 2:1 ratio to receive a 
single dose of NmCV-5 or a single dose of MenACWY-TT. 
“Enhanced” EPI vaccines will be co-administered and will 
consist of 2-doses of a measles and rubella-containing vaccine 
administered at 9 months and 15 months and a single dose of 
yellow fever vaccine administered at 9 months. 
 
Study Rationale: 
 
Progressive introduction of MenAfriVac since 2010 has resulted 
in a substantial reduction in cases of serogroup A meningococcal 
disease. However, regular large-scale epidemics due to 
serogroups C, W and X remain common in the African 
meningitis belt. An affordable and scalable pentavalent 
meningococcal conjugate vaccine (NmCV-5) has been 
developed by SIIPL, the manufacturer of MenAfriVac. NmCV-5 
is designed to protect against serogroups A, C, W, Y and X. The 
immediate goal for the clinical development of NmCV-5 is for 
WHO Pre-Qualification (WHO-PQ), to enable the vaccine to be 
used in the Meningitis Belt of sub-Saharan Africa. 
 
The current Phase 3 study, as agreed under the WHO-PQ 
strategy, is a study of NmCV-5 in the infant Expanded Program 
on Immunization (EPI) schedule in sub-Saharan Africa.  This 

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study protocol is designed to provide evidence that concomitant 
vaccination with NmCV-5 will not significantly affect the 
immune responses of infants to their normally scheduled EPI 
vaccines. We have specifically designed this study to provide 
information at two distinct timepoints, 9 months and 15 months.  
The WHO-PQ quadrivalent meningococcal conjugate vaccine 
MenACWY-TT (Nimenrix®, manufactured by Pfizer) is to be 
the control comparator vaccine to NmCV-5. MenACWY-TT is 
approved for use in infants as young as 6 weeks of age. WHO 
supports the evaluation of the age ranges of 9 months and 15 
months under which NmCV-5 is intended to be adopted by 
stakeholder countries in the Meningitis Belt. 
 
The current Mali EPI schedule consists of a measles only 
vaccine, yellow fever vaccine, and MenA vaccine at 9 months of 
age; there is no 15 months of age EPI vaccine visit and typically 
only a single dose of a measles-containing vaccine is 
administered.  However, to satisfy the conditions for WHO-PQ, 
study participants will receive two doses of a measles-containing 
vaccine, at 9-months and 15-months.  Furthermore, the non-
inferiority evaluation must include an assessment of the rubella 
vaccine responses. These modifications to the standard Malian 
EPI schedule provide a level-of-care that is higher than the 
current standard-of-care for the general population.  Within the 
context of this study, we will refer to this as an “enhanced” EPI 
schedule. 
 
Study Phase: 
3 
Study Population: 
 
Healthy infants aged 9-11 months who reside in Bamako, Mali. 
Number of Sites: 
1  
 
Description of Study 
Products: 
 
NmCV-5 (the experimental meningococcal vaccine) is a 
pentavalent meningococcal (A, C, Y, W, X) polysaccharide-
conjugate vaccine composed of capsularpolysaccharides (PS) 
from Neisseria meningitidis serogroups A, C, Y, W, and X 
individually conjugated to a protein carrier, either mutant 
diphtheria  toxoid (CRM197) or tetanus toxoid (TT). 
 

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MenACWY-TT (the comparator meningococcal vaccine) is a 
WHO-PQ quadrivalent meningococcal (A, C, Y, W) 
polysaccharide-conjugate vaccine manufactured by Pfizer 
(known as Nimenrix®). 
 
“Enhanced” EPI Vaccines:  
The combined measles-rubella (MR) vaccine is WHO-PQ and 
manufactured by SIIPL.  
The yellow fever (YF) vaccine is WHO-PQ and manufactured 
by Sanofi Pasteur (Stamaril®). 
 
Primary Objectives 
Primary Endpoints  
• To demonstrate that the immune responses 
to meningococcal serogroups A, C, Y, W, 
and X elicited by one dose of NmCV-5 at 9 
months of age are non-inferior to the 
immune responses to meningococcal 
serogroups A, C, Y, W elicited by one dose 
of MenACWY-TT at 9 months of age, 
as measured by rabbit serum bactericidal 
antibody (rSBA) titers at 28 days 
after vaccination, and when meningococcal 
vaccines are given concomitantly with 
routine vaccines.  
• To demonstrate that the immune 
responses to meningococcal serogroups A, 
C, Y, W, and X elicited by one dose 
of NmCV-5 at 15 months of age are non-
inferior to the immune responses to 
meningococcal serogroups A, C, Y, W  
elicited by one dose of MenACWY-TT at 
15 months of age, measured by rSBA titers 
at 28 days after vaccination, and when 
meningococcal vaccines are given 
concomitantly with routine vaccines.  
• The percentage of participants with 
seroprotective response (rSBA antibody 
titers ≥ 8) against each meningococcal 
serogroup A, C, W and Y in the NmCV-5 
arm, 28 days after a single dose of 
meningococcal vaccine, relative to the 
percentage of participants with 
seroprotective response against each 
serogroup A, C, W and Y in the 
MenACWY-TT arm, among participants 
vaccinated at either 9 months or 15 months 
of age.  The percentage of participants with 
seroprotective response to serogroup X in 
the NmCV-5 arm, to be compared to the 
percentage of participants with the lowest 
seroprotective response among serogroups 
A, C, W and Y in the MenACWY-TT arm. 
 
Secondary Objectives 
Secondary Endpoints 
• To assess the safety and tolerability of a 
single dose of NmCV-5 or MenACWY-TT, 
when given concomitantly with routine 
vaccines.  
 
• All Serious Adverse Events (SAE), 
reported during the first 6-months of 
follow-up period after meningococcal 
vaccination.  
• All solicited AEs reported during a 7-day 
follow-up period after meningococcal 
vaccination. Solicited AEs include injection 

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site tenderness, injection site 
swelling/induration, injection site erythema, 
irritability, drowsiness, anorexia, vomiting,  
fever, and feverishness. 
• All unsolicited AEs reported through 28 
days after meningococcal vaccination. 
• To demonstrate that the immune responses 
to meningococcal serogroup X elicited by 
one dose of NmCV-5 (at either 9 or 15 
months of age) is superior to 
that elicited by MenACWY-TT (at either 9 
or 15 months of age) measured 
by rSBA titers at 28 days after vaccination.  
• The percentage of participants with 
seroprotective response (rSBA antibody 
titers ≥ 8) to serogroup X in the NmCV-5 
arm compared to the percentage of 
participants with seroprotective response to 
serogroup X in the MenACWY-TT arm, 28 
days after a single dose of meningococcal 
vaccine. 
• To demonstrate the non-inferiority of the 
immune responses to EPI vaccines 
(measles-rubella, yellow fever, measles 
booster) when co-administered with NmCV-
5 (at either 9 or 15 months of age) compared 
to the immune responses when co-
administration with MenACWY-TT (at 
either 9 or 15 months).  
• Proportion of participants with seropositive 
response for measles and rubella, and 
seroprotective titers for yellow fever 
vaccine. The seropositive response to 
measles vaccine is defined as anti-measles 
IgG concentration > 200 mIU/mL, at Day 
29. The seropositive response to rubella 
vaccine is defined as anti-rubella IgG 
concentration >20 IU/mL, at Day 29. The 
seroprotective response to yellow fever 
vaccine is defined as yellow fever 
neutralizing antibody titers ≥ 1:10. 
• To assess clinically significant immune 
response indicators elicited by a single dose 
of NmCV-5, given concomitantly with 
routine vaccines, as compared to those 
elicited by MenACWY-TT.  
 
• Level of rSBA titers (GMTs) against 
meningococcal serogroups A, C, W, X and 
Y at 28 days after a single dose of 
meningococcal vaccine at either 9 or 15 
months of age. 
• Percentage of participants with 
seroresponse* in rSBA titers to 
meningococcal serogroups A, C, W, X and 
Y at 28 days after a single dose of 
meningococcal vaccine at either 9 months 
or 15 months of age (subset of participants). 
*Seroresponse is defined as a post-
immunization (Day 29) rSBA titer of 32 or 
greater if the participant’s pre-immunization 
(Baseline) rSBA titer was < 8; or a ≥ four-fold 
increase over baseline at Day 29 post-
immunization if the participant’s pre-
immunization rSBA titer was ≥ 8. 

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• Number and proportion of participants with 
rSBA titers ≥ 128 at 28 days after a single 
dose of meningococcal vaccine. 
Tertiary Objective 
Tertiary Endpoint 
• To assess the safety of a single dose of 
NmCV-5 or MenACWY-TT through 2 
years of follow-up after meningococcal 
vaccination. 
• All SAEs, reported through 2 years of 
follow-up or during the entire study period.  
• To assess the persistence of the immune 
responses at 6 months and 2 years after 
meningococcal vaccination. 
• The number and proportion of participants 
with rSBA titers ≥ 8 and ≥ 128 and the 
calculated rSBA GMTs against each of the 
five meningococcal serogroups at 6 months 
and 2 years following meningococcal 
vaccination. 
Exploratory Objectives 
Exploratory Endpoints 
• To compare the immune responses of the 9-
month and 15-month group against each of 
the five meningococcal serogroups at Day 
29. 
• The comparison of the 9-month and 15-
month group proportions of seroprotective 
response rates and rSBA GMTs against 
each of the five meningococcal serogroups 
at Day 29. 
 
Study Eligibility Criteria: 
 
Inclusion Criteria: 
1. Male and female children between 9 months and 11 months 
old inclusive. 
2. Parent(s)/legal guardian(s) have provided written informed 
consent, after the nature of the study has been explained 
according to local regulatory requirements. 
3. The investigator believes that their parent(s)/guardian(s) will 
be available for all the subjects visits and will comply with 
the requirements of the protocol (e.g., timely reporting of 
adverse events). 
4. Individual is in good health as determined by medical 
history, physical examination, and clinical judgement of the 
investigator. (Note: the physical examination may have been 
performed on a separate screening day and will be 
considered valid if within 14 days of enrollment) 
5. Individual has completed their local infant EPI vaccines, not 
including 9-month EPI vaccines (at the 9-month visit) or 15-
month EPI vaccines (at the 15-month visit).  A birth dose of 
oral polio vaccine is not required. 
 

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Exclusion Criteria: 
1. History of receipt of any meningococcal vaccine. 
2. Has received a measles-containing vaccine. 
3. Current or previous, confirm or suspected disease caused by 
N. meningitidis. 
4. Household contact with and/or intimate exposure to an 
individual with any laboratory confirmed N. meningitidis 
infection within 60 days of enrolment or study vaccination 
(for the 15-month age group). 
5. History of severe allergic reactions after previous 
vaccinations or hypersensitivity to any study vaccine 
component including tetanus, diphtheria and mutant 
diphtheria toxoid (CRM197). 
6. Acute or chronic, clinically significant pulmonary, 
cardiovascular, metabolic, neurological, hepatic, or renal 
functional abnormality, as determined by medical history or 
physical examination. 
7. Any confirmed or suspected condition with impaired or 
altered function of the immune system (e.g., 
immunodeficiency, autoimmune conditions, malnutrition). 
8. Have any bleeding disorder which is considered a 
contraindication to intramuscular injection or blood draw. 
9. Severe acute malnutrition. Note: a weight-for-length Z-score 
of less than –3 satisfies this exclusion criteria. 
10. History of either hepatitis B or hepatitis C virus infection, 
human immunodeficiency virus infection, or hereditary 
immunodeficiency. 
11. Presence of major and clinically significant congenital 
defects.  
12. Chronic administration (defined as more than 14 days) of 
immunosuppressants or other immune-modifying drugs 
within three months prior to the study vaccination or 
planned use throughout the study period (for corticosteroids, 
this means prednisone, or equivalent, ≥ 0.5 mg/kg per day. 
Inhaled, intranasal, and topical steroids are allowed).  
13. Administration of blood, blood products and/or plasma 
derivatives or any parenteral immunoglobulin preparation in 
the past 3 months or planned use throughout the study 
period. 

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14. Administration of any vaccine within 14 days prior to 
enrolment in the study or planned administration of any 
vaccine within 14 days before or after study vaccination. 
15. Use of any investigational or non-registered drug or vaccine 
within 28 days prior to the administration of study vaccine 
or planned during the study. 
16. Malaria infection as confirmed by a Rapid Diagnostic Test. 
Note: subjects positive at screening may be treated for 
malaria as per national guidelines outside of the study, and 
if the subject remains eligible, vaccinated no earlier than 5 
days after completing treatment. 
17. Individuals who are close family member* of individuals 
conducting this study. *defined as a child with direct genetic 
relationship to a member of the study team. 
18. Have experienced a moderate or severe acute infection 
and/or fever (defined as temperature ≥ 37.5°C) within 3 days 
prior to enrolment or study vaccination. 
19. Have received systemic antibiotic treatment within 3 days 
prior to enrolment or study vaccination. 
20. Non-residence in the study area or intent to move out within 
six months. 
21. Any condition which, in the opinion of the investigator, 
might pose additional risk to the subject due to participation 
in the study. 
 
Duration of Individual 
Subject Participation: 
 
Approximately 24 or 30 months  
 
Estimated Time to Last 
Subject/Last Study Day: 
 
Approximately 4 years 
 
 
 

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Figure 1: 
 Schematic of Study Design 
 
 
Schedule of Events 
 
 Group 1: Participant Age (9-month group) 9 mon 
9 mon 
9 mon 10 mon 15 mon 33 mon 
 
Visit Screen Visit 1 
Visit 2 Visit 3 
Visit 4 
Visit 5 
ET 
Study Day 
 
1 
8 
29 
181 
730 
 
Window 
 
 
+3 
+7 
±14 
±45 
 
Informed Consent 
X 
 
 
 
 
 
 
Demographics1 
X 
 
 
 
 
 
 
Medical History including review of systems1  
X 
 
 
 
 
 
 
Determination / Confirmation of Eligibility 
X 
X 
 
 
 
 
 
Rapid Diagnostic Test for malaria 
 
X 
 
 
 
 
 
Photo of child 
 
X 
 
 
 
 
 
Vital Signs1,2 including axillary temperature 
X 
 
X 
X 
X 
X 
(X) 
Height, weight1 
X 
 
 
 
 
 
 
Physical exam1 
X 
 
X 
X 
X 
X 
(X) 
Randomization Step 1 
X 
 
 
 
 
 
 
Randomization Step 2 
 
X 
 
 
 
 
 
Blinded Vaccination 
 
X 
 
 
 
 
 
Administration of enhanced EPI vaccines† 
 
X 
 
 
X 
 
 
30-minute observation period post meningitis 
vaccination 
 
X 
 
 
 
 
 
7-day Memory Aid (dispense & collect) 4 
 
D 
C 
 
 
 
 
                  
           
      
                         
                
     
                 
     
      
     
         
     
                                                
                                                
                                                
                                           
                                           
                      
                                              
                                      
                                           
                                              
                                           
                                          
                                           
                                       
      
     
         
     
       
       
     
     
     
     
       
       
         
            
                 
                
      
      
      
      
       
       
       
       
       
       
       
       
       
                      
                         
                        
                         
                             
                  
                             
                        
                                       
                                      
                                       
                                
                               
                       
     
                       
     
        
     
        
     
        
     
        
     

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AE assessment 
 
X 
X 
X 
 
 
(X) 
Concomitant medications and vaccinations1,3 
X 
X 
X 
X 
 
 
X 
SAE assessment 
 
X 
X 
X 
X 
X 
X 
Research Blood Draw (mL) 
 
5 mL 
 
10 mL 
5 mL 
5 mL 
5 mL 
 
 
Group 2: Participant Age (15-month group) 
9 mon 15 mon 15 mon 16 mon 21 mon 39 mon 
 
Visit Screen Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 
ET 
Study Day 
 
1 
8 
29 
181 
730 
 
Window 
 
 
+3 
+7 
±14 
±45 
 
Informed Consent 
X 
 
 
 
 
 
 
Demographics1 
X 
 
 
 
 
 
 
Medical History including review of systems1 
X 
X 
 
 
 
 
 
Determination / Confirmation of Eligibility 
X 
X 
 
 
 
 
 
Rapid Diagnostic Test for malaria 
 
X 
 
 
 
 
 
Photo of child 
 
X 
 
 
 
 
 
Vital Signs1,2 including axillary temperature 
X 
X 
X 
X 
X 
X 
(X) 
Height, weight1 
X 
X 
 
 
 
 
 
Physical exam1 
X 
X 
X 
X 
X 
X 
(X) 
Randomization Step 1 
X 
 
 
 
 
 
 
Randomization Step 2 
 
X 
 
 
 
 
 
Blinded Vaccination 
 
X 
 
 
 
 
 
Administration of enhanced EPI vaccines† 
X 
X 
 
 
 
 
 
30-minute observation period post meningitis 
vaccination 
 
X 
 
 
 
 
 
7-day Memory Aid (dispense & collect) 4 
 
D 
C 
 
 
 
 
AE assessment 
 
X 
X 
X 
 
 
(X) 
Concomitant medications and vaccinations1,3 
X 
X 
X 
X 
 
 
X 
SAE assessment 
 
X 
X 
X 
X 
X 
X 
Research Blood Draw (mL) 
 
5 mL 
 
10 mL 
5 mL 
5 mL 
5 mL 
†, Enhanced EPI vaccines at 9-months consist of measles-rubella (MR) and yellow fever (YF) vaccine; the Enhanced 
EPI vaccine at 15-months consists of MR vaccine. 
1 Conducted after consent obtained. 
2 Vital signs include heart rate and respiratory rate. 
3 Concomitant medication and vaccination history will be updated at study visits through Day 29. 
4Field workers will visit homes as described in Section 5.4. 
( ) As applicable 
 

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BACKGROUND AND SCIENTIFIC RATIONALE 
 
Background  
Meningococcal meningitis, caused by invasive strains of Neisseria meningitidis, is a major 
public health concern because of its considerable morbidity and mortality in sub-Saharan Africa. 
Case fatality during meningococcal meningitis epidemics can surpass 15%, and rates of 
permanent sequelae among meningitis survivors in Africa are twice as high as they are in high-
income countries. Because of the fulminant clinical course of invasive bacterial meningitis and 
difficulties in access to care in the African meningitis belt, prevention by vaccination is the 
optimal way to reduce meningococcal meningitis morbidity and mortality. Before 2010, 
serogroup A meningococcal strains were routinely responsible for the majority (70-96%) of 
invasive meningococcal disease in sub-Saharan Africa.1 An annual epidemic could be associated 
with an incidence of meningococcal disease which could range between 100-1000 cases per 
100,000 persons in any given year.2 
In 2001, the Meningitis Vaccine Project (MVP), a partnership between the World Health 
Organization (WHO) and PATH, was established to develop an inexpensive monovalent 
meningococcal serogroup A vaccine which could address the high burden of disease in sub-
Saharan Africa.3 MVP created the meningococcal serogroup A polysaccharide tetanus toxoid 
conjugate vaccine known as MenAfriVac, which was manufactured by Serum Institute of India 
Pvt. Ltd. (SIIPL, Pune, India). Progressive introduction of MenAfriVac since 2010 resulted in a 
substantial reduction in cases of serogroup A meningococcal disease, such that by 2011-13, the 
incidence had dropped to 0.02 cases per 100,000 persons;4 by 2017, there were only two 
documented cases of serogroup A disease.5 
Despite the introduction of the highly effective and affordable monovalent conjugate vaccine, 
regular large-scale epidemics due to serogroups C, W and X remain common in the African 
meningitis belt. Although serogroup C (NmC) was historically known for only causing 
infrequent and sporadic cases of meningitis, in recent years NmC has been the cause of an 
increasing number of epidemics. In 2013, a novel NmC clone (ST-10217)6 emerged and has 
since been a source for a marked rise in the burden of serogroup C disease in sub-Saharan 
Africa.7,8 In 2017 alone, the largest outbreak of serogroup C disease was recorded, causing over 
14,000 cases in northern Nigeria.9 Serogroup W (NmW, formerly referred to as W-135) was also 
previously associated with infrequent epidemics, but NmW clone (ST11/ET37) was the cause of 
a substantial outbreak during the Hajj in 2000,10 and NmW has since been a major cause of 
meningococcal disease in sub-Saharan Africa.11 Similarly, although serogroup X (NmX) was 
formerly recognized as a rare cause of meningitis cases, NmX is now another important cause of 
meningococcal disease in sub-Saharan Africa.12 
No current polyvalent meningococcal conjugate vaccines are affordable at large scale for use in 
sub-Saharan Africa. Plus, there are no vaccines which address NmX. 

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An affordable and scalable pentavalent meningococcal conjugate vaccine (NmCV-5) has been 
developed by SIIPL, the manufacturer of MenAfriVac. NmCV-5 is designed to protect against 
serogroups A, C, W, Y and X. NmCV-5 contains meningococcal serogroups A and X 
polysaccharides conjugated to tetanus toxoid (TT) and serogroups C, W, and Y polysaccharides 
conjugated to Cross Reactive Material 197 (CRM197) protein, a genetically detoxified mutant 
diphtheria toxin.13 
1.1.1 Summary of Pre-Clinical Studies with NmCV-5 
NmCV-5 underwent preclinical studies.14 No safety concerns were observed and immune 
responses to all five serogroups were recorded. The United States Food and Drug Administration 
(U.S. FDA) reviewed the nonclinical studies, as part of an Investigational New Drug (IND) 
application, prior to the conduct of the first-in-human phase 1 trial. A summary of the completed 
pre-clinical studies is in Table 1. 
Table 1: Completed pre-clinical studies of NmCV-5 candidates 
Table 1: Completed pre-clinical studies of NmCV-5 candidates 
Study Title 
Site 
Type 
Animal Model 
5-week subcutaneous dose-ranging 
immunogenicity study of monovalent 
serogroup X conjugate (MenX-TT) 
with and without aluminum phosphate 
adjuvant 
SIIPL 
Immunogenicity; 
non-GLP 
Swiss albino 
mice 
7-week subcutaneous immunogenicity 
study of NmCV-5 with and within 
aluminum phosphate adjuvant 
National Institute for 
Biological Standards and 
Control (NIBSC), London, 
UK 
Immunogenicity; 
non-GLP 
BALB/c mice 
5-week intramuscular immunogenicity 
study of NmCV-5 formulations in 
comparison to commercial vaccine 
SIIPL 
Immunogenicity; 
non-GLP 
New Zealand 
white rabbits 
5-week intramuscular dose-ranging 
immunogenicity study of NmCV-5 
(tox formulation) with and without 
aluminum phosphate adjuvant 
SIIPL 
Immunogenicity; 
non-GLP 
New Zealand 
white rabbits 
7-week intramuscular toxicity study of 
NmCV-5 
MPI Research, Inc., 54943 
North Main St., Mattawan, 
MI 49071-8353, USA 
Toxicity & 
Immunogenicity; 
GLP 
New Zealand 
white rabbits 
Series of studies of 4-
pyrrolidinopyridine (a byproduct of 1-
cyano-4-
pyrrolininopyridiniumtetrafluoroborat
e conjugation chemistry) 
MPI Research, Inc., 54943 
North Main St., Mattawan, 
MI 49071-8353, USA 
And BioReliance Corp., 
14920 Broschart Rd., 
Rockville, MD, 20850-3349, 
USA 
Byproduct 
toxicology &  
Mutagenicity; GLP 
Rats, guinea 
pigs, prokaryotic 
& eukaryotic 
cells 
 
 

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1.1.2 Summary of Clinical Studies of NmCV-5 
Phase 1, Adults in U.S. 
A first-in-man phase 1 trial of NmCV-5 was performed at CVD (Baltimore, MD, U.S.A.) among 
healthy young American adults (published, NCT02810340).15 This is the only clinical study of 
NmCV-5 registered with the U.S. FDA. In this phase 1 trial, 60 consenting subjects 18 to 45 
years of age were randomly assigned in a 1:1:1 ratio to receive a single dose of either one of two 
formulations of NmCV-5 (adjuvanted with aluminum phosphate or non-adjuvanted) or the 
control vaccine, Menactra® (quadrivalent meningococcal polysaccharide diphtheria toxoid 
conjugate vaccine). The overall reported solicited reactogenicity (within 7-days post-
immunization) was 65, 60, and 50% of subjects for the adjuvanted NmCV-5, non-adjuvanted 
NmCV-5, and control groups, respectively. Injection site pain was the most common local 
reaction and headache was the most common systemic reaction. Most solicited reactogenicity, 
for the 7 days following vaccination, was mild and all were self-limiting.  Unsolicited AEs were 
also generally mild, and all resolved. There were no significant differences between the three 
vaccination groups in any solicited reaction.  All three vaccination groups demonstrated immune 
responses, by rabbit-complement serum bactericidal antibody (rSBA) assay, four weeks after 
vaccination to the A, C, Y, and W serogroups, whereas only the adjuvanted and non-adjuvanted 
NmCV-5 vaccination groups demonstrated immune responses to serogroup X. The four-fold or 
greater rises in rSBA titers for serogroups A, C, Y, and W appeared comparable across treatment 
groups, and for serogroup X, in the NmCV-5 groups, appeared comparable to frequencies seen 
with the other serogroups for the same vaccines. Moreover, four weeks after immunization, for 
all five serogroups, all subjects who received non-adjuvanted NmCV-5 and 95 to 100% of 
subjects who received adjuvanted NmCV-5 had serum rSBA titers of 128 or higher. 
Phase 2, Children in Mali 
A phase 2 trial of NmCV-5 was performed at CVD-Mali (Bamako, Mali) among healthy Malian 
children aged 12-16 months and evaluated two doses of NmCV-5 (both adjuvanted and 
nonadjuvanted formulations given 3 months apart (published, NCT03295318).16 In this trial, 375 
Malian children were randomly assigned in a 2:2:1 ratio to receive two doses, three months 
apart, of either one of two formulations of NmCV-5 (adjuvanted with aluminum phosphate or 
non-adjuvanted) or the control vaccine, Menactra®. The overall frequency for systemic solicited 
reactogenicity was 4.0, 3.9, and 5.4%; the frequency of local solicited reactogenicity was 1.3, 
3.0, and 0.7%. All solicited reactogenicity were reported as mild in severity, except for one 
instance of moderate fever; all solicited reactogenicity were self-limited. During the 28 days after 
receipt of the first dose, 26%, 25%, and 30% reported unsolicited AEs; none of these 122 AEs, 
other than 2 events of diarrhea in participants in the nonadjuvanted NmCV-5 group, were 
assessed by the investigator as being related to a trial vaccine. During the 28 days after receipt of 
the second dose, 12%, 16%, and 22% reported unsolicited AEs; none of these 58 AEs were 
assessed by the investigator as being related to a trial vaccine. At four weeks following the first 
dose of vaccine, seroresponse rates to all five serogroups were similar when comparing the 
adjuvanted and non-adjuvanted NmCV-5 groups; both NmCV-5 groups demonstrated higher 

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immune responses to all five serogroups when comparing to the control vaccine (Table 2). 
Based upon these data for safety and the lack of any apparent significant immune response 
benefits with aluminum phosphate adjuvant, a single-dose of the unadjuvanted NmCV-5 
formulation was selected for advancement in clinical development. 
Table 2: Percentage of subjects with seroresponse at 28-days following first dose in Malian 
Children 
Table 2: Percentage of subjects with seroresponse at 28-days following first dose in Malian Children 
 
Non-adjuvanted NmCV-5 
Adjuvanted NmCV-5 
Control 
Serogroup 
N 
% (95% CI) 
N 
% (95% CI) 
N 
% (95% CI) 
A 
146 
99.3 (96.3, 100) 
148 
100 (97.5, 100) 
72 
97.3 (90.6, 99.7) 
C 
144 
98.0 (94.2, 99.6) 
145 
98.0 (94.2, 99.6) 
52 
70.3 (58.5, 80.3) 
W 
143 
97.3 (93.2, 99.3) 
144 
97.3 (93.2, 99.3) 
67  90.5 (81.5, 96.1) 
X 
147 
100 (97.5, 100) 
146 
98.6 (95.2, 99.8) 
12 
16.2 (8.7, 26.6) 
Y 
143 
97.3 (93.2, 99.3) 
146 
98.6 (95.2, 99.8) 
64 
86.5 (76.5, 93.3) 
Phase 3 trials for Licensure and WHO Pre-Qualification 
The immediate goal for the clinical development of NmCV-5 is for WHO Pre-Qualification 
(WHO-PQ), to enable the vaccine to be used in the Meningitis Belt of sub-Saharan Africa. The 
NmCV-5 vaccine is registered with the National Regulatory Authority in India, under the Central 
Drugs Standard Control Organisation (CDSCO) office which is a component of the Drugs 
Controller General of India (DCGI). The most recent meeting between SIIPL, CDSCO, and the 
WHO-PQ team was held on October 9, 2020 to confirm the plan for regulatory registration in 
India (for licensure) as a requirement for WHO-PQ and allowing for the immediate use of the 
vaccine in sub-Saharan Africa. Since a longer-term goal for NmCV-5 is licensure in Europe, a 
scientific advisory meeting was held with the Paul Ehrlich Institute (PEI, Germany) on March 
26, 2020 to validate the nonclinical, clinical, and chemistry, manufacturing, and control (CMC) 
programs for NmCV-5—a review and approval of our current WHO-PQ strategy. There are no 
immediate plans for U.S. licensure of NmCV-5, therefore the U.S. FDA does not have a role in 
the regulatory oversight of the continuing development of NmCV-5. 
Three Phase 3 trials have been agreed upon as necessary for WHO-PQ, as reviewed by WHO 
and the WHO’s Strategic Advisory Working Group of Experts (SAGE) working group on 
meningococcal vaccines. Two of these Phase 3 trials are already underway, and this study 
protocol represents the third Phase 3 trial necessary for WHO-PQ.  
One Phase 3 study is being conducted in Mali (CVD-Mali) and The Gambia among 2-29-year-
olds (NCT03964012). A total of 1800 eligible participants were randomized 2:1 to NmCV-5 or 
control vaccine (Menactra®) in each of the three age strata 18-29 years, 11-17 years & 2-10 years 
(with n=400 NmCV-5 recipients and n=200 control vaccine recipients in each age stratum). Each 
subject received a single dose of study vaccine and was followed up for 6 months post 
vaccination during which solicited reactions (for seven days), unsolicited AEs (28 days) and 
SAEs (until the end of study, i.e., 180 days after vaccination) were collected. A blood sample 
was collected at baseline (pre-vaccination) and at day 28 post-vaccination for immunogenicity 

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assessment by rSBA. This phase 3 African multi-site study is anticipated to be completed by end 
of 2021. 
The second Phase 3 study is a lot-to-lot consistency study being conducted in India among 18-
85-year-old adults (NCT04358731). The immune responses to three consecutively manufactured 
lots of NmCV-5 are to be statistically compared against the control vaccine (Menactra®).  A total 
of 1640 subjects 18 to 85 years of age will be accrued contemporaneously across three age strata 
18 to 29 years, 30 to 60 years, and 61 to 85 years. Within each age stratum, subjects will be 
randomly assigned in a 3:1 ratio to receive either NmCV-5 or control vaccine. The NmCV-5 
subjects in the 18-29-year age group will be further randomized 1:1:1 to receive one of the three 
different lots of NmCV-5 (Lot A, B, or C). All the randomized subjects will receive a single dose 
of 0.5 ml of NmCV-5 or control vaccine on Day 1. Post vaccination site visits are planned on 
Days 8, 29 and 180; a telephone call follow-up visit will be completed at Day 85. This phase 3 
lot-to-lot consistency study is also anticipated to be completed by end of 2021. 
The third and last Phase 3 study, as agreed under the WHO-PQ strategy, is a study of NmCV-5 
in the infant EPI schedule in sub-Saharan Africa—this is the present study described in this 
protocol.  This study protocol is designed to provide evidence that concomitant vaccination with 
NmCV-5 will not significantly affect the immune responses of infants to their normally 
scheduled EPI vaccines. In sub-Saharan Africa, there are large differences between individual 
countries and their own EPI schedules. For example, MenAfriVac® is scheduled to be 
administered at 9 months in Mali, 12 months in The Gambia, 15 months in Burkina Faso, and at 
18 months in Ghana.  Because NmCV-5 will eventually be adopted within each respective 
country according to their own existing EPI schedules, we have specifically designed this study 
to provide information at two distinct timepoints, 9 months and 15 months.  The WHO-PQ 
quadrivalent meningococcal conjugate vaccine MenACWY-TT (Nimenrix®, manufactured by 
Pfizer) is to be the control comparator vaccine to NmCV-5. MenACWY-TT is approved for use 
in infants as young as 6 weeks of age. Menactra® is approved for use in children 1 year of age 
and older, thus cannot be used as the comparator vaccine for infants age 9 months. WHO 
supports the evaluation of the age ranges of 9 months and 15 months under which NmCV-5 is 
intended to be adopted by stakeholder countries in the Meningitis Belt. 
Table 3: Current EPI Schedule in Mali 
Table 3: Current EPI Schedule in Mali 
Birth 
6 weeks 
10 weeks 
14 weeks 
9 months 
15 months 
BCG 
OPV 
OPV 
DTwP 
Hib 
HepB 
PCV 
Rotavirus 
OPV 
DTwP 
Hib 
HepB 
PCV 
Rotavirus 
OPV 
DTwP 
Hib 
HepB 
PCV 
Rotavirus 
IPV 
Measles only 
Yellow fever 
MenA 
(none*) 
BCG, Bacillus Calmette–Guérin vaccine; OPV, oral poliovirus vaccine; DTwP, diphtheria-tetanus-pertussis vaccine; Hib, Haemophilus 
influenzae type b vaccine; HepB, hepatitis B virus vaccine; PCV, pneumococcal conjugate vaccine; IPV, inactivated poliovirus vaccine 
*Mali is beginning to implement a second dose of measles-containing vaccine within the EPI schedule in certain locations, but this is not yet 
widespread among the general population 

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The study design of this Phase 3 EPI study requires two notable modifications to the current 
standard EPI schedule in Mali. The current Mali EPI schedule consists of a measles only 
vaccine, yellow fever vaccine, and MenA vaccine at 9 months of age; there is no 15 months of 
age EPI vaccine visit and typically only a single dose of a measles-containing vaccine is 
administered.  However, to satisfy the conditions for WHO-PQ, study participants will receive 
two doses of a measles-containing vaccine, at 9-months and 15-months.  Furthermore, the WHO-
PQ non-inferiority evaluation must include an assessment of the potential effect on rubella 
vaccine responses. In order to satisfy the conditions for WHO-PQ, the measles-containing 
vaccine must contain rubella vaccine.  Therefore, the study design will include 2-doses of a 
measles and rubella-containing vaccine (measles and rubella vaccine [MR]; the first dose will be 
at 9 months of age (per the current EPI in Mali) and the second at 15 months of age.  These 
modifications to the standard Malian EPI schedule provide a level-of-care that is higher than the 
current standard-of-care for the general population.  Within the context of this study, we will 
refer to this as an “enhanced” EPI schedule. 
Table 4: “Enhanced” EPI Schedule for study participants 
“Enhanced” EPI Schedule for study participants 
Birth 
6 weeks 
10 weeks 
14 weeks 
9 months 
15 months 
No change 
from existing 
EPI schedule 
in Mali 
No change 
from existing 
EPI schedule 
in Mali 
No change 
from existing 
EPI schedule 
in Mali 
No change 
from existing 
EPI schedule 
in Mali 
Measles-Rubella 
Yellow fever 
(MenConjugate)* 
Measles-Rubella 
(MenConjugate)* 
 
*a pentavalent (NmCV-5) or quadrivalent (MenACWY-TT) meningococcal conjugate vaccine will be administered once, either at 9 months 
or at 15 months 
 
Scientific Rationale 
1.2.1 Purpose of Study 
This phase 3 study will evaluate a single dose of NmCV-5 at two time points in the EPI calendar 
where it is most likely to be used (i.e., at 9 months and 15 months of age). The comparator 
vaccine, MenACWY-TT is licensed as a single-dose vaccine for this age group. The primary aim 
is to determine whether a single dose of NmCV-5 given at 9 or 15 months is non-inferior to a 
single dose of MenACWY-TT in mounting immune responses against N. meningitidis 
serogroups A, C, W, and Y one month (28 days) after vaccination. Secondary aims (SA) include: 
to demonstrate that administration of NmCV-5 does not interfere with EPI vaccine responses 
(measles-rubella, yellow fever, measles booster) and to demonstrate that NmCV-5 elicits 
immune responses against serogroup X.  
1.2.2 Study Population 
The study will be conducted in healthy infants aged 9 and 15 months who reside in Bamako, 
Mali.   

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Potential Risks and Benefits 
1.3.1 Potential Risks 
Risks from NmCV-5 
This is an experimental meningococcal vaccine which is not locally approved. Among toddlers 
that have received intramuscular (IM) doses of NmCV-5, reactions over the 7 days after 
vaccination included injection site pain, redness, and swelling; there was also irritability, 
drowsiness, anorexia, vomiting, and fever. These local and systemic reactions were not severe, 
and all resolved without any permanent consequences.  No immediate allergic reactions have 
been observed but this is a theoretical risk with all vaccines.  Persons with a history of any severe 
allergic reactions to components in the vaccine (e.g., CRM or TT) are contraindicated from 
receipt of NmCV-5.  Since this is an experimental vaccine, there is a possibility of side effects 
that are not yet known, including rare allergic reactions that could be severe. Participants will be 
observed for any immediate reactions for 30 minutes after being vaccinated. 
Risks from Comparator Vaccine, MenACWY-TT 
This is a locally licensed meningococcal vaccine, approved for infants as young as 6 weeks of 
age. The very common (>10%) side effects of this vaccine include pain, swelling, and redness at 
the injection site, and fever, tiredness, headache, drowsiness, loss of appetite, and irritability. 
Other common (<10%) side effects include injection site bruising, diarrhea, vomiting, nausea, 
and rash. The uncommon (<1%) side effects of this vaccine may include crying, itching, feeling 
dizzy, aching muscles, arm and leg pain, generally feeling unwell, difficulty sleeping, lump at 
the injection site, and limb swelling. Persons with a prior severe allergic reaction to this vaccine 
or to a component of this vaccine (e.g., TT) are contraindicated from receipt of MenACWY-TT.  
Risks from Measles-Rubella Vaccine 
This is a WHO-PQ vaccine, approved for infants as young as 6 months of age. The common side 
effects of this vaccine include fever (<15%), transient rashes (5%), transient lymphadenopathy 
(5%).  Other possible side effects may include coryza, cough pharyngitis, headache, 
conjunctivitis, nausea, vomiting, lymphadenopathy, and joint pain. Febrile seizures are rare and 
may occur with a frequency of 1 case per 3000 doses administered. Immune thrombocytopenic 
purpura, a disorder affecting blood platelet counts, are rare and may occur with a frequency of 1 
case per 40,000 doses administered. Anaphylactic reactions are another very rare event which 
may occur with a frequency of 1.8 cases per million doses administered. Because this is a live, 
attenuated virus vaccine, the vaccine is contraindicated in persons who are severely 
immunocompromised as a result of congenital disease, HIV infection with immunocompromise, 
advanced leukemia or lymphoma, serious malignant disease, or treatment with high-dose 
steroids, alkylating agents or anti-metabolites, or in persons who are receiving 
immunosuppressive therapeutic radiation. The vaccine may contain traces of neomycin, so 
history of anaphylactic reactions to neomycin and history of severe allergic reaction to any 
component of the vaccine are absolute contraindications. There are extremely rare reports of 

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hypersensitivity reactions in persons allergic to cow’s milk. Such individuals should not receive 
the vaccine. 
Risks from Yellow Fever Vaccine 
This is a locally licensed vaccine, approved for infants as young as 6 months of age and is the 
same vaccine used in the current Mali EPI program. The common side effects of this vaccine 
include headache (33%), myalgia (25%), malaise (19%), low-grade fever (15%), chills (11%), 
and injection site pain and swelling.  Anaphylactic reactions are very rare and may occur at 0.8 
cases per 100,000 doses administered. The live, attenuated vaccine is associated with very rare 
vaccine-associated neurologic disease (YF-AND) which can be fatal and has been observed with 
persons <6 months of age, older persons >60 years of age, and persons with underlying 
immunosuppressive conditions. Vaccine-associated viscerotropic disease (YF-AVD) is another 
very rare event which can mimic natural infection with yellow fever virus, it may occur at 0.4 
cases per 100,000 doses administered.  An increased risk of YF-AVD is associated with older 
age (>60 years), history of thymus disease, or thymectomy. The vaccine is contraindicated for 
persons with a history of severe allergic reactions to any of the vaccine components, including 
eggs or egg products (persons who can eat eggs may receive the vaccine), chicken proteins, 
gelatin, or latex rubber (from the vial stopper). The vaccine is also contraindicated for persons 
with a thymus disorder that is associated with abnormal immune cell function (e.g., thymoma or 
myasthenia gravis), HIV infection, and persons who are severely immunocompromised. 
Risks with Blood Draws 
Drawing blood may cause pain, bruising, lightheadedness, fainting, bleeding, and rarely 
infection. The research team will use gloves and sterile equipment and will cleanse the site of 
blood draw with alcohol prior to blood draw to reduce the risk of infection. 
Risk to Confidentiality 
We will collect personal health information (PHI) on all participants and this sensitive 
information is intended to be maintained as confidential, within the limits of the law. We will 
also take photographs of the children as part of ensuring that study participants can be re-
identified on subsequent visits, this is a locally accepted practice to help the study team match 
study participants with their identify and helps to ensure the research records are accurate. 
However, there is a risk for unauthorized access this PHI. Paper research records will be kept in 
locked files or maintained in locked rooms in the research area.  Electronic research records will 
be password protected. Only authorized study personnel who are involved in the study will be 
allowed to have access to this PHI. Any publication from this study will not use information 
which will reveal the identities of individuals.  
Risk with Delayed Meningococcal Vaccination 
Some study participants will be randomized to delay the receipt of meningococcal vaccination to 
15-months. The monovalent MenA vaccine is normally administered at the 9-month EPI visit.  
The local epidemiology of serogroup A meningococcal disease has been nearly eliminated since 

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the beginning of routine MenA EPI vaccination. Therefore, there is a very small risk that the 
delayed vaccination will present a window of vulnerability to invasive serogroup A 
meningococcal disease. Furthermore, WHO recommends MenA vaccination may be 
administered anytime between 9 and 18 months, so this does not represent a delay according to 
WHO’s recommendation. 
Unknown Risks 
The study vaccine is experimental. There is a chance that there are additional risks that we 
cannot foresee right now. Study personnel will inform study participants if there is any 
significant new information regarding the risks or benefits of this study. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by US Law. This web site will not include information that can identify subjects. This web site 
will include a summary of the results in a tabular format including participant flow; demographic 
and baseline characteristics; primary outcomes, as well as results of any scientifically appropriate 
statistical tests; and adverse event information. 
There may be other risks, discomforts, or side effects that are unknown at this time. 
1.3.2 Potential Benefits 
All study participants will be given the opportunity to receive “enhanced” EPI vaccination. There 
should be improved protection against measles with the receipt of two doses of a measles-
containing vaccine.  The receipt of this vaccine, containing rubella, also benefits the infant 
through protection from rubella. Instead of the monovalent meningitis vaccine (MenAfriVac), 
participants will receive either the pentavalent NmCV-5 vaccine or the quadrivalent 
MenACWY-TT vaccine. There is the possible benefit of being afforded protection against some 
of the additional meningococcal serogroups which are known to cause invasive disease in sub-
Saharan Africa.  All study participants will have close monitoring with scheduled follow-up 
visits with the research clinic and this close follow-up may also provide a benefit to the infant 
through improved access to medical care. 
 

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STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR OUTCOME MEASURES 
 
Study Design Description 
Infants aged 9 months (eligibility 9-11 months) will be consented, enrolled at Step 1, and 
randomized. A first-step randomization at a 1:1.2 ratio will determine whether the infant will 
receive blinded meningococcal study product at the 9-month (Group 1, n=600) or the 15-month 
(Group 2, n=720) enhanced EPI vaccination visit.  Within the 9-month or 15-month age groups, 
a second-step randomization at a 2:1 ratio will determine whether the study participant will 
receive a single dose of NmCV-5 (Group 1A or 2A) or a single dose of control vaccine, 
MenACWY-TT (Group 1B or 2B). The infant will be considered enrolled upon the successful 
first step randomization of the study, which will occur at the time of presenting to their 9-month 
EPI visit.   
If the randomized study product is to be administered at the 15-month visit, the prospectively 
identified and consented infants will complete their designated “enhanced” EPI immunizations at 
the 9-month visit, except no meningococcal vaccine will be administered. At their 15-month visit 
(eligibility 15-17 months), these infants will receive a single dose of NmCV-5 or a single dose of 
control vaccine, as per the second-step randomization at a 2:1 ratio. Because we anticipate up to 
20% of infants may be lost to follow-up (i.e., fail to return to the clinic for their 15-month visit) 
or may become ineligible (e.g., receives MenAfriVac prior to the 15-month visit), there is the 
plan to over randomize study infants into the 15-month group—this is the underlying reason for 
the first-step randomization at 1:1.2.  Upon successful randomization of 600 eligible infants into 
the 15-month groups, all remaining prospectively identified infants (up to n=120) regardless of 
age upon return will be offered immunization with MenACWY-TT and the “enhanced” EPI 
vaccinations from available study supply, but otherwise are no longer eligible for the study (i.e., 
will not be followed in the context of this study). If “enhanced” EPI vaccinations are declined or 
not available, infants will be referred to local clinic for standard EPI vaccination. 
In this study, “enhanced” EPI vaccines will be co-administered at indicated time points. There 
will be a measles and rubella-containing vaccine (i.e., MR) and yellow fever vaccine at 9-months 
and a second dose of a measles and rubella-containing vaccine at 15-months.  Concurrent 
administration of these EPI vaccines with the blinded study product (i.e., co-administration of 
these vaccines in the same visit) is acceptable and preferred. Study blood samples are to be 
obtained at four timepoints for all study infants; at baseline prior to meningococcal vaccination, 
at 28-days, 6-months and 2 years after meningococcal vaccination. The study is designed to have 
at least 90% power to meet both the primary non-inferiority objective compared to MenACWY-
TT and the objectives related to non-interference with co-administered vaccines.  
 
 

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Table 5: Study Group Design 
Group  
9 
(9) months of age 
151 
(15) months of age 
Primary endpoint 
measurement 
Immuno- 
persistence 
1A (n=400)  
NmCV-5 
+ MR + YF 
 
MR 
Serology 28-days 
post-vaccination 
Serology 6-
months and 2-
years 
post-vaccination 
1B (n=200)  
MenACWY-TT 
+ MR + YF 
 
MR 
2A (n=400)  
 
MR + YF 
NmCV-5 
+ MR 
2B (n=200) 
 
MR + YF 
MenACWY-TT 
+MR 
NmCV-5 = pentavalent meningococcal conjugate vaccine; MenACWY-TT = quadrivalent meningococcal 
conjugate vaccine; MR = measles-rubella containing vaccine; YF = yellow fever vaccine; 
1 Once 600 children are randomized to Groups 2A and 2B, the remaining prospectively identified infants (up to 
n=120) will be provided immunization with MenACWY-TT + MR and will not complete follow up study visits.  
Because the study vaccines may have different appearances, it may not be possible for the 
vaccinator to be blinded. Designated vaccinators will not partake in any post-vaccination 
evaluation. Parents or guardians of participants, laboratory personnel, and the researchers 
responsible for evaluation will remain blinded. Study vaccinations will be administered in a 
monitored environment where treatment for immediate reactions such as anaphylaxis, will be 
available. Study physicians will be onsite during all vaccinations, and subjects will be observed 
for 30 minutes following vaccination. The rabbit complement-dependent serum bactericidal 
antibody (rSBA) assay will be performed at UK Health Security Agency (UKHSA) in 
Manchester, UK, an international reference laboratory for meningococcal vaccine immunology. 
UKHSA performed the assays for all trials of MenAfriVac as well as the Phase I and II trials of 
NmCV-5. Immunological assays for measles, rubella, and yellow fever will be performed at 
VisMederi in Siena, Italy. .  
 
Study Objectives 
2.2.1 Primary   
• To demonstrate that the immune responses to meningococcal serogroups A, C, Y, W, and 
X elicited by one dose of NmCV-5 at 9 months of age are non-inferior to the immune 
responses to meningococcal serogroups A, C, Y, W elicited by one dose of MenACWY-
TT at 9 months of age, as measured by rabbit serum bactericidal antibody (rSBA) titers at 
28 days after vaccination, and when meningococcal vaccines are given concomitantly 
with routine vaccines.  
• To demonstrate that the immune responses to meningococcal serogroups A, C, Y, W, and 
X elicited by one dose of NmCV-5 at 15 months of age are non-inferior to the immune 
responses to meningococcal serogroups A, C, Y, W elicited by one dose of MenACWY-
TT at 15 months of age, measured by rSBA titers at 28 days after vaccination, and when 
meningococcal vaccines are given concomitantly with routine vaccines.  

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2.2.2 Secondary   
• To assess the safety and tolerability of a single dose of NmCV-5 or MenACWY-TT, 
when given concomitantly with routine vaccines.  
• To demonstrate that the immune responses to meningococcal serogroup X elicited by one 
dose of NmCV-5 (at either 9 or 15 months of age) is superior to that elicited by 
MenACWY-TT (at either 9 or 15 months of age) measured by rSBA titers at 28 days 
after vaccination.  
• To demonstrate the non-inferiority of immune responses to EPI vaccines (measles-
rubella, yellow fever, measles booster) when co-administered with NmCV-5 (at either 9 
or 15 months of age) compared to the immune responses when co-administration with 
MenACWY-TT (at either 9 or 15 months).  
• To assess other clinically significant immune response indicators elicited by a single dose 
of NmCV-5, given concomitantly with routine vaccine, as compared to those elicited by 
MenACWY-TT.  
2.2.3 Tertiary 
• 
To assess the safety of a single dose of NmCV-5 or MenACWY-TT through 2 years of 
follow-up after meningococcal vaccination. 
• 
To assess the persistence of the immune responses at 6 months and 2 years after 
meningococcal vaccination. 
2.2.4 Exploratory  
• To compare the immune responses of the 9-month and 15-month group against each of 
the five meningococcal serogroups at Day 29. 
 
Study Endpoints or Outcome Measures   
2.3.1 Primary  
Primary Outcome Measures - Immunogenicity 
• The percentage of participants with seroprotective response (rSBA antibody titers ≥ 8) 
against each meningococcal serogroup A, C, W, X and Y in the NmCV-5 arm, 28 days 
after a single dose of meningococcal vaccine, relative to the percentage of participants 
with seroprotective response against each serogroup A, C, W and Y in the MenACWY-
TT arm, among participants vaccinated at either 9 months or 15 months of age.  The 
percentage of participants with seroprotective response to serogroup X in the NmCV-5 
arm, to be compared to the percentage of participants with the lowest seroprotective 
response among serogroups A, C, W and Y in the MenACWY-TT arm. 
2.3.2 Secondary 
Secondary Outcome Measures - Meningococcal Response 

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• The percentage of participants with seroprotective response (rSBA antibody titers ≥ 8) to 
serogroup X in the NmCV-5 arm compared to the percentage of participants with 
seroprotective response to serogroup X MenACWY-TT arm, 28 days after a single dose 
of meningococcal vaccine. 
• 
Level of rSBA titers (GMTs) against meningococcal serogroups A, C, W, X and Y at 28 
days after a single dose of meningococcal vaccine at either 9 or 15 months of age. 
• 
Percentage of participants with seroresponse* in rSBA titers to meningococcal 
serogroups A, C, W, X and Y at 28 days after a single dose of meningococcal vaccine at 
either 9 months or 15 months of age (subset of participants). *Seroresponse is defined as 
a post-immunization (Day 29) rSBA titer of 32 or greater if the participant’s pre-
immunization (Baseline) rSBA titer was < 8; or a ≥ four-fold increase over baseline at 
Day 29 post-immunization if the participant’s pre-immunization rSBA titer was ≥ 8. 
• 
Number and proportion of participants with rSBA titers ≥ 128 at 28 days after a single 
dose of meningococcal vaccine. 
Secondary Safety Endpoints 
• Any Serious Adverse Events (SAE), reported during the first 6-months of follow-up 
period after meningococcal vaccination.  
• All solicited AEs reported during a 7-day follow-up period after meningococcal 
vaccination. Solicited AEs include injection site tenderness, injection site 
swelling/induration, injection site erythema, irritability, drowsiness, anorexia, vomiting, 
fever, and feverishness. 
• All unsolicited AEs reported through 28 days after meningococcal vaccination. 
Secondary Immunogenicity Endpoints 
• Proportion of participants with seropositive response for measles and rubella and 
seroprotective titers for yellow fever vaccine. The seropositive response to measles 
vaccine is defined as anti-measles IgG concentration >200 mIU/mL, at Day 29. The 
seropositive response to rubella vaccine is defined as anti-rubella IgG concentration >20 
IU/mL, at Day 29. The seroprotective response to yellow fever vaccine is defined as 
yellow fever neutralizing antibody titers ≥ 1:10. 
2.3.3 Tertiary 
Tertiary Safety Endpoints 
• 
All SAEs, reported through 2 years of follow-up or during the entire study period.  
• 
The number and proportion of participants with rSBA titers ≥ 8 and ≥ 128 and the 
calculated rSBA GMTs against each of the five meningococcal serogroups at 6 months 
and 2 years following meningococcal vaccination. 

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2.3.4 Exploratory 
Exploratory Immunogenicity Endpoints 
• The comparison of the 9-month and 15-month group proportions of seroprotective 
response rates and rSBA GMTs against each of the five meningococcal serogroups at 
Day 29. 

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STUDY INVERVENTION/INVESTIGATIONAL PRODUCT 
 
Study Product Description 
3.1.1 Formulation, Packaging, and Labeling 
NmCV-5 Vaccine: Active Product(s) and Components 
The NmCV-5 investigational vaccine, manufactured by SIIPL, is formulated as a lyophilized 
powder containing meningococcal serogroups A and X polysaccharides conjugated to TT and 
meningococcal serogroups C, W and Y polysaccharides conjugated to CRM197 protein. The 
vaccine is to be reconstituted with normal saline just prior to administration. The NmCV-5 
lyophilized powder component contains sucrose, sodium citrate and trometamol as excipients. 
This vaccine is presented as a freeze-dried powder in a single-dose vial. 
0.9% Sodium Chloride (normal saline) is the diluent used to prepare NmCV-5 and it is provided 
with vaccine. The diluent is a clear, colorless liquid.  For the preparation of the NmCV-5 from a 
single dose vial, the contents are contemporaneously reconstituted with 0.63 ± 0.03 mL of 
provided diluent (normal saline). After reconstitution, a single 0.5 mL dose of NmCV-5 
injectable solution will have the following composition: 5 mcg of weight for each of the five 
polysaccharides (A, C, Y, W, and X), tetanus toxoid, CRM197, sucrose, sodium citrate, TRIS 
(trometamol), and sodium chloride. 
MenACWY-TT: Comparator Vaccine  
The comparator vaccine is the licensed meningococcal ACWY-TT conjugate vaccine, 
manufactured by Pfizer. MenACWY-TT is supplied as a single-dose vial of lyophilized powder 
containing meningococcal serogroups A, C, W, and Y polysaccharides conjugated to TT; the 
vaccine vial also contains sucrose and trometamol as excipients. The vaccine is to be 
reconstituted with the solvent, consisting of sodium chloride and water for injection, from a pre-
filled single-use syringe. The reconstituted MenACWY-TT vaccine contains: 5 mcg of weigh for 
each of the four polysaccharides (A, C, W, and Y), tetanus toxoid, sucrose, trometamol, and 
sodium chloride. 
Measles and Rubella Vaccine 
The MR vaccine is WHO-PQ and manufactured by SIIPL. MR is prepared from live, attenuated 
Edmonston-Zagreb measles virus and Wistar RA27/3 rubella virus propagated in human diploid 
cells. MR is supplied as a single-dose vial of lyophilized powder, when reconstituted with the 
provided diluent in the vaccine package, each dose of 0.5 mL contains ≥1000 CCID50 (cell 
culture infective dose 50%) measles virus and ≥1000 CCID50 rubella virus. 
Yellow Fever Vaccine 
The YF vaccine (Stamaril®, manufactured by Sanofi Pasteur) is WHO-PQ and will be acquired 
through the EPI program. YF was prepared from live, attenuated 17D yellow fever virus 
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embryos. YF is supplied as lyophilized powder in vials with solvent containing lactose, sorbitol, 
histidine, alanine, and sodium chloride.  Each reconstituted dose of YF contains ≥1000 LD50 
(historically the units refer to a weanling mouse intracerebral lethal dose 50%) yellow fever 
virus. 
3.1.2 Product Storage and Stability 
NmCV-5 
The NmCV-5 vaccine including diluent should be stored at 2°C to 8°C. Do not freeze. Following 
reconstitution with normal saline, it is recommended to be administered immediately and no 
more than two hours and may be kept at room temperature. 
MenACWY-TT 
MenACWY-TT vaccine including solvent should be stored at 2°C to 8°C. Do not freeze. A 
single dose vial (type I glass vial with butyl rubber stopper) containing lyophilized vaccine 
powder and a pre-filled syringe with solvent is provided for each dose of vaccine. Following 
reconstitution with solvent, it is recommended to be administered immediately. 
Measles and Rubella Vaccine 
MR vaccine including diluent should be stored in the dark at 2°C to 8°C. It is important to 
protect both the freeze-dried and reconstituted vaccine from the light. For long-term storage of 
the freeze-dried vaccine, -20°C (-15°C or colder) is recommended. The diluent should not be 
frozen but should be kept at refrigeration, 2°C to 8°C. Following reconstitution with diluent, the 
vaccine should be used within 2 hours but may be stored in the dark at 2°C to 8°C for no longer 
than 6 hours. 
Yellow Fever Vaccine 
YF vaccine including solvent should be stored at 2°C to 8°C. Do not freeze. Following 
reconstitution with solvent, it is recommended to administer the dose within six hours and stored 
at 2°C to 8°C. 
 
Acquisition/Distribution 
The study product NmCV-5 and MR vaccine will be provided by SIIPL to the clinical site. The 
control vaccine MenACWY-TT will be acquired from a commercial source by Centre pour le 
Développement des Vaccins, Mali (CVD-Mali). The YF vaccine will be acquired from the Mali 
EPI program. Detailed information regarding the acquisition and distribution of the study 
product will be included in the Manual of Procedures (MOP).  
 

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Dosage/Regimen, Preparation, Dispensing and Administration of Study 
Intervention/Investigational Product 
NmCV-5: Active Product(s) 
 NmCV-5 is reconstituted by transferring the entire volume of diluent from ampoule into the 
lyophilized vaccine vial. After reconstitution the vaccine must be used as soon as possible but 
not later than two hours, during which time it may be kept at room temperature but must not be 
frozen.  0.5 mL is then injected to the subject intramuscularly. The preferred site of 
administration is the anterolateral aspect of the thigh. 
MenACWY-TT: Comparator Vaccine  
MenACWY-TT must be reconstituted by adding the entire content of the pre-filled syringe of 
solvent to the vial containing the lyophilized powder vaccine. This reconstituted vaccine should 
be maintained at room temperature. Following reconstitution, it is recommended to be 
administered promptly within two hours. Approximately 0.5 mL of the contents is then injected 
to the subject intramuscularly. The preferred site of administration is the anterolateral aspect of 
the thigh. 
Measles and Rubella Vaccine 
MR should be reconstituted only with the entire diluent supplied. The reconstituted vaccine 
should be used immediately but may be stored in the dark at 2°C to 8°C for no longer than 6 
hours. All of the contents from the reconstituted vaccine vial will be drawn. A single dose of 0.5 
mL should be administered by deep subcutaneous injection into the deltoid.  
Yellow Fever Vaccine 
YF should be reconstituted only with the entire solvent supplied. The reconstituted vaccine 
should be used immediately but may be refrigerated and stored at 2°C to 8°C for up to 6 hours. A 
single dose of 0.5 mL should be administered by subcutaneous route into the deltoid. 
 
Pre-determined Modification of Study Intervention/Investigational Product for an 
Individual Subject 
Prior to vaccination, subjects must be determined to be eligible for study vaccination and it must 
be clinically appropriate in the judgement of the investigator to vaccinate. Eligibility review will 
include a specific assessment for whether the subject has received a meningococcal vaccine. 
Concomitant administration of routine EPI vaccines is to be documented as concomitant 
medications and are not considered study vaccines. 
 
Accountability Procedures for the Study Intervention/Investigational Product(s) 
The study product NmCV-5 and MR will be provided by SIIPL to the clinical site. The control 
vaccine MenACWY-TT will be acquired from a commercial source. The YF vaccine will be 

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acquired from the Mali EPI program. Once received, the study products will be stored in and 
dispensed from the CVD-Mali Investigational Pharmacy. Instructions on study product 
destruction will be included in the MOP.  
The Investigator is responsible for ensuring that a current record of product disposition is 
maintained, and product is dispensed only at an official study site by authorized personnel as 
required by applicable regulations and guidelines. Records of product disposition consist of the 
date received, date administered, quantity administered, and the subject number to whom the 
drug was administered.  
The Investigational Pharmacist will be responsible for maintaining accurate records of the 
shipment and dispensing of the investigational product. The pharmacy records must be available 
for inspection by the DMID monitoring contractors and is subject to inspection by a regulatory 
agency as applicable at any time. An assigned Study Monitor will review the pharmacy records. 
Unused reconstituted investigational product vials will be stored at 2oC to 8oC in the 
Investigational Pharmacy until clinical trial accountability is completed. At study termination, all 
unused investigational product will be disposed in accordance with the MOP following complete 
drug accountability and monitoring. 

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SELECTION OF SUBJECTS AND STUDY ENROLLMENT AND WITHDRAWAL 
 
Eligibility Criteria 
4.1.1 Subject Inclusion Criteria 
In order to participate in this study, all subjects must meet ALL of the inclusion criteria 
described. 
1. Male and female children between 9 months and 11 months old inclusive. 
2. Parent(s)/legal guardian(s) have provided written informed consent, after the nature of the 
study has been explained according to local regulatory requirements. 
3. The investigator believes that their parent(s)/guardian(s) will be available for all the subjects 
visits and will comply with the requirements of the protocol (e.g., timely reporting of adverse 
events). 
4. Individual is in good health as determined by medical history, physical examination, and 
clinical judgement of the investigator. (Note: the physical examination may have been 
performed on a separate screening day and will be considered valid if within 14 days of 
enrollment) 
5. Individual has completed their local infant EPI vaccines, not including 9-month EPI vaccines 
(at the 9-month visit) or 15-month EPI vaccines (at the 15-month visit).  A birth dose of oral 
polio vaccine is not required. 
4.1.2 Subject Exclusion Criteria 
In order to participate in this study, all subjects must meet NONE of the exclusion criteria 
described. 
1. History of receipt of any meningococcal vaccine. 
2. Has received a measles-containing vaccine. 
3. Current or previous, confirm or suspected disease caused by N. meningitidis. 
4. Household contact with and/or intimate exposure to an individual with any laboratory 
confirmed N. meningitidis infection within 60 days of enrolment or study vaccination (for the 
15-month age group). 
5. History of severe allergic reactions after previous vaccinations or hypersensitivity to any 
study vaccine component including tetanus, diphtheria and mutant diphtheria toxoid 
(CRM197). 
6. Acute or chronic, clinically significant pulmonary, cardiovascular, metabolic, neurological, 
hepatic, or renal functional abnormality, as determined by medical history or physical 
examination. 

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7. Any confirmed or suspected condition with impaired or altered function of the immune 
system (e.g., immunodeficiency, autoimmune conditions, malnutrition). 
8. Have any bleeding disorder which is considered a contraindication to intramuscular injection 
or blood draw. 
9. Severe acute malnutrition. Note: a weight-for-length Z-score of less than –3 satisfies this 
exclusion criteria. 
10. History of either hepatitis B or hepatitis C virus infection, human immunodeficiency virus 
infection, or hereditary immunodeficiency. 
11. Presence of major and clinically significant congenital defects.  
12. Chronic administration (defined as more than 14 days) of immunosuppressants or other 
immune-modifying drugs within three months prior to the study vaccination or planned use 
throughout the study period (for corticosteroids, this means prednisone, or equivalent, ≥ 0.5 
mg/kg per day. Inhaled, intranasal, and topical steroids are allowed).  
13. Administration of blood, blood products and/or plasma derivatives or any parenteral 
immunoglobulin preparation in the past 3 months or planned use throughout the study period. 
14. Administration of any vaccine within 14 days prior to enrolment in the study or planned 
administration of any vaccine within 14 days before or after study vaccination. 
15. Use of any investigational or non-registered drug or vaccine within 28 days prior to the 
administration of study vaccine or planned during the study. 
16. Malaria infection as confirmed by a Rapid Diagnostic Test. Note: subjects positive at 
screening may be treated for malaria as per national guidelines outside the study, and if the 
subject remains eligible, vaccinated no earlier than 5 days after completing treatment. 
17. Individuals who are close family member* of individuals conducting this study. *defined as 
a child with direct genetic relationship to a member of the study team. 
18. Have experienced a moderate or severe acute infection and/or fever (defined as temperature 
≥ 37.5°C) within 3 days prior to enrolment or study vaccination. 
19. Have received systemic antibiotic treatment within 3 days prior to enrolment or study 
vaccination. 
20. Non-residence in the study area or intent to move out within six months. 
21. Any condition which, in the opinion of the investigator, might pose additional risk to the 
subject due to participation in the study. 

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Withdrawal from the Study, Discontinuation of Study Product, or Study Termination  
4.2.1 Withdrawal from the Study or Discontinuation of the Study Product  
Parent(s)/legal guardian(s) may voluntarily withdraw their consent for study participation at any 
time without penalty or loss of benefits to which they are otherwise entitled.   
An investigator may also withdraw a subject from receiving the study product for any reason. 
Follow-up safety evaluations will be conducted if the subject agrees.  If a subject withdraws or is 
withdrawn prior to completion of the study, the reason for this decision must be recorded in the 
electronic case report forms (eCRFs).  
The reasons, might include, but are not limited to the following: 
• 
Subject no longer meets eligibility criteria 
• 
Subject meets halting criteria (reference to Section 7.6.1) 
• 
Study has been halted 
• 
Subject becomes noncompliant 
• 
Medical disease or condition, or new clinical finding(s) for which continued 
participation, in the opinion of the investigator might compromise the safety of the 
subject, interfere with the subject's successful completion of this study, or interfere with 
the evaluation of responses 
• 
Subject lost to follow-up 
• 
Subject does not receive meningococcal study product as part of step 2 randomization at 
the 15-month visit, due to the study having already filled the total enrollment number. 
• 
Determined by a physician’s discretion to require additional therapy not indicated in the 
protocol to ensure subject’s health and well-being (or treatment failure, if applicable) 
The investigator should be explicit regarding study follow-up (e.g., safety follow-up) that might 
be carried out despite the fact the subject will not receive further study product.  If the subject 
consents, every attempt will be made to follow all AEs through resolution.  The procedures that 
collect safety data for the purposes of research must be inclusive in the original informed consent 
or the investigator may seek subsequent informed consent using an IRB/IEC-approved consent 
form with the revised procedures. 
The investigator will inform the subject that already collected data will be retained and analyzed 
even if the subject withdraws from this study.  
4.2.2 Subject Replacement 
Subjects who withdraw, or are withdrawn from this study, or are lost to follow-up after signing 
the informed consent form (ICF) and either before or after administration of the study product 
will not be replaced. 

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4.2.3 Participants who are randomized into Group 2 (15-month) but are not 
vaccinated with a randomized meningococcal vaccine 
Subjects that are randomized to Group 2 (with Step 1 randomization) and present to the 15-
month of age visit that do not have second-step randomization because the target enrollment 
sample size has been fulfilled will be offered “enhanced” EPI vaccination (i.e., MR vaccine and 
MenACWY-TT vaccine in open-label fashion) but will not receive further scheduled follow-up 
visits in the study.  
4.2.4 Study Termination  
If the study is prematurely terminated by the sponsor, any regulatory authority, or the 
investigator for any reason, the investigator will promptly inform the study subjects and assure 
appropriate therapy or follow-up for the subjects, as necessary. The investigator will provide a 
detailed written explanation of the termination to the IRB/IEC. 

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STUDY PROCEDURES 
Complete study schedule details listed by type of visit are described below. 
 
Screening  
Community Permission 
Given the local social structure, once the ethical and regulatory approvals are in place, 
community meetings will be organized to present the study to the communities where the site 
team plans to conduct the study. These meetings will be organized following these procedures: 
• The informed consent forms will be translated into the local language and recorded 
through a certified process; 
• Community meetings will be scheduled with the elders, the religious representatives, the 
social leaders and village chiefs in each community where the study will be conducted. 
At these meetings, the study will be explained in detail and, when applicable, the 
recording of the consent will be played;  
• The study will be discussed and the study team will answer any questions. The 
community leaders will review the information and confirm their permission for the 
conduct of the study and a signed list of presence of attendance list will be obtained. 
• The leaders or a local crier will announce the study and direct interested persons to the 
site. The study site team will then be allowed to start recruitment activities and approach 
potential subjects. 
• As part of the ongoing consent of the community, an end of study community meeting 
will be conducted to communicate the overarching study results. If new information 
arises with regards to the safety or possible benefit (e.g., failure of the NmCV-5 to 
achieve non-inferior immunogenicity) of the study, then an ad hoc community meeting 
will be conducted to communicate this new information. 
Site Recruitment 
The site will develop a study specific recruitment plan and will use several approaches for 
recruitment: 
• The list of children 7-9 months of age with their contact information will be obtained 
from the demographic surveillance system. Participants may also be enrolled from the 
greater Bamako area through community engagement activities that may include 
meetings with local health care providers and leaders. Community liaisons/field workers 
will visit each household and inform parents/guardians about the study. If interested, the 
parent/guardian will be directed to visit the site clinic for more information. 
• The study team will collaborate with the community clinics to search for potential 
subjects when they come for their EPI vaccinations. Study staff will be present at the 
community clinics during vaccination days. If interested, the parent/guardian will be 

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referred to the site staff for information on the study. 
Individual Informed Consent 
"Informed consent" is the voluntary agreement of an individual or his/her legal guardian to 
participate in research. Consent must be given with free will of choice, and without inducement. 
The individual must have sufficient knowledge and understanding of the nature of the proposed 
research, the anticipated risks and potential benefits, and the requirements of the research to be 
able to make an informed decision. Informed consent of the parents/guardians following local 
IRB/EC guidance must be obtained before conducting any study-specific procedures.  
The informed consent process will be conducted on potential study participants as early as 9 
months of age. At this stage, the parent(s)/guardian(s), based on their interest in the study will 
decide if they agree to potentially delay their child’s meningococcal vaccine dose until the 
child’s 15-month EPI visit. If they agree, the subject’s parent(s)/guardian(s) will be asked to sign 
the informed consent document. Upon this initial consent, a first step randomization (Step 1 
Randomization) will be performed which will determine whether the infant will be enrolled into 
the study at the 9-month visit or at the 15-month EPI visit. The infant will be considered enrolled 
upon the successful first step randomization of the study, which will occur at the time of 
presenting to their 9-month EPI visit.   
This process of obtaining informed consent for study participation should be documented in the 
source documents. Two originals of the informed consent form should be signed and dated. 
One original will be given to the parent(s)/guardian(s) and one original will be kept at the site. 
The adult literacy rate in Mali is relatively low, only ~25% of adults can read French. The 
informed consent is presented in entirety in the local language (in the major local dialects) by 
audio recording. Furthermore, if the subject’s parent(s)/guardian(s) is unable to read, an impartial 
witness will be present during the entire informed consent process and discussion. An impartial 
witness is defined as a person who is independent from study conduct, who cannot be unfairly 
influenced by those involved with the study, who attends the informed consent process if the 
subject's parent/guardian cannot read, and who reads the informed consent form and any other 
written information supplied to the parent/guardian.  
After the written informed consent form and any other written information to be provided to 
subject’s parent/guardian, is heard or read and explained to the subject’s guardian/parent and 
after the subject’s parent/guardian has verbally consented to the subject’s participation in the 
study and, if capable of doing so, has signed the informed consent form, the witness will sign and 
personally date the consent form. For persons unable to read or write, an “X” or other marking is 
a currently locally acceptable signature. By signing the consent form, the witness attests that the 
information in the consent form and any other written information was accurately explained to, 
and apparently understood by, the subject’s parent/guardian and that informed consent was freely 
given by the subject’s parent/guardian. 

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After informed consent, the following procedures will be performed as part of the Screening 
Visit: 
• Entry of the subject identification (ID) into a screening log 
• Confirm the individual meets all inclusion and no exclusion criteria 
• Collect and review demographic information, including age, gender, race, and ethnicity 
• Collect and review medical history and including review of systems 
• Perform a general physical examination including assessment of height, weight, heart 
rate, respiratory rate, and axillary body temperature 
• Collect and review prior/concomitant medications and prior vaccinations 
• Obtain consent for enrollment 
• Perform Step 1 Randomization 
 
Enrollment 
At Visit Day 1, upon confirmation of ongoing informed consent and the eligibility of the subject, 
there will be a second step randomization (Step 2 Randomization) at a 2:1 ratio to determine 
whether the infant will receive experimental vaccine or active control vaccine, as a blinded study 
product. This second step randomization will occur on the day subjects are to receive their first 
study injection (at 9 or 15 months of age based on Step 1 Randomization), after confirmation of 
eligibility and immediately prior to injection. 
The unblinded designated personnel will be provided with the randomization list that includes 
treatment assignment. Based on the assigned treatment the unblinded personnel will prepare the 
study vaccine to be given to each subject. The unblinded personnel will maintain the 
randomization list in a secure place.  
If for any reason, after signing the informed consent form, the subject (who has passed 
screening) fails to be randomized, the reason for not being randomized should be recorded in 
source documents and eCRFs. For the 15-month groups, if the target Step 2 randomized sample 
size of 600 has been achieved, then the study will be closed to further second step 
randomizations. Study participants that are unable to receive meningococcal study product with 
step 2 randomization, due to closure to further enrollments, will be provided quadrivalent 
meningococcal conjugate vaccine (open-label) and will not be required to have further study 
follow up. 
Visit #1 (Day 1 for Group 1) 
• Confirm informed consent 
• Review for any changes to the medical history (if not same day as screening), including 
review of systems. 
o Review of systems: an interview that queries the subject’s parent/guardian as to 
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same day as screening). The questions tend to be grouped by system organ class 
and are intended to remind the parent/guardian of any forgotten or medical 
conditions that may be relevant. 
• Review of prior/concomitant medications and prior vaccinations (if not same day as 
screening) 
• Perform a general physical examination (if not same day as screening, must be within 14 
days of screening) including measurement of axillary body temperature, height, weight, 
and resting vital signs: heart rate and respiratory rate. The height and weight need to be 
recorded in source documents or eCRFs. Note: If the subject’s axillary body temperature 
is ≥37.5°C, vaccination must be postponed until three days after the fever has resolved. 
Vaccination is also postponed for any clinically significant acute infection and/or 
systemic antibiotic use within 3 days. 
• Perform Rapid Diagnostic Test for malaria. In case of a positive result, vaccination 
should be postponed until at least five days after completing treatment as per national 
guidelines.  
• Study personnel will take a photo of the subject and his/her parent/guardian for the study 
identification card. This study identification card will be given to each subject’s 
parent/guardian and will have phone numbers with 24 hours access in case of emergency. 
• Perform Step 2 Randomization. Unblinded staff will perform Step 2 Randomization. 
• For participants randomized into Group 1: 
o Collect blood sample (approximately 5 mL) for serology testing prior to 
vaccination. 
o Administer blinded study meningococcal vaccine, according to randomization 
assignment. The preparation and administration of study meningococcal vaccine 
will be performed by unblinded staff. 
o After vaccination, the subject will be observed for at least 30 minutes for any 
immediate post-vaccination reactions, with appropriate medical treatment readily 
available in case of a rare anaphylactic reaction following the administration of 
vaccines. Solicited local and systemic AEs, any unsolicited AEs, vital signs and 
axillary body temperature will be recorded. All safety data collected within 30 
minutes post-vaccination should be recorded in the subject’s source documents or 
eCRFs. 
o The participant’s infant immunization card and medical record will be updated to 
indicate the receipt of a serogroup A meningococcal vaccine. 
o Schedule Visit 2 approximately 7 days after vaccination 
o Field workers will visit participant homes each day for the next 4 to 7 days as 
described in Section 5.4. 
• For participants randomized into either Group 1 or Group 2, a measles-rubella-containing 
vaccine and yellow fever vaccine will be administered, according to the “enhanced” EPI 

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schedule. Note: these administered “enhanced” EPI vaccines are also to be recorded on 
the participant’s infant immunization card and medical record. 
• For participants randomized into Group 2 (the 15-month group), they will return in 6 
months for Visit 1B for the study meningococcal vaccine randomization (Step 2) and 
vaccination. For participants randomized into the 15-month group and not randomized or 
enrolled to receive the study meningitis vaccine, refer to Section 4.2.3. 
Group 2 only, Visit #1B (at 15 months of age), Study Day 1 
• Confirm ongoing informed consent 
• Confirm subject ID and the individual continues to meet all inclusion and no exclusion 
criteria. 
• Review for any changes to the medical history, including review of systems. 
o Review of systems: an interview that queries the subject’s parent/guardian as to 
any clinical findings the subject has experienced across each organ system. The 
questions tend to be grouped by system organ class and are intended to remind the 
parent/guardian of any forgotten or medical conditions that may be relevant. 
• Review of prior/concomitant medications and prior vaccinations 
• Perform a general physical examination including measurement of axillary body 
temperature, height, weight, and resting vital signs: heart rate and respiratory rate. The 
height and weight need to be recorded in source documents or eCRFs. Note: If the 
subject’s axillary body temperature is ≥37.5°C, vaccination must be postponed until three 
days after the fever has resolved. Vaccination is also postponed for any clinically 
significant acute infection and/or systemic antibiotic use within 3 days. 
• Perform Rapid Diagnostic Test for malaria. In case of a positive result, vaccination 
should be postponed until at least five days after completing treatment as per national 
guidelines. 
• Perform Step 2 Randomization. (Unblinded staff) 
• Collect blood sample (approximately 5 mL) for serology testing prior to vaccination. 
• Administer blinded meningococcal vaccine, according to randomization assignment. The 
preparation and administration of study meningococcal vaccine will be performed by 
unblinded staff. 
• After vaccination, the subject will be observed for at least 30 minutes for any immediate 
post-vaccination reactions, with appropriate medical treatment readily available in case of 
a rare anaphylactic reaction following the administration of vaccines. Solicited local and 
systemic AEs, any unsolicited AEs, vital signs and axillary body temperature will be 
recorded. All safety data collected within 30 minutes post-vaccination should be recorded 
in the subject’s source documents or eCRFs. 
• The participant’s infant immunization card and medical record will be updated to indicate 
the receipt of a serogroup A meningococcal vaccine. 

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• A measles-rubella-containing vaccine will be administered, according to the “enhanced” 
EPI schedule. Note: the administered “enhanced” EPI vaccines are also to be recorded 
on the participant’s infant immunization card. 
• Schedule Visit 2 approximately 7 days after vaccination. 
• Field workers will visit participant homes each day for the next 4 to 7 days as described 
in Section 5.4 
 
Planned Study Visits 
5.3.1 Follow-up  
Visit #2 (Day 8 + 3 days after study meningococcal vaccination) 
Study subjects will return for follow-up evaluation to the clinical study site approximately 7 days 
following meningococcal vaccination. Alternatively, a home visit may be performed by a 
medically qualified site personnel. At this visit, investigator or delegate will perform the 
following: 
• Review of solicited and unsolicited AEs experienced during the initial 4 days after 
vaccination, assisted by review of home visit worksheets which are completed by a daily 
visit by field workers during the first 4 days following vaccination 
• Assessment of any ongoing solicited AEs on Day 8 post-vaccination (note that all 
ongoing solicited AEs beyond Day 8 must be followed up daily by site staff until 
resolution) 
• Medical interview of subject’s parents/guardians to assess any unsolicited AEs, SAEs 
since previous study visit 
• Collection of concomitant medications and vaccinations 
• Physical examination including assessment of vital signs (heart rate and respiratory rate) 
and axillary body temperature 
• Schedule Visit 3, approximately 28 days after vaccination 
Visit #3 (Day 29 + 7 days after study meningococcal vaccination) 
Study subjects will return for follow-up evaluation to the clinical study site approximately 28 
days following meningococcal vaccination. At this visit, investigator or delegate will perform the 
following: 
• Review of unsolicited AEs experienced during the 28 days after vaccination using home 
visit worksheets 
• Medical interview of subject’s parents/guardians to determine if any unsolicited AEs or 
SAEs occurred and if any concomitant medication or vaccines were received since the 
last study visit. 
• Check any ongoing AEs and concomitant medications since the last study visit and 
record resolution date (the end date), if available in the source documents or eCRFs.  
• Physical examination including assessment of heart rate, respiratory rate, and axillary 
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• Collection of blood sample (approximately 10 mL) for serology testing. 
• Schedule Visit 4, approximately 6 months after vaccination 
Visit #4 (Day 181 ± 14 days after study meningococcal vaccination) 
Study subjects will return for follow-up evaluation to the clinical study site approximately 6 
months following meningococcal vaccination. At this visit, investigator or delegate will perform 
the following: 
• Medical interview of subject’s parents/guardians to determine if any SAEs occurred since 
the last study visit. 
• Physical examination including assessment of heart rate, respiratory rate, and axillary 
body temperature 
• Collection of blood sample (approximately 5 mL) for serology testing. 
• For participants randomized and enrolled in the 9-month groups, a measles-rubella 
containing vaccine will be administered at this 15-month old visit. 
• Schedule Visit 5, approximately 2 years after vaccination 
5.3.2 Final Study Visit 
Visit #5, Final Visit (Day 730 ± 45 days after study meningococcal vaccination) 
Study subjects will return for follow-up evaluation to the clinical study site approximately 2 
years following meningococcal vaccination. At this visit, investigator or delegate will perform 
the following: 
• Medical interview of subject’s parents/guardians to determine if any SAEs occurred since 
the last study visit. 
• Physical examination including assessment of heart rate, respiratory rate, and axillary 
body temperature 
• Collection of blood sample (approximately 5 mL) for serology testing. 
5.3.3 Early Termination Visit  
A subject may discontinue study participation at any time prior to the last planned study visit. 
This is referred to as an early termination from the study. The reasons for early termination from 
the study include: adverse event, death, withdrawal of consent, lost to follow-up, administrative 
reason, protocol deviation, or other reasons upon the investigator’s judgement.  The investigator 
should make every effort to investigate whether or not safety concerns (adverse event, SAE or 
death) may have been related to the subject’s discontinuation from the study. If a safety concern 
has been associated with the subject’s discontinuation, this must be described on the Termination 
electronic case report form (eCRF) page, even if it is not the primary reason for the subject’s 
discontinuation. 
When possible, an early termination clinic visit should be performed so that a PE including 
assessment of vital signs and axillary temperature, can be performed and the collection of blood 
(approximately 5 mL) may be possible. Concomitant medications and vaccinations may be 
collected through Day 29. 

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Field Worker Home or Community Visits 
In lieu of phone calls, electronic messaging, and postal mail, study team members who are 
designated as community field workers commonly visit with study participant homes and local 
villages throughout the study to facilitate the communication of important study information, 
such as providing reminders for upcoming study visits and to continue to address any questions 
or concerns regarding the study.  During the first 4-days post-vaccination, field workers will 
interview parent(s)/guardian(s) and complete the memory aid document required for the 
assessment of daily reactogenicity described in Section 7.1.2. For instances where there is 
reactogenicity of grade 2 or higher at the fourth day post-vaccination (Day 5), then field workers 
will continue the daily visits to complete the memory aid document until resolution or the 
severity of the reactogenicity is grade 1. The active community engagement of the study team 
members helps to enable trust, enhances study compliance, and decreases the risk of losses to 
follow-up. Reactogenicity events or other clinical concerns noted by the field workers will be 
discussed with the study physicians. These field worker visits may lead to unscheduled study 
visits, upon investigator judgement.  
 
Unscheduled Study Visits  
Unscheduled clinic visits may be conducted for safety concerns, upon investigator judgement. A 
medical evaluation may determine that the study participant may need escalated care and will be 
provided appropriate referral, when the need arises. 
 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or protocol-
specific MOP requirements.  The noncompliance may be either on the part of the subject, the 
investigator, or the study site staff.  As a result of deviations, corrective actions should be 
developed by the site and implemented promptly.  It is the responsibility of the site Principal 
Investigator (PI) and other study personnel to use continuous vigilance to identify and report 
protocol deviations.  All individual protocol deviations will be addressed in subject study 
records.  All protocol deviations, either individual, product, or site-specific will be collected and 
the record stored in a sponsor-determined location.  Protocol deviations must be sent to the local 
IRB/IEC per its guidelines.  The site PI and other study personnel are responsible for knowing 
and adhering to their IRB/IEC requirements. 
It is the responsibility of the site PI and personnel to use continuous vigilance to identify and 
report deviations within five working days of identification of the protocol deviation, or within 
five working days of the scheduled protocol-required activity.  All deviations must be promptly 
reported to DMID per the Data Coordinating Center (DCC) protocol deviation reporting 
procedures. 

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All protocol deviations, as defined above, must be addressed in study subject data collection 
forms.  A completed copy of the DMID Protocol Deviation Form must be maintained in the 
Regulatory File, as well as in the subject's chart.  Protocol deviations must be sent to the local 
IRB/IEC per their guidelines.  The site PI and personnel are responsible for knowing and 
adhering to their IRB requirements. 

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DESCRIPTION OF CLINICAL AND LABORATORY EVALUATIONS 
 
Clinical Evaluations 
Complete medical history will be obtained by interview of subjects on the day of study 
vaccination prior to the study vaccination. Subjects will be queried regarding a history of 
significant medical disorders of the head, eyes, ears, nose, throat, mouth, cardiovascular system, 
lungs, gastrointestinal tract, liver, pancreas, kidney, urologic system, nervous system, blood, 
lymph nodes, endocrine system, musculoskeletal system, skin, and genital/reproductive tract. A 
history of any allergies, cancer, immunodeficiency, and autoimmune disease will be solicited. At 
follow-up visits after the study vaccination, an interim medical history will be obtained by 
interview of subjects noting any changes since the previous clinic visit or contact. All 
concomitant medications and an updated vaccination history will also be collected through Day 
29. 
At the Day 1 visit prior to the study vaccination, a physical examination will be performed on all 
subjects to include the following organs and organ systems: including skin, head and neck, lungs, 
heart, liver, spleen, extremities, lymph nodes, and nervous system, by a study clinician (site 
principal investigator or sub-investigator). At follow-up visits after the first study vaccination, a 
targeted physical examination may be performed, if indicated based on the subject’s interim 
medical history, by a study licensed clinician as the site principal investigator or sub-
investigator. Targeted physical examinations should also include an assessment for any adverse 
events. 
Vital signs (heart rate and respiratory rate) and axillary body temperature will be collected prior 
to study vaccination and at follow-up visits.   
Height and weight will be collected at the Day 1 visit prior to the first study vaccination for the 
assessment of nutritional status age Z-score (HAZ/LAZ).  
Subjects will be observed in the clinic for at least 30 minutes after receiving the study meningitis 
vaccination. The study vaccination site will be examined, post-administration reactogenicity 
assessments will be performed, and any AE/SAEs will be recorded on the appropriate data 
collection form prior to discharge from the clinic. 
Reactogenicity assessments will include an assessment of solicited AEs occurring from the time 
of each study meningitis vaccination through Day 8 after study vaccination with a 
meningococcal vaccine, which includes an assessment of meningitis vaccine injection site 
reactions including erythema (redness), swelling, and pain, as well as systemic reactions 
including fever, feverishness, irritability, decrease eating, vomiting, and drowsiness. Pre-
administration reactogenicity assessments will be performed prior to each study meningitis 
vaccination to establish baseline, then the study vaccination will be given. 

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Parents/guardians, with the help of study field workers, will complete a subject memory aid from 
the time of study vaccination through at least 4 days. Subject memory aids will be reviewed by 
study staff for AEs (solicited injection site and systemic reactions and unsolicited AEs) at the 
clinic Visit 2 (Day 8). 
 
Laboratory Evaluations 
6.2.1 Clinical Laboratory Evaluations 
None required. 
6.2.2 Research Assays  
Venous blood for the measurement of serum-based immune response measures will be 
performed from collected blood prior to vaccination (Day 1), 4 weeks (Day 29), 6 months (Day 
181), and 2 years (Day 730) after vaccination. Subjects who withdraw early or are lost to follow-
up will have their immune response measures on available sera. The assays to measure the 
immune responses to vaccination will be performed at the following indicated specialized 
laboratories:  
• Assays for meningococcal serogroup-specific rSBA will be performed at UKHSA 
(Manchester, UK).  
• Enzyme-Linked Immunosorbent Assays (ELISAs) for anti-Measles and anti-Rubella IgG 
antibody will be performed at VisMederi (Siena, Italy). 
• Yellow Fever plaque reduction neutralization test (PRNT) will be performed at 
VisMederi (Siena, Italy).  
Due to sensitivity regarding blood volumes drawn from young children, we calculated the 
approximate serum volumes required for each assay (including backup sample volumes) and the 
timing of the blood draws, to provide justification for the blood collection. This information is 
available in the MOP.  
Individual study results will not be reported to parent or placed in medical record. 
 
6.2.2.1 Laboratory Specimen Preparation, Handling, and Storage 
The blood will be processed and aliquoted according to the Manual of Procedures. All serum 
aliquots will be stored at a temperature of -20°C or below.  
6.2.2.2 Laboratory Specimen Shipping 
Samples for immunogenicity testing will be packaged according to International Air Transport 
Association (IATA) regulations and shipped via an international shipping courier to the 
respective laboratories according to the MOP. 

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ASSESSMENT OF SAFETY 
 
Assessing and Recording Safety Parameters 
7.1.1 Adverse Events (AEs) 
Adverse Event (AE): ICH E6 GCP defines an AE as any untoward medical occurrence in a 
patient or clinical investigation subject administered a pharmaceutical product regardless of its 
causal relationship to the study treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product. The occurrence of an AE may 
come to the attention of study staff members during study visits (including field visits) and 
interviews of a study recipient presenting for medical care, or upon review by a study monitor. 
AEs, including solicited injection site and systemic (subjective and quantitative) reactions, not 
meeting the protocol-defined criteria for SAEs, will be recorded on the appropriate data 
collection form (DCF) or entered into the eCRF. Information to be collected for unsolicited non-
serious AEs includes event description, date of onset, licensed study physician’s assessment of 
severity and relationship to study product or alternate etiology (if not related to study product), 
date of resolution, seriousness, and outcome. AEs occurring during the trial-collection and 
reporting period will be documented appropriately regardless of relationship to study product. 
AEs will be followed through resolution. 
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and not reported as an AE. However, if the severity of any pre-existing medical 
condition increases, it will be recorded as an AE. The time of reference for the AE is to be the 
time from receipt of the randomized blinded meningococcal vaccine.  
7.1.1.1 Adverse Events Grading 
All AEs (laboratory and clinical symptoms) will be graded for severity and assessed for 
relationship to study product (see definitions). AEs characterized as intermittent require 
documentation of onset and duration of each episode.  The start and resolution date of each 
reported AE will be recorded on the appropriate data collection form and eCRF. Increases in the 
severity of an AE will be documented to allow an assessment of the duration of the event at each 
level of intensity. Whereas, only the resolution date and not each decrease in severity is required 
to be documented. 
Severity of Event:   
AEs will be assessed by the investigator using a protocol-defined grading system (Appendix B).  
For events not included in the protocol-defined grading system, the following guidelines will be 
used to quantify severity: 

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• 
Mild (Grade 1):  Events that are usually transient and may require only minimal or no 
treatment or therapeutic intervention and generally do not interfere with the subject’s usual 
activities of daily living. 
• 
Moderate (Grade 2):  Events that are usually alleviated with additional specific 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. 
• 
Severe (Grade 3):  Events interrupt usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.  Severe events are usually 
incapacitating. 
• 
Potentially Life-Threatening (Grade 4): Events that are potentially life-threatening and 
require hospitalization. 
• 
Death (Grade 5): Events resulting in death (Note: this grade is not specifically listed in the 
grading tables) 
Relationship to Study Product: The assessment of the AE’s relationship to study product will 
be done by the licensed study physician and the assessment will be part of the documentation 
process.  Whether the AE is related or not, is not a factor in determining what is or is not 
reported in this trial.  If there is any doubt as to whether a clinical observation is an AE, the event 
should be reported.  In a clinical trial, the study product must always be suspect.  The 
relationship to study product will be assessed for AEs using the terms related or not related: 
• 
Related – There is a reasonable possibility that the study product caused the AE. Reasonable 
possibility means that there is evidence to suggest a causal relationship between the study 
product and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
7.1.2 Reactogenicity  
Reactogenicity events are AEs that are common and known to occur following administration of 
this type of study vaccine. The following Toxicity Grading Scales will be used to grade solicited 
local (meningitis vaccine injection site) and systemic (subjective and quantitative) reactions: 
Reactogenicity events are AEs that are common and known to occur following administration of 
this type of study vaccine. The following are the local and systemic solicited AE which are to be 
collected during the study. 
Solicited local reactions: pain/tenderness, swelling/induration, and erythema/redness 
Solicited systemic reactions: irritability, drowsiness/lethargy, decrease eating/anorexia, 
vomiting, fever, and feverish 

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Table 6. Toxicity Grading Scale – Solicited Local Reactions 
Local 
(Administration 
Site) Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially Life-
Threatening 
(Grade 4) 
Pain/tenderness 
Causes no or 
minimal limitation 
of use of limb 
Causes greater than 
minimal limitation 
of use of limb 
Inability to perform 
usual social & 
functional activities 
with the limb 
Inability to perform 
basic self-care 
function OR 
hospitalization 
indicated 
Swelling/induration 
≤2.5 cm in diameter 
>2.5 cm in diameter  
Presence of 
ulceration 
OR secondary 
infection 
OR phlebitis 
OR sterile abscess 
OR drainage 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Erythema/Redness 
≤2.5 cm in diameter 
>2.5cm up to 5 cm 
>5 cm 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
 
Table 7. Subjective Solicited Systemic Reactogenicity Grading 
Systemic 
(Subjective) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially Life-
Threatening 
(Grade 4) 
Irritability 
Causes no or 
minimal 
interference with 
usual social & 
functional activities 
with no intervention 
indicated 
Causes greater than 
minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated 
Causes inability to 
perform usual social 
& functional 
activities with 
intervention or 
hospitalization 
indicated 
Inability to perform 
basic self-care 
function AND 
hospitalization 
indicated 
Drowsiness/ 
Lethargy 
Decrease 
Eating/Anorexia 
Vomiting 
Transient or 
intermittent AND 
no or minimal 
interference with 
oral intake 
Frequent episodes 
with no or mild 
dehydration 
Persistent vomiting 
resulting in 
orthostatic 
hypotension  
OR aggressive 
rehydration 
indicated (e.g., IV 
fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Fever (Axillary) 
38.0 to <38.6°C 
≥38.6 to <39.3°C 
≥39.3°C to <40.0°C 
≥40.0°C 
Feverish 
Events that are 
usually transient and 
maybe require only 
minimal or no 
treatment or 
therapeutic 
Events that are 
usually alleviated 
with additional 
specific therapeutic 
intervention. The 
event interferes with 
Events interrupt 
usual activities of 
daily living, or 
significantly affects 
clinical status, or 
may require 
Events that are 
potentially life-
threatening and 
require 
hospitalization. 

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intervention and 
generally do not 
interfere with the 
subject’s usual 
activities of daily 
living 
usual activities of 
daily living, causing 
discomfort but 
poses no significant 
or permanent risk of 
harm to the research 
participant. 
intensive 
therapeutic 
intervention. Severe 
events are usually 
incapacitating. 
  
7.1.3 Serious Adverse Events (SAEs) 
Serious Adverse Event (SAE): An adverse event or suspected adverse reaction is considered 
“serious” if, in the view of either the site principal investigator or sponsor, it results in any of the 
following outcomes: 
1. Death. 
2. Is life-threatening (i.e., the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred); it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
3. Required or prolonged hospitalization. 
4. Persistent or significant disability or incapacity (i.e., the event causes a substantial 
disruption of a person’s ability to conduct normal life functions). 
5. Congenital anomaly/birth defect. 
6. An important and significant medical event that may not be immediately life threatening 
or resulting in death or hospitalization but, based upon appropriate medical judgment, 
may jeopardize the subject or may require intervention to prevent one of the outcomes 
listed above. 
AEs which do not fall into these categories are defined as non-serious AEs. It should be noted 
that a severe AE need not be serious in nature and that a SAE need not, by definition, be severe. 
 
Specification of Safety Parameters 
Safety will be assessed by the frequency and severity of solicited local and systemic adverse 
reactions within 7 days of blinded study meningococcal vaccine; unsolicited adverse events 
within 28 days of blinded study meningococcal vaccine; and serious adverse events during the 
entire study period (i.e., enrollment through last visit). 
7.2.1 Unsolicited Events 
Unsolicited events are any other AEs that occur following administration of study product.   
7.2.2 Medically-Attended Adverse Events (MAAEs)  
Not applicable.  

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Reporting Procedures 
Solicited injection site and systemic reactogenicity events will be documented and reported from 
the time of study vaccination through 7 days after study meningococcal vaccination. Note that 
community field workers will only perform the daily visits to complete the documentation of 
axillary body temperature, size of swelling/induration, and other reactogenicity during the initial 
4 days following vaccination.  The remaining days prior to Visit 2 may not be documented if the 
events are grade 1 or resolved, especially from illiterate families, and this will not be considered 
a protocol deviation. For instances where there is reactogenicity of grade 2 or higher at the 
fourth day post-vaccination (Day 5), then field workers will continue the daily visits to complete 
the memory aid document until resolution or the severity of the reactogenicity is grade 1. 
However, through interviewing the parent/guardian, reactogenicity events through 7 days after 
study meningococcal vaccination are intended to be collected. Unsolicited non-serious AEs will 
be documented and reported from the time of study meningococcal vaccination through 28 days 
after study meningococcal vaccination. SAEs will be documented and reported from the time of 
enrollment through approximately 2 years after study meningococcal vaccination.  
7.3.1 Reporting Serious Adverse Events 
SAEs will be: 
• 
Captured both on the SAE form as well as on the AE eCRF.  
• 
Will be reported within 24 hours of the site becoming aware of the event to the DMID 
Pharmacovigilance Group noted in this section.  
• 
Will be reported by the investigator to their corresponding EC/IRB or applicable 
regulatory authorities in accordance with institutional policy/regulatory requirements and 
adequate documentation of this notification must be recorded in the regulatory file. 
The SAE form should be completed as thoroughly as possible with all available details of the 
event. Even if the investigator does not have all information regarding an SAE, the SAE should 
still be submitted within 24 hours. Once additional relevant information is received, the SAE 
form should be updated within 24 hours.  The investigator will always provide an assessment of 
causality at the time of the initial report. 
The Sponsor and its designee must also comply with the applicable regulatory requirement(s) 
related to the reporting of Suspected Unexpected Serious Adverse Reactions (also referred to as 
“SUSARs”) to the regulatory authority(ies) and the IRB/EC. If a SUSAR or other safety signal 
relating to use of one of the study vaccines is reported to the sponsor or its designee, the sponsor 
will communicate the information to the investigator and the investigator will be responsible for 
submitting this information to the EC/IRB and other relevant authorities.  
SAEs will be followed until resolution even if this extends beyond the study-reporting period.  
Resolution of an AE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic.  

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Any AE that meets a protocol-defined serious criterion must be submitted immediately 
(within 24 hours of site awareness) on an SAE form to the DMID Pharmacovigilance 
Group, at the following address: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
In addition to the SAE form, select SAE data fields must also be entered into the DCC system. 
Please see the protocol-specific MOP for details regarding this procedure.  
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible.  
The site will send a copy of the SAE report(s) to the Independent Safety Monitor (ISM) (as 
deemed necessary) when they are provided to the DMID Pharmacovigilance Group.  The DMID 
Medical Monitor (MM) and DMID Clinical Project Manager will be notified of the SAE by the 
DMID Pharmacovigilance Group.  The DMID MM will review and assess the SAE for 
regulatory reporting and potential impact on study subject safety and protocol conduct. 
At any time after completion of the study, if the site principal investigator (PI) or appropriate 
sub-investigator becomes aware of an SAE that is suspected to be related to study product, the 
site PI or appropriate sub-investigator will report the event to the DMID Pharmacovigilance 
Group. 
7.3.2 Regulatory Reporting for Studies Not Conducted Under DMID-
Sponsored IND 
Following notification from the investigator, the Sponsor will report events that are both serious 
and unexpected that are related to study product(s) to the Indian and Malian Regulatory 
Authority within the required timelines as specified in the local guidelines.   
7.3.3 Reporting of Pregnancy 
Not applicable. 
 
Type and Duration of Follow-up of Subjects after Adverse Events 
AEs will be assessed and followed from initial recognition of the AE through end of the protocol 
defined follow-up period.  SAEs will be followed up through resolution even if duration of 
follow-up goes beyond the protocol-defined follow-up period. Resolution of an AE is defined as 
the return to pre-treatment status or stabilization of the condition with the expectation that it will 
remain chronic. 

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Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
• 
Not applicable to this protocol.  
 
Halting Rules 
7.6.1 Study Halting Criteria 
Additional enrollment and study interventions/administration of study products in this trial will 
be halted for Data and Safety Monitoring Board (DSMB) review/recommendation if any of the 
following are reported: 
• 
Any subject experiences ulceration, abscess or necrosis at the injection site that is 
considered related to study product administration. 
• 
One or more subjects experience laryngospasm, bronchospasm or anaphylaxis within 1 
day after administration of study product that is considered related to study product. 
• 
Any subject experiences any Grade 4 AE or an SAE after administration of study product 
that is considered related to study product. 
• 
5% or more of subjects (with a minimum of 3 subjects) who received a dose of study 
vaccine experience the same severe (Grade 3) study vaccine-related injection site 
reaction, within 7 days of vaccination. Induration (hardness)/edema (swelling) will be 
measured in mm, but size will not be used as halting criteria. 
• 
5% or more of subjects (with a minimum of 3 subjects) who received a dose of study 
vaccine experience the same severe (Grade 3) study vaccine-related subjective systemic 
reaction, within 7 days of vaccination, for which the severity (grade) is corroborated by 
study personnel. 
If any of the halting rules are met, then the trial will not continue with the remaining enrollments 
without a review by and recommendation from the DSMB to proceed. 
 
Safety Oversight  
7.7.1 Independent Safety Monitor (ISM) 
An ISM is a physician with relevant expertise whose primary responsibility is to provide 
independent safety monitoring in a timely fashion.   Participation is for the duration of the study 
and the ISM must meet the conflict-of-interest requirements of DMID.   
The ISM: 
• 
Will have experience in pediatrics. 
• 
Is in close proximity to the study site and has the authority and ability to readily access 
subject records in real time. 
• 
May be a member of the participating institution’s staff but preferably be from a different 
organizational group within the institution. 

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• 
Should not be in a direct supervisory relationship with the investigator. 
• 
Should have no direct involvement in the conduct of the study. 
The ISM will: 
• 
Sign a Conflict of Interest (COI) certification at the time they are asked to participate and 
provide updates to this information as needed. 
• 
Receive reports of SAEs deemed related to the study from the site investigator and will 
be notified by email when DMID is notified of the SAE. 
• 
Evaluate the SAE and report their clinical assessment to DMID, PI and Site Investigator. 
• 
Communicate with the investigator at the participating site as needed. 
• 
Review additional safety related events at the request of DMID. 
• 
Provide additional information to DMID and/or the DSMB by teleconference as 
requested. 
7.7.2 Data and Safety Monitoring Board (DSMB) 
Safety oversight will be conducted by a DSMB that is an independent group with expertise to 
interpret data from this study and will monitor subject safety and advise DMID. The DSMB 
members will be separate and independent of study personnel participating in this study and 
should not have scientific, financial or other conflict of interest related to this study. DSMBs 
must consist of at least three voting members, including a biostatistician experienced in statistical 
methods for clinical trials and a clinician with relevant expertise. 
The DSMB will operate under the rules of a DMID-approved charter that defines the data 
elements to be assessed and the procedures for data reviews and will be written at the 
organizational meeting of the DSMB. Procedures for DSMB reviews/meetings will be defined in 
the charter. Reports may include enrollment and demographic information, medical history, 
concomitant medications, physical assessments, clinical laboratory values, dosing compliance, 
and solicited and unsolicited AE/SAEs.  The DSMB will review SAEs on a regular basis and ad 
hoc during this trial. The DMID MM and the ISM (as deemed necessary) will be responsible for 
reviewing SAEs in real time.  
As defined in the charter in Section 9.5.1, the DSMB will review data at specified times during 
the course of the study for subject and overall study progress (at a minimum of annually) and 
will conduct ad hoc reviews as appropriate when a halting rule is met or for immediate concerns 
regarding observations during this study. A final review meeting will also be held 6 to 8 months 
after clinical database lock to review the cumulative unblinded safety and efficacy data for the 
study.  
Additional data may be requested by the DSMB, and interim statistical reports may be generated 
as deemed necessary and appropriate by DMID. The DSMB may receive data in aggregate and 
presented by treatment arm. The DSMB may also be provided with expected and observed rates 
of the expected AEs in an unblinded fashion and may request the treatment assignment be 
unblinded for an individual subject if required for safety assessment. The DSMB will review 

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grouped and unblinded data in the closed session only. As an outcome of each review/meeting, 
the DSMB will make a recommendation as to the advisability of proceeding with study 
vaccinations (as applicable), and to continue, modify, or terminate this trial. 
7.7.3 Internal Safety Reviews 
A biweekly internal safety review will be conducted throughout the enrollment period of the 
study. From completion of enrollment through the follow-up period, the regularity of these 
internal safety reviews may be less frequent.  The internal safety review members will consist of 
the protocol chair, Vaccine and Treatment Evaluation Unit (VTEU) principal investigator, site 
principal investigators, the DMID MO and MM. The information to be reviewed will consist of 
the enrollment and visit compliance of study participants, AE reports, and reactogenicity. These 
reports (in aggregate or listings) will be presented as blinded and uncleaned data from weekly 
and monthly safety reports generated from SCHARP. SCHARP weekly reports are scheduled to 
be posted every Thursday and monthly reports on the first Thursday of each month.  Whereupon 
any safety concerns are potentially detected, the issue may be directed to the DSMB’s awareness 
for discussion.  A temporary halt may be declared, upon investigator’s judgement.   

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HUMAN SUBJECTS PROTECTION 
 
Institutional Review Board/Independent Ethics Committee 
This study will be conducted in accordance with the ethical principles set out in the World 
Medical Association Declaration of Helsinki, The Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines for Biomedical Research Involving 
Human Subjects, and in conformity with ICH GCP and with local Mali applicable regulations. 
This study will be conducted under the auspices of the following Institutional Review Boards 
(IRBs)/ Ethics Committees (ECs): 
• 
Research Ethics Committee of the Faculté de Médecine, de et d’Odonto-Stomatologie – 
Faculté de Pharmacie (FMOS-FAPH), Bamako, Mali (DHHS OHRP Federal Wide 
Assurance number 00009970) 
• 
University of Maryland, Baltimore Institutional Review Board (UMB IRB), Baltimore, 
Maryland, U.S.A. (DHHS OHRP Federal Wide Assurance number 00007145) 
The principal investigator will obtain EC/IRB approvals for this protocol and send supporting 
documentation to the DMID before initiating recruitment of subjects.  The IRB/IEC must be 
registered with OHRP as applicable to the research.  DMID must receive the documentation that 
verifies IRB/IEC-approval for this protocol, associated informed consent documents, and upon 
request any recruitment material and handouts or surveys intended for the subjects, prior to the 
recruitment and enrollment of subjects. Any amendments to the protocol or consent materials 
will be approved by the IRB/IEC before they are implemented.  IRB/IEC review and approval 
will occur at least annually throughout the enrollment and follow-up of subjects and may cease if 
annual review is no longer required by applicable regulations and the IRB/IEC.  The investigator 
will notify the IRB/IEC of deviations from the protocol and reportable SAEs, as applicable to the 
IRB/IEC policy. 
The IRB/IEC will determine that adequate provisions are made for soliciting the permission of 
each child's parent(s) or legal guardian, including whether permission of one parent is sufficient 
for research or whether permission is to be obtained from both parents. 
8.2 
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to participate (or 
agreeing that their child can participate) in the study and continues throughout the subject’s 
participation in the study. Before any study-related activities and in agreement with ICH-GCP 
and the applicable local ethical and regulatory requirements, the site investigator must ensure 
that the subject (or subject’s parent/guardian) is fully informed about the objectives, procedures, 
potential risks, and potential benefits of study participation. 
During the informed consent process, a suitably delegated member of the clinical trial team will 
review the content of the ICF line by line with the subject’s parent/guardian. If the subject or 

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subject’s parent/guardian is literate (French in Mali), this review will take place in French. If the 
subject’s parent/guardian is not sufficiently literate (French in Mali) to read and understand the 
ICF, the content of the same document will be translated in writing and recorded line by line in 
the local national Malian language, Bambara. This translation and recording will be performed 
by only Government national language translation office in country. The process must be 
witnessed by an impartial witness who is fluent in both French and in Bambara and who will 
subsequently be required to sign to attest that the information in the ICF has been provided 
accurately and in full to the participant. As local languages are spoken but not written, attempts 
to translate the French ICF into ICFs written in the local languages has proved unsuccessful 
(when subjected to back-translation); hence the process for verbal translation has been developed 
and approved by the local EC. In all cases, the subject or subject’s parent/guardian will be 
encouraged to ask questions about the study and must have the questions answered and be given 
sufficient time to decide if they would like to participate (or would like their child to participate) 
in the study. It will be emphasized that participation is voluntary, and that the subject has the 
right to discontinue (or to have their child discontinue) from the study at any time without giving 
any reason and without compromising their other rights in any way. The site investigator or their 
designee must obtain the subject’s (or subject’s parent/guardian’s) voluntary, signed or 
fingerprinted or personally marked, and dated ICF (also signed by the impartial witness if 
applicable), before any study-related procedures are performed. Study staff must document the 
informed consent process in the source document. The ICF will be completed and signed in two 
originals (or in one original with certified copy), of which one original will be kept in the site 
study file, and one original or certified copy will be given to the subject (or subject’s 
parent/guardian) for their records. 
8.3 
Consent for Future Use of Stored Specimens and Data 
Residual samples/specimens are those that are left over after protocol-specified testing and this 
study has been completed. Subjects will be asked for permission to keep any remaining 
(residual) specimens (serum) derived from venous blood samples for possible use in future 
research studies, such as examining additional immunological assessments or testing for 
antibodies against other vaccines, viruses or bacteria. These residual specimens will be stored 
coded indefinitely at the CVD (Baltimore, MD). Specimens may be shared with DMID, SIIPL, 
PATH, UKHSA, or VisMederi. Future-use stored specimens which have been coded may be 
shared with other investigators in the future. The recipients of specimens will be informed that 
these specimens have a NIH certificate of confidentiality. The information provided to a 
recipient will not contain direct identifiable information. 
8.4 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and 
the sponsor(s) and their agents. This confidentiality includes documentation, investigation data, 
subject’s clinical information, and all other information generated during participation in the 
study. No information concerning the study, or the data generated from the study will be released 

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to any unauthorized third party without prior written approval of the DMID and the subject. 
Subject confidentiality will be maintained when study results are published or discussed in 
conferences.  The study monitor or other authorized representatives of the sponsor or 
governmental regulatory agencies may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the subjects in this study. The clinical study site will permit 
access to such records. 
All records will be kept locked, and all computer entry and networking programs will be carried 
out with coded numbers only and with password protected systems. All non-clinical specimens, 
evaluation forms, reports, and other records that leave the site will be identified only by a coded 
number. 
 
8.5 
Costs, Subject Compensation, and Research Related Injuries 
Subjects (or their parent/guardian) in Mali will be compensated for their time in this study and be 
reimbursed for travel to attend study visits. These will be explained in the ICF. Study subjects (or 
their parent/guardian) will not be charged for study immunizations, research clinic visits, 
research-related examinations, or research-related laboratory tests. As part of the assessment and 
management of AEs, all medical care required by the subjects according to good national 
medical practice will be provided by the study team for the study duration and the subject’s 
parent/guardian will not need to pay for this. Subjects may be compensated for their participation 
in this trial.  Compensation will be in accordance with the local IRB’s policies and procedures, 
and subject to IRB approval. 
If it is determined by the site principal investigator that an injury occurred to a subject as a direct 
result of the tests or treatments that are done for this trial, then referrals to appropriate health care 
facilities will be provided to the subject. Clinical trial insurance is legally required in Mali.  
Study personnel will try to reduce, control, and treat any complications from this trial, but 
chronic care will not be provided.  Immediate medical treatment may be provided by the 
participating site.   
 

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STATISTICAL CONSIDERATIONS 
 
Overview and Study Design 
This is a Phase 3, randomized, single site, blinded non-inferiority trial to test the safety and 
immunogenicity of the NmCV-5 vaccine when administered at 9 months of age and when 
administered at 15 months of age. All participants will be randomly assigned to receive either 
NmCV-5 or MenACWY-TT, and all participants will be randomly assigned to receive one of 
these vaccines at either 9 months of age or at 15 months of age, along with scheduled EPI 
vaccines (Section 2.1). 
 
Study Hypotheses 
The co-primary objectives of the study are to demonstrate non-inferiority of the overall 
seroprotective response of NmCV-5 as compared to the seroprotective response of MenACWY-
TT when administered as a single dose at either 9 months of age or 15 months of age. To achieve 
these co-primary objectives, the study will test the null hypothesis that the seroprotective 
response elicited by NmCV-5 to at least one of the meningococcal serotypes A, C, W, X or Y is 
inferior to the seroprotective response elicited by MenACWY-TT in favor of the alternative 
hypothesis that the seroprotective response to all five meningococcal serogroups elicited after 
one dose of NmCV-5 are non-inferior to those elicited by one dose of MenACWY-TT. For each 
vaccination age group and for each of the serogroups A, C, Y and W, the corresponding 
hypothesis test will be based on the difference in the proportion of participants randomized to 
receive NmCV-5 who show seroprotective response to the specific serogroup, relative to the 
proportion of participants randomized to receive MenACWY-TT who show seroprotective 
response to the same serogroup. For serogroup X, the hypothesis test will be based on the 
difference in the proportion of participants randomized to receive NmCV-5 who show 
seroprotective response to the serogroup X relative to the proportion of participants randomized 
to receive MenACWY-TT showing seroprotective response to the serogroup with the lowest 
proportion of seroprotective response in that arm. For each meningococcal serogroup, vaccine 
seroprotective response will be based on a rabbit serum bactericidal antibody (rSBA) assay and 
the primary immunological endpoint is defined as post-vaccination rSBA titers ≥ 8 at Day 29. 
Within each age group, non-inferiority of the vaccine for each serogroup will be declared if the 
lower bound of the two-sided 95% confidence intervals for the difference in proportions of 
participants with seroprotective response is above -10% (-0.1). Overall non-inferiority at a given 
vaccination age (at 9 months of age and at 15 months of age) will be declared if the criteria for 
non-inferiority of the vaccine seroprotective response, as defined above, is achieved for all five 
serogroups.   
Consistent with the secondary safety endpoint to assess the safety and tolerability of a single 
dose of NmCV-5, a descriptive analysis approach will be used, with no statistical tests of 
hypothesis. These analyses are described in Section 9.6. 

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A secondary immunogenicity objective is to demonstrate the superiority of the NmCV-5 vaccine 
to elicit seroprotective response to the meningococcal serogroup X. To achieve this objective, the 
study will test a null hypothesis of the difference in the proportion of participants with vaccine 
seroprotective response to serogroup X equal or less than 30% (0.3) versus an alternative 
hypothesis of the difference in proportions of 30% or greater. Vaccine seroprotective response to 
serogroup X has been defined above, with non-inferiority declared if the lower bound of the two-
sided 95% confidence interval for the difference in proportion of participants with seroprotective 
response is at or above 10%.  
The secondary objective related to the immunogenicity of EPI vaccines is to demonstrate that 
seroprotective response elicited by EPI vaccines when co-administered with NmCV-5 is non-
inferior to the seroprotective response elicited by these same vaccines when co-administered 
with MenACWY-TT. The study will test the null hypothesis that, for each EPI vaccine, the 
difference in the proportion of participants showing seroprotective response (in the NmCV-5 arm 
relative to the MenACWY-TT arm) is equal or less than 10% (-0.1) in favor of the alternative 
hypothesis that the difference is greater than -10% (0.1). The seroprotective response to measles 
vaccination is defined as anti-measles IgG concentration > 90 mIU/mL, the seroprotective 
response to yellow fever vaccine is defined as neutralizing antibody titers ≥ 1:8, and the 
seroprotective response to rubella vaccine is to be according to the manufacturer’s specified 
cutoff, for a commercially-available and validated rubella IgG assay, all from samples collected 
at Day 29 visit. For each EPI vaccine, non-inferiority will be declared if the lower bound of a 
two-sided 95% confidence interval of the difference in proportion of participants with 
seroprotective response is above -10% (-0.1).  
 
Sample Size Considerations 
Table 8 shows power to test the non-inferiority of the seroprotective response to each of the 
serogroups A, C, W and Y elicited by the NmCV-5 vaccine, relative to the seroprotective 
response elicited by the MenACWY-TT vaccine, when administered as a single dose at either 9 
months of age or 15 months of age. These calculations assume a non-inferiority margin of -10% 
(-0.1) for a one-sided hypothesis test, with a 2.5% Type I error rate, and using the Miettinen-
Nurminen method for estimation of the 95% CI for the difference in proportions. The resulting 
power correspond to the sample size of at least 183 and 366 evaluable participants in each of the 
MenACWY-TT and NmCV-5 arms, respectively, where this target sample size results from the 
following assumptions: 
• At least 600 enrolled participants will be randomly assigned to receive the study vaccine 
at 9 months of age and  
• Among those randomized to receive the study vaccine at 15 months of age, at least 600 
participants will receive it at the scheduled visit.  
• For each vaccination age, participants will be randomly assigned, in a 1:2 ratio, to 
receive the MenACWY-TT or the NmCV-5 vaccine.  

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• At least 92.5% of the 600 enrolled and vaccinated participants will be followed up and 
contribute a sample for assessment at their Day 29 visit.  
Finally, calculation of Power in Table 8 is based on assumed proportions of seroprotective 
response in the MenACWY-TT arms that are consistent with, if somewhat more conservative 
than, to those reported in the literature.  
Table 8. Power to test non-inferiority of the proportion of participant with seroprotective 
response at Day 29 for serogroup A, C, W and Y, for a non-inferiority 
margin of -10% (-0.1) and a sample size of at least 183 and 366 evaluable 
participants in MenACWY-TT and NmCV-5 arms, respectively.  
Serogroup 
Proportion of Sero-
response in MenACWY-
TT arm 
Difference in proportion of sero-response  
(NmCV-5 – MenACWY-TT) 
Power  
Under the Null 
(H0) 
Under the Alternative (H1) 
A 
0.95 
-0.1 
0 
99.97% 
C 
0.95 
-0.1 
0 
99.97% 
W 
0.90 
-0.1 
0 
97.50% 
Y 
0.90 
-0.1 
0 
97.50% 
 
Power calculations were performed computationally, based on the exact distribution of the 
primary endpoint of interest under the alternative hypothesis. The probability of each 
combination of outcomes in the active and control arms was obtained under the assumption that 
they follow independent binomial distributions. The power of the test was calculated as the sum 
of probabilities of those scenarios where the outcomes meet the non-inferiority criterion. A 
simulation was also conducted to corroborate the results.  
Table 9 shows power to test the non-inferiority of the seroprotective response to serogroup X. 
Unlike serogroups A, C, W and Y, non-inferiority of the vaccine for serogroup X will be based 
on the difference in the proportion of participants randomized to receive NmCV-5 with 
seroprotective response to serogroup X  minus the proportion of participants randomized to 
receive MenACWY-TT with seroprotective response to the serogroup with the lowest proportion 
of seroprotective response. Thus, for this test, and consistent with our assumptions listed above, 
we assume that the lowest proportion of seroprotective response in the MenACWY-TT will be 
90% or higher.  
Table 9. Power to test non-inferiority of the proportion of participant with seroprotective 
response at Day 29 for serogroup X, when compared to lowest seroprotective 
response rate among A, C, W, Y serogroups, with a non-inferiority margin of 
-10% (-0.1) and a sample size of at least 183 and 366 evaluable participants 
in MenACWY-TT and NmCV-5 arms, respectively. 
Serogroup 
Lowest Proportion of 
Sero-response among 
Serogroups A, C, W, 
Difference in sero-response  
(Serogroup X in NmCV-5 - 
 lowest proportion among Serogroups A, C, W, 
Y in MenACWY-TT) 
Power 

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Y in MenACWY-TT 
arm 
Under the Null (H0) 
Under the Alternative 
(H1) 
  X 
0.90 
-0.1 
0 
97.50% 
Under the assumption that the test statistics used for the five non-inferiority tests described above 
are independent, the power to declare overall non-inferiority of NmCV-5 relative to MenACWY-
TT at a given vaccination age is calculated to be at least 92.6%. We note, however, that this is a 
conservative assumption and, given the likely correlation between seroprotective response rates 
among all the serogroups, the overall power may be higher.  
 
Treatment Assignment Procedures 
9.4.1 Randomization Procedures 
Participants will be randomly assigned to one of four possible vaccination schedule arms in two 
stages. First, enrolled participants will be randomly assigned, in a 1:1.2 ratio, to receive the study 
vaccine at 9 months of age or at 15 months of age. Participants who are assigned to receive the 
study vaccine at 9 months of age will be randomly assigned in a 2:1 ratio to receive either 
NmCV-5 or MenACWY-TT, co-administered with MR and YF EPI vaccines at 9 months of age 
and followed by a MR vaccine at 15 months of age. Participants who are assigned to receive the 
study vaccine at 15 months of age will first receive the MR and YF vaccine at 9 months of age. 
They will later be randomly assigned, in a 2:1 ratio, to receive either NmCV-5 or MenACWY-
TT, co-administered with the MR vaccine, at 15 months.  
To ensure balanced allocation to the four vaccination arms, the randomized assignments will be 
done in blocks of random sizes, stratified by age group. The randomization scheme will be 
generated and maintained by SCHARP. 
 
9.4.2 Masking Procedures 
This section describes blinding of researchers and participants to the random assignment of each 
individual participant (Step 2 randomization) to receive one of two meningitis vaccines (NmCV-
5 or MenACWYTT). Random allocation to receive either meningitis vaccine at 9 months of age 
or at 15 months of age (Step 1 randomization) will be done open label. 
Because the study vaccines may have different appearances, it may not be possible for the 
vaccinator to be blinded. Designated vaccinators will not partake in any post-vaccination 
evaluation. Parents or guardians of participants, laboratory personnel, and the researchers 
responsible for evaluation will remain blinded to participants’ random assignment of meningitis 
study vaccine (Step 2 randomization). 
The unblinded designated personnel will be provided with the randomization assignment that 
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prepare the study vaccine to be given to each subject. The unblinded personnel will maintain the 
randomization assignment in a secure location (apart from the rest of the participant file).  
Participants and researchers will remain blinded to individual participant random assignment of 
meningitis study vaccine until after all scheduled activities related to evaluation and collection of 
specimens are completed at the last study visit (Visit 5, Study Day 730). Unblinding of 
individual participants’ assignment during the conduct of the trial will be generally avoided, but 
emergency or non-emergency unblinding may be done for safety reasons, as described in the 
Treatment Unblinding Procedure document. There are no circumstances under which it is 
expected that unblinding will be necessary for provision of medical treatment or to otherwise 
protect the safety of study participants. If the site investigator or designee feels that specific 
product knowledge is necessary to protect participant safety, the site investigator or designee will 
notify the PC and DMID according to procedures described in the MOP. In the event of a serious 
adverse event requiring submission to regulatory authorities, unblinding information for the 
specific participant will be provided by SCHARP as required.  
 
Planned Interim Analyses 
9.5.1 Interim Safety Review 
Safety oversight will be conducted by a DSMB. The DSMB will review SAEs on a regular basis 
and on an ad hoc basis during the trial. The DMID MM and the ISM (as deemed necessary) will 
be responsible for reviewing SAEs in real time. If any of the halting rules listed in Section 7.6 of 
the protocol are met, cumulative safety data from all enrolled subjects will be summarized for 
DSMB review. 
In addition to any unscheduled DSMB reviews resulting from halting rules being met, the DSMB 
will review cumulative AE data as follows:  
• A safety review will be conducted after all participants randomly assigned to receive the 
meningococcal vaccine at 9 months of age have completed Day 29 visit.  
• A safety review will be conducted after all participants randomly assigned to receive the 
meningococcal vaccine at 15 months of age have completed Day 29 visit.  
• As per DSMB request, a review of the available study data from the 9 months of age 
group subjects will be conducted prior to initiating dosing of subjects randomized to 
receive meningococcal vaccine at 15 months of age subjects. 
Procedures for DSMB reviews/meetings will be defined in the charter. Reports may include 
enrollment and demographic information, medical history, concomitant medications, physical 
assessments, clinical laboratory values, dosing compliance, and solicited and unsolicited 
AE/SAEs. The DSMB will have access to closed study reports with information presented by 
vaccine arm, without masking. This is due to simple masking not being possible under 
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We note that statistical analyses of secondary safety endpoints (along with other primary and 
secondary immunogenicity endpoints) will be conducted before the end of the study, as detailed 
in Section 9.6.  
 
9.5.2 Interim Immunogenicity or Efficacy Review 
No formal interim analyses (i.e. formal test of hypothesis) on partially accumulated data (data 
available in only a fraction of the targeted number of participants) will be conducted. No 
statistical interim analyses will be conducted, understanding by this the sequential testing of a 
statistical hypothesis for which adjustment of type I error probability is required.  
However, and as per request of the DSMB, basic descriptive statistics related to immunogenicity 
endpoints may be included, if and when available, in the close portion of the DSMB reports. 
These may include statistics per vaccination arm, but will not include the estimation of the 
statistic on which the evaluation of non-inferiority will be based upon (i.e. 95% confidence 
interval for the difference in the proportion of participants with seroprotective response). Thus, 
no formal interim testing of the primary or secondary immunogenicity endpoints are planned, 
and no adjustment on the type I error rate will be conducted.  
We note that statistical analyses of primary and secondary immunogenicity endpoints (along 
with secondary safety endpoints) will be conducted before the end of the study, as detailed in 
Section 9.6.  
 
 
Analysis Plan 
This section describes the statistical analyses for the primary and secondary endpoints. Analysis 
of tertiary and exploratory endpoints will be described in the Statistical Analysis Plan.  
The main statistical analyses of the primary and secondary immunogenicity endpoints (up to Day 
29 visit) and of secondary safety endpoints (up to 6 months of follow-up) will be completed 
before the end of the study, as soon as the relevant data is available for each of the age groups. 
Unblinded results (through grouped analysis) from these statistical analyses will be summarized 
in at least two study reports (one per age group), which will be  submitted to WHO, as these data 
are critical for timely WHO-PQ review process.   
The analyses described above may also be available for presentation and publication to inform 
the scientific community. Publication of manuscripts may occur at the discretion of the sponsor 
in accordance with DMID’s Expanded Distribution of Clinical Research Endpoint Data Policy. 
The Clinical Study Report (CSR) will be completed when all primary and secondary safety, 
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Any available data from the exploratory endpoints may also be included. Additional exploratory 
endpoint data may be included in an addendum to the CSR, publication of manuscript(s), or 
other report.  
The Safety Analysis Set will include all participants who received the NmCV-5 or MenACWY-
TT vaccine at the randomly assigned vaccination age. All safety data from participants in the 
Safety Analysis Set will be analyzed according to the vaccine group to which the participant was 
randomized. In the rare instance that a participant receives the wrong intervention vaccine, the 
Statistical Analysis Plan (SAP) will address how to analyze the participant’s safety data.  
The Immunogenicity Analysis Set will include all participants who receive the expected 
meningococcal vaccine, within the randomly assigned age and for whom post-vaccine 
immunogenicity data is available at least at one timepoint post-vaccination. Analyses of primary 
and secondary immunogenicity endpoints will be conducted in the Immunogenicity Analysis Set.  
Before the final analysis, protocol deviations may be reviewed to determine which protocol 
deviations could affect the analysis. The per protocol (PP) analysis set will then be defined. 
Additional analyses of immunogenicity data may be conducted on the PP analysis set. Some or 
all of the following exclusions may apply: (i) data from all available visits for subjects found to 
be ineligible at baseline, (ii) data from all visits subsequent to the protocol deviations that are 
considered to affect the science (iii) data from any visit that occurs substantially out of window. 
Analyses of primary endpoints will be performed using SAS v9.4. 
No formal multiple comparison adjustments will be employed for multiple primary or secondary 
endpoints. Unless otherwise noted, 95% confidence intervals (CIs) will be calculated. Statistical 
tests of non-inferiority and superiority will be 1-sided.  
A SAP will be developed by the IDCRC Statistical and Data Science Unit (SDSU) and SCHARP 
and finalized prior to data lock, and prior to the main analysis of the primary and secondary 
endpoints. Unless specified otherwise in the SAP, missing data will not be imputed. 
General Approach 
Unless otherwise noted in the SAP, continuous variables will be summarized using the following 
descriptive statistics: mean, standard deviation, median, quartiles (25th and 75th percentiles), 
maximum and minimum. The frequency and percentages (based on the non-missing sample size) 
of observed levels will be reported for all categorical measures. Unless otherwise specified in the 
SAP, geometric means of relevant continuous endpoints will be computed as Williams means. 
Analysis of the Co-Primary Immunogenicity Endpoint(s) 
Analysis of the co-primary immunogenicity endpoints will be conducted for the Immunogenicity 
Analysis Set. In each arm, the proportion of participants with vaccine seroprotective response, 
defined as post-vaccination rSBA titers ≥ 8 at Day 29, will be calculated for all serogroups. The 

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difference in proportions will be estimated and 95% CI will be calculated using the Miettinen-
Nurminen method.  
For serogroup X, the test for non-inferiority will be based on the different in the proportion of 
participants with seroprotective response to serogroup X among those randomized to NmCV-5 
and the proportion of participants with seroprotective response to the serogroup with the lowest 
seroprotective response rate among those randomized to MenACWY-TT.   
Analysis of the Secondary Immunogenicity Endpoint(s) 
The superiority of seroprotective response to serogroup X among those randomized to NmCV-5 
relative to those randomized to MenACWY-TT will be based on the difference in proportions of 
participants with seroprotective response to serogroup X and its 95% CI, as estimated using the 
Miettinen-Nurminen method.  
The non-inferiority of seroprotective response to EPI vaccines administered concurrently with 
the NmCV-5 or MenACWY-TT meningococcal vaccines will be based on the difference in the 
proportion of participants with seroprotective response to each of these vaccines, between 
vaccination arms. The difference of proportions and the corresponding 95% CI will be calculated 
using the Miettinen-Nurminen method.  
Finally, to better understand and illustrate the immunological response elicited by the NmCV-5 
and MenACWY-TT vaccines, further descriptive analyses will be conducted by vaccination arms 
for each of the vaccination schedules. These include estimating the proportion of participants 
(along with 95% confidence intervals) with rSBA titers above 32 and above 128 at their Day 29 
visit, as well as the proportion of participants with a 4-fold increase from baseline to their Day 29 
visit. Geometric Mean Titers (GMT), with 95% CIs, will also be reported. Similar descriptive 
analyses will be done at other timepoints (at Day 181 and Day 730 visits), to explore the duration 
of the immunological response.  
Analysis of the Safety Secondary Endpoint(s) 
Analysis of the secondary safety endpoint, as well as descriptive analyses of safety data 
(solicited signs and symptoms and AEs) will be presented for the Safety Analysis Population. 
Solicited reactogenicity signs and symptoms (local and systemic) will be summarized by severity 
for each day post vaccination (Days 1-8) and as the maximum severity over all 7 days. The 
number and proportion of participants reporting each of the solicited reactogenicity signs and 
symptoms will be reported, along with 95% confidence intervals, as well as the number and 
proportion of participants reporting (i) any solicited reactogenicity sign or symptom, (ii) any 
solicited local reactogenicity sign or symptom and (iii) any solicited systemic reactogenicity sign 
or symptom.  
Unsolicited non-serious AEs will be collected from the time of first vaccination through 28 days 
after each vaccination. Unsolicited AEs will be coded by the Medical Dictionary for Regulatory 

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Activities (MedDRA) for preferred term and system organ class SOC. All SAEs will be collected 
from the time of first vaccination through the end of the study. SAEs will be described by 
detailed listings showing the event description, MedDRA preferred term and SOC, relevant dates 
(vaccinations and AEs), severity, relatedness, and outcome for each event. Non-serious 
unsolicited AEs will be summarized as number and percentage of subjects reporting at least one 
event in each MedDRA preferred term and SOC, cross tabulated by severity and relationship to 
study product. Additionally, the proportion of subjects and exact 95% CIs of AEs in aggregate 
and by MedDRA categories will be computed. 
Clinical laboratory data will be summarized as change from baseline and by severity for each 
visit, and as the maximum over all post study vaccination visits. 
Baseline Descriptive Statistics 
Summaries of demographic variables such as age at vaccination and sex, will be presented by 
arm. Summaries of clinical variables, such as weight, length and WHO standardized z-scores of 
length-for-age, weight-for-age and weight-for-length, at time of vaccination will also be 
presented by arm.  
Tabulation of Individual Subject Data 
In general, all data will be listed, sorted by arm and subject, and when appropriate by visit 
number within subject. 
 
 

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 ELECTRONIC CASE REPORT FORMS, SOURCE DOCUMENTS AND ACCESS 
TO SOURCE DATA 
The participating site will maintain appropriate medical and research records in compliance with 
ICH E6, Section 4.9 and regulatory and institutional requirements for the protection of 
confidentiality of subjects. Source data are all information in original records (and certified 
copies of original records) of clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial. Source data should be attributable, 
legible, contemporaneous, original, accurate, and complete. Each participating site will maintain 
appropriate medical and research records for this trial, in compliance with ICH GCP, regulatory, 
and institutional requirements.  
The study uses direct data entry into an eCRF as source documents by research staff, as well as 
entering data into the eCRF from source documentation on data collection forms or other types 
of source documents. The eCRFs serve as the source documents for data collected and entered 
directly (not recorded elsewhere).  The staff will maintain a tracker of eCRFs that serve as the 
source documents.   
A list of all authorized staff as data originators will be included on the Study Personnel/Signature 
Responsibility List. The staff who will enter source data directly into the eCRF are called “DDE 
Data Originators”. “Data Entry” staff  will enter the data on DCFs into the eCRF.     
Paper case report forms derived from the eCRF are provided by the DCC or designee and are to 
be used when the eCRF is unavailable. Data collected by staff at the homes of subjects will be 
entered on data collection forms.  Details on source data, and instructions for use of the system 
and completion of the eCRFs are provided in the study MOP. 
Each site will permit authorized representatives of the DMID, its designees, and appropriate 
regulatory agencies to examine (and when required by applicable law, to copy) clinical records 
for the purposes of quality assurance reviews, audits, and evaluation of the study safety and 
progress. These representatives will be permitted access to eCRFs, source data and source 
documents, which include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ memory aid or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified 
after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, and subject files and records kept at the pharmacy, at the laboratories, 
and medico-technical departments involved in the clinical trial.  
Interview of subjects’ parent or legal guardian is sufficient for obtaining medical history.  

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 QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, the site will be responsible 
for conducting routine quality assurance (QA) and quality control (QC) activities to internally 
monitor study progress and protocol compliance.  The site principal investigator will provide 
direct access to all study-related sites, eCRFs, source data/data collection forms, and reports for 
the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities.  The site principal investigator will ensure all study personnel are appropriately 
trained and applicable documentations are maintained on site. 
The DCC will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database.  Any missing data or data 
anomalies will be communicated to the participating site(s) for clarification and resolution. 
 

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 DATA HANDLING AND RECORD KEEPING 
 Data Collection and Management Responsibilities 
 Data collection is the responsibility of the study staff at the participating site under the 
supervision of the participating site PI. The site PI is responsible to ensure the accuracy, 
completeness, and timeliness of the data reported.  
The eCRFs and DCF may serve as source documents for data collected. Source documents also 
include medical records, research charts, or other documents where data is first recorded. 
Clinical research data from source documentation or eCRFs, including, but not limited to, 
AEs/SAEs, concomitant medications, medical history, physical assessments, and clinical 
laboratory data, will then be collected by the participating site or direct data entered into eCRFs 
via a 21 CFR Part 11-compliant internet data entry system provided by the DCC, SCHARP. The 
data system includes password protection and internal quality checks, such as automatic range 
checks, to identify data that appear inconsistent, incomplete, or inaccurate. AEs and concomitant 
medications will be coded according to the most current versions of MedDRA and WhoDrug, 
respectively.  
Details on data handling procedures, procedures for data monitoring, and instructions for use of 
the system and completion of the eCRFs are provided in the study MOP and CRF Completion 
Guidelines. The MOP will detail which data will be documented onto paper case report forms or 
when eCRFs will serve as the source documents for data collected. Paper case report forms 
derived from the eCRF are to be used when the data system or internet is unavailable.  
The IDCRC SDSU and SCHARP will be responsible for data management, quality review, 
analysis, and reporting of the study data. 
The IDCRC SDSU, PI and site are responsible for review of data collection tools and processes, 
and review of data and reports in collaboration with the DMID 
The sponsor and/or its designee will provide guidance to the site principal investigators and other 
study personnel on making corrections to the eCRF.  
 
 
 Data Coordinating Center/Biostatistician Responsibilities 
All eCRFs and source documentation must be reviewed by the clinical team and data entry 
personnel, who will ensure that they are accurate and complete. AEs must be recorded on the 
appropriate eCRF, assessed for severity and relationship, and reviewed by the site PI or 
appropriate sub-investigator. 

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The data coordinating center for this study will be responsible for data management, quality 
review, analysis, and reporting of the study data. 
At the end of the study, a copy of all datasets, including annotated CRFs and data dictionary, will 
be provided to DMID. 
 
 Data Capture Methods 
Clinical (including, but not limited to, AE/SAEs, concomitant medications, medical history, and 
physical assessments) and reactogenicity will be collected as described in the Manual of 
Procedures either on data collection forms by study personnel then entered into the data system 
or direct data entered into eCRFs via a 21 CFR Part 11-compliant internet data entry system 
provided by the study data coordinating center.  The data system includes password protection 
and internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate. 
The eCRF will be considered a source document when the information is direct data entry (DDE) 
for source data. The staff who will enter source data directly into the eCRF are called “DDE Data 
Originators”.  The PI will list all staff delegated as DDE Data Originators on the Study 
Personnel/Signature Responsibility List. 
 Types of Data 
Data for this trial will include clinical, safety, and outcome measures (e.g., reactogenicity, AEs, 
and immunogenicity data). 
 
 Study Records Retention 
Study records and reports including, but not limited to, eCRFs, source documents, ICFs, 
laboratory test results, and study drug disposition records will be retained for 2 years after a 
marketing application is approved for the study product for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for the study 
product, until 3 years after the investigation is discontinued. These documents will be retained 
for a longer period, however, if required by local regulations. ICFs for future use will be 
maintained as long as the sample/specimen exists. 
No records will be destroyed without the written consent of the sponsor. It is the responsibility of 
the sponsor to inform the site principal investigator when these documents no longer need to be 
retained. The participating VTEU sites must contact DMID for authorization prior to the 
destruction of any study records. 

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 CLINICAL MONITORING 
Site monitoring is conducted to ensure that the human subjects’ protections, study and laboratory 
procedures, study intervention administration, and data collection processes are of high quality 
and meet sponsor, ICH/GCP guidelines and applicable regulations, and that this trial is 
conducted in accordance with the protocol, protocol-specific MOP and applicable sponsor 
standard operating procedures (SOPs).  DMID, the sponsoring agency, or its designee will 
conduct site-monitoring visits as detailed in the clinical monitoring plan. 
Site visits will be made at standard intervals as defined by DMID and may be made more 
frequently as directed by DMID.  Monitoring visits will include, but are not limited to, review of 
regulatory files, accountability records, eCRFs, informed consent forms, medical and laboratory 
reports, and protocol and GCP compliance. Site monitors will have access to each participating 
site, study personnel, and all study documentation according to the DMID-approved site 
monitoring plan.  Study monitors will meet with site principal investigators to discuss any 
problems and actions to be taken, and will document site visit findings and discussions. 
 

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 PUBLICATION POLICY 
Sections 9.5 and 9.6 describe the dissemination of unblinded analysis planned during the study.  
 
Following completion of the study, the lead Principal Investigator is expected to publish the 
results of this research in a scientific journal.  All investigators funded by the NIH must submit 
or have submitted for them to the National Library of Medicine’s PubMed Central 
(http://www.ncbi.nlm.nih.gov/pmc/) an electronic version of their final, peer-reviewed 
manuscripts upon acceptance for publication, to be made publicly available no later than 12 
months after the official date of publication.  The NIH Public Access Policy ensures the public 
has access to the published results of NIH funded research.  It requires investigators to submit 
final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication.  Further, the policy stipulates that these papers must be 
accessible to the public on PubMed Central no later than 12 months after publication. 
Refer to: 
• 
NIH Public Access Policy, http://publicaccess.nih.gov/ 
• 
NIH Office of Extramural Research (OER) Grants and Funding, 
http://grants.nih.gov/grants/oer.htm 
As of January 2018, all clinical trials supported by the NIH must be registered on 
ClinicalTrials.gov, no later than 21 days after the enrollment of the first subject. Results of all 
clinical trials supported by the NIH, generally, need to be submitted no later than 12 months 
following the primary completion date. A delay of up to 2 years is available for trials that meet 
certain criteria and have applied for certification of delayed posting. 
As part of the result posting a copy of this protocol (and its amendments) and a copy of the 
Statistical Analysis Plan will be posted on ClinicalTrials.gov. 
For this trial the responsible party is DMID which will register the trial and post results.   
 

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 LITERATURE REFERENCES 
1 
Marc LaForce, F., Ravenscroft, N., Djingarey, M. & Viviani, S. Epidemic meningitis due 
to Group A Neisseria meningitidis in the African meningitis belt: a persistent problem 
with an imminent solution. Vaccine 27 Suppl 2, B13-19, 
doi:10.1016/j.vaccine.2009.04.062 (2009). 
2 
Harrison, L. H., Trotter, C. L. & Ramsay, M. E. Global epidemiology of meningococcal 
disease. Vaccine 27 Suppl 2, B51-63, doi:10.1016/j.vaccine.2009.04.063 (2009). 
3 
Tiffay, K., Jodar, L., Kieny, M. P., Socquet, M. & LaForce, F. M. The Evolution of the 
Meningitis Vaccine Project. Clin Infect Dis 61 Suppl 5, S396-403, 
doi:10.1093/cid/civ594 (2015). 
4 
Lingani, C. et al. Meningococcal Meningitis Surveillance in the African Meningitis Belt, 
2004-2013. Clin Infect Dis 61 Suppl 5, S410-415, doi:10.1093/cid/civ597 (2015). 
5 
bulletin, W. M. w.     (World Health Organization). 
6 
Funk, A. et al. Sequential outbreaks due to a new strain of Neisseria meningitidis 
serogroup C in northern Nigeria, 2013-14. PLoS Curr 6, 
doi:10.1371/currents.outbreaks.b50c2aaf1032b3ccade0fca0b63ee518 (2014). 
7 
Preparedness for outbreaks of meningococcal meningitis due to Neisseria meningitidis 
serogroup C in Africa: recommendations from a WHO expert consultation. Wkly 
Epidemiol Rec 90, 633-636 (2015). 
8 
Continuing risk of meningitis due to Neisseria meningitidis serogroup C in Africa: 
revised recommendations from a WHO expert consultation. Wkly Epidemiol Rec 92, 612-
617 (2017). 
9 
Nnadi, C. et al. Large Outbreak of Neisseria meningitidis Serogroup C - Nigeria, 
December 2016-June 2017. MMWR Morb Mortal Wkly Rep 66, 1352-1356, 
doi:10.15585/mmwr.mm6649a3 (2017). 
10 
Lingappa, J. R. et al. Serogroup W-135 meningococcal disease during the Hajj, 2000. 
Emerg Infect Dis 9, 665-671, doi:10.3201/eid0906.020565 (2003). 
11 
Retchless, A. C. et al. The Establishment and Diversification of Epidemic-Associated 
Serogroup W Meningococcus in the African Meningitis Belt, 1994 to 2012. mSphere 1, 
doi:10.1128/mSphere.00201-16 (2016). 
12 
Xie, O., Pollard, A. J., Mueller, J. E. & Norheim, G. Emergence of serogroup X 
meningococcal disease in Africa: need for a vaccine. Vaccine 31, 2852-2861, 
doi:10.1016/j.vaccine.2013.04.036 (2013). 
13 
Alderson, M. R. et al. Eliminating Meningococcal Epidemics From the African 
Meningitis Belt: The Case for Advanced Prevention and Control Using Next-Generation 
Meningococcal Conjugate Vaccines. J Infect Dis 220, S274-S278, 
doi:10.1093/infdis/jiz297 (2019). 
14 
Chilukuri, S. R. et al. Process development and immunogenicity studies on a serogroup 
'X' Meningococcal polysaccharide conjugate vaccine. Biologicals 42, 160-168, 
doi:10.1016/j.biologicals.2013.12.001 (2014). 
15 
Chen, W. H. et al. Safety and immunogenicity of a pentavalent meningococcal conjugate 
vaccine containing serogroups A, C, Y, W, and X in healthy adults: a phase 1, single-

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centre, double-blind, randomised, controlled study. Lancet Infect Dis 18, 1088-1096, 
doi:10.1016/S1473-3099(18)30400-6 (2018). 
16 
Tapia, M. D. et al. Meningococcal Serogroup ACWYX Conjugate Vaccine in Malian 
Toddlers. N Engl J Med 384, 2115-2123, doi:10.1056/NEJMoa2013615 (2021). 

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  APPENDICES 
 
Schedule of Events 
 
 Group 1: Participant Age (9-month 
group) 
9 mon 
9 mon 9 mon 10 mon 15 mon 33 mon 
 
Visit 
Screen 
Visit 1 Visit 2 Visit 3 Visit 4 
Visit 5 
ET 
Study Day 
 
1 
8 
29 
181 
730 
 
Window 
 
 
+3 
+7 
±14 
±45 
 
Informed Consent  
X 
 
 
 
 
 
 
Demographics1 
X 
 
 
 
 
 
 
Medical History including review of 
systems1 
X 
 
 
 
 
 
 
Determination / Confirmation of Eligibility 
X 
X 
 
 
 
 
 
Rapid Diagnostic Test for malaria 
 
X 
 
 
 
 
 
Photo of child 
 
X 
 
 
 
 
 
Vital Signs1,2 including axillary temperature 
X 
 
X 
X 
X 
X 
(X) 
Height, weight1 
X 
 
 
 
 
 
 
Physical exam1 
X 
 
X 
X 
X 
X 
(X) 
Randomization Step 1 
X 
 
 
 
 
 
 
Randomization Step 2 
 
X 
 
 
 
 
 
Blinded Vaccination 
 
X 
 
 
 
 
 
Administration of enhanced EPI vaccines† 
 
X 
 
 
X 
 
 
30-minute observation period post 
meningitis vaccination 
 
X 
 
 
 
 
 
7-day Memory Aid (dispense & collect)4 
 
D 
C 
 
 
 
 
AE assessment 
 
X 
X 
X 
 
 
(X) 
Concomitant medications and 
vaccinations1,3 
X 
X 
X 
X 
 
 
X 
SAE assessment 
 
X 
X 
X 
X 
X 
X 
Research Blood Draw (mL) 
 
5 mL 
 
10 mL 
5 mL 
5 mL 
5 mL 
 
 
Group 2: Participant Age (15-month group) 
9 mon 15 mon 15 mon 16 mon 21 mon 39 mon 
 
Visit Screen Visit 1b Visit 2 
Visit 3 Visit 4 Visit 5 
ET 
Study Day 
 
1 
8 
29 
181 
730 
 
Window 
 
 
+3 
+7 
±14 
±45 
 
Informed Consent  
X 
 
 
 
 
 
 
Demographics1 
X 
 
 
 
 
 
 
Medical History including review of systems1 
X 
X 
 
 
 
 
 
Determination / Confirmation of Eligibility 
X 
X 
 
 
 
 
 
Rapid Diagnostic Test for malaria 
 
X 
 
 
 
 
 
Photo of child 
 
X 
 
 
 
 
 
Vital Signs1,2 including axillary temperature 
X 
X 
X 
X 
X 
X 
(X) 
Height, weight1 
X 
X 
 
 
 
 
 
Physical exam1 
X 
X 
X 
X 
X 
X 
(X) 
Randomization Step 1 
X 
 
 
 
 
 
 

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Randomization Step 2 
 
X 
 
 
 
 
 
Blinded Vaccination 
 
X 
 
 
 
 
 
Administration of enhanced EPI vaccines† 
X 
X 
 
 
 
 
 
30-minute observation period post meningitis 
vaccination 
 
X 
 
 
 
 
 
7-day Memory Aid (dispense & collect) 4 
 
D 
C 
 
 
 
 
AE assessment 
 
X 
X 
X 
 
 
(X) 
Concomitant medications and vaccinations1,3 
X 
X 
X 
X 
 
 
X 
SAE assessment 
 
X 
X 
X 
X 
X 
X 
Research Blood Draw (mL) 
 
5 mL 
 
10 mL 
5 mL 
5 mL 
5 mL 
†, Enhanced EPI vaccines at 9-months consist of measles-rubella (MR) and yellow fever (YF) vaccine; the Enhanced 
EPI vaccine at 15-months consists of MR vaccine. 
1 Conducted after consent obtained  
2 Vital signs include heart rate and respiratory rate. 
3 Concomitant medication and vaccination history will be updated at study visits through Day 29. 
4Field workers will visit homes as described in Section 5.4. 
( ) As applicable 
 
 
 

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TOXICITY TABLE 
The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Version 2.1 consists of parameters, or AEs, with severity grading guidance that are to be 
used in DAIDS clinical trials for safety data reporting to maintain accuracy and consistency in 
the evaluation of AEs. This study intends to report AEs in alignment with the DAIDS grading 
guidance. The following table contains the grading of some common reactions and is not 
intended to be an exhaustive listing. In addition, all deaths related to an AE are to be classified as 
grade 5. 
Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially Life-
Threatening 
Clinical adverse 
event NOT 
identified elsewhere 
in the complete 
grading table 
Mild symptoms 
causing no or 
minimal interference 
with usual social & 
functional activities 
with intervention not 
indicated 
Moderate symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
with intervention 
indicated 
Severe symptoms 
causing inability to 
perform usual social 
& functional 
activities with 
intervention or 
hospitalization 
indicated 
Potentially life-
threatening 
symptoms causing 
inability to perform 
basic self-care 
functions with 
intervention 
indicated to prevent 
permanent 
impairment, 
persistent disability, 
or death 
Arrhythmia  
No symptoms AND 
no intervention 
indicated 
No symptoms AND 
non-urgent 
intervention 
indicated 
Non-life-threatening 
symptoms AND 
non-urgent 
intervention 
indicated 
Life-threatening 
arrhythmia OR 
Urgent intervention 
indicated 
Hemorrhage 
NA 
Symptoms AND no 
transfusion indicated 
Symptoms AND 
Transfusion of ≤ 10 
cc/kg of packed 
RBCs indicated 
Life-threatening 
hypotension OR 
Transfusion of > 10 
cc/kg of packed 
RBCs indicated 
Bruising 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Cellulitis 
NA 
Non-parenteral 
treatment indicated 
IV treatment 
indicated 
Life-threatening 
consequences (e.g., 
sepsis, tissue 
necrosis) 
Hyper or 
Hypopigmentation 
Slight or localized 
causing no or 
minimal interference 
with usual social & 
functional activities 
Marked or 
generalized causing 
greater than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Petechiae 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 

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Pruritus 
Itching causing no 
or minimal 
interference with 
usual social & 
functional activities 
Itching causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Itching causing 
inability to perform 
usual social & 
functional activities 
NA 
Rash 
Localized rash 
Diffuse rash OR 
Target lesions 
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial 
ulcerations of 
mucous membrane 
limited to one site 
Extensive or 
generalized bullous 
lesions OR 
Ulceration of 
mucous membrane 
involving two or 
more distinct 
mucosal sites OR 
Stevens-Johnson 
syndrome OR toxic 
epidermal 
necrolysis 
Bloating or 
Distension (of 
abdomen) 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Constipation 
NA 
Persistent 
constipation 
requiring regular use 
of dietary 
modifications, 
laxatives, or enemas 
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Dysphagia or 
Odynophagia 
Symptoms but able 
to eat usual diet 
Symptoms causing 
altered dietary 
intake with no 
intervention 
indicated 
Symptoms causing 
severely altered 
dietary intake with 
intervention 
indicated 
Life-threatening 
reduction in oral 
intake 
Diarrhea 
Liquid stools (more 
unformed than 
usual) by usual 
number of stools 
Liquid stools with 
increased number of 
stools OR mild 
dehydration 
Liquid stools with 
moderate 
dehydration 
Life-threatening 
consequences (e.g., 
liquid stools 
resulting in severe 
dehydration, 
hypotensive shock) 
Mucositis or 
Stomatitis 
Mucosal erythema 
Patchy 
pseudomembranes 
or ulcerations 
Confluent 
pseudomembranes 
or ulcerations OR 
mucosal bleeding 
with minor trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) 
OR Tissue necrosis 
OR Diffuse 
spontaneous 
mucosal bleeding 
Arthralgia 
Joint paint causing 
no or minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
inability to perform 
usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic self-
care functions 

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Myalgia 
(generalized) 
Muscle pain causing 
no or minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
inability to perform 
usual social & 
functional activities 
Disabling muscle 
pain causing 
inability to perform 
basic self-care 
functions 
Seizures 
Seizure lasting < 
5minutes with < 24 
hours postictal state 
Seizure last 5 to < 
20 minutes with < 
24 hours postictal 
state 
Seizure lasting ≥ 20 
minutes OR > 24 
hours postictal state 
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to control 
(e.g., refractory 
epilepsy) 
Syncope 
Near syncope 
without loss of 
consciousness (e.g., 
pre-syncope) 
Loss of 
consciousness with 
no intervention 
indicated 
Loss of 
consciousness AND 
Hospitalization or 
intervention required 
NA 
Acute Allergic 
Reaction 
Localized urticaria 
(wheals) with no 
medical intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with no 
intervention 
indicated 
General urticaria OR 
Angioedema with 
intervension 
indicated OR 
Symptoms of mild 
bronchospasm 
Acute anaphylaxis 
OR Life-
threatening 
bronchospasm OR 
Laryngeal edema