A Phase 1, Double Blind, Randomized, Controlled Study to Evaluate the Safety and Immunogenicity of a New Meningococcal Conjugate Vaccine Containing Serogroups A,C,Y,W and X in Healthy Adults
Phase: PHASE1
Conditions: Meningococcal Vaccines
Sponsor: PATH

Study Protocol: ACYWX-001/VAC 046 
 
Version 4.0: 27 September 2016 
 
 
ACYWX-001/ VAC-046 
 
 
 
 
A Phase 1, double blind, randomized, controlled study to evaluate 
the safety and immunogenicity of a new Meningococcal Conjugate 
Vaccine containing serogroups A,C,Y,W and X in healthy adults. 
 
 
 
 
Sponsored by: 
 
PATH 
 
Collaborating Partner and Pharmaceutical Support:  
 
Serum Institute of India Private Limited (SIIPL) 
 
 
 
Principal Investigator:  
Dr. Wilbur H. Chen 
 
 
Version 4.0; 27 September 2016 
 
 
 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ......................................................................... 6 
PROTOCOL SIGNATURE PAGE .............................................................................................. 8 
PARTICIPATING INSTITUTIONS .............................................................................................. 9 
STUDY SYNOPSIS .................................................................................................................. 10 
1. 
BACKGROUND AND INTRODUCTION .......................................................................... 18 
1.1. 
Pathogen ...............................................................................................................18 
1.2. 
Burden of Disease ................................................................................................18 
1.3. 
Meningococcal Vaccines .....................................................................................19 
1.3.1. 
Polysaccharide Vaccines........................................................................... 19 
1.3.2. 
Conjugate Vaccines .................................................................................. 20 
1.3.3. 
Monovalent Conjugated Vaccine against Meningococcal Serogroup C 
(MenCCV) ................................................................................................. 21 
1.3.4. 
Monovalent Conjugated Vaccine against Meningococcal Serogroup A 
(MenAfriVac®) ........................................................................................... 21 
1.3.5. 
Tetravalent Conjugate Meningococcal Vaccines (TCMV) .......................... 23 
1.3.6. 
Overall Impact of Meningococcal Vaccines ............................................... 24 
1.3.7. 
Vaccine against B Serogroup .................................................................... 24 
1.3.8. 
Vaccine against X Serogroup .................................................................... 24 
1.4. 
Study Vaccine .......................................................................................................24 
1.5. 
Summary of Nonclinical Studies .........................................................................25 
1.5.1. 
Non-Good Laboratory Practice (GLP) Nonclinical Pharmacology/Proof of 
Concept Studies ........................................................................................ 25 
1.5.2. 
Toxicology Studies .................................................................................... 26 
1.5.3. 
Immunogenicity Studies ............................................................................ 27 
1.6. 
Clinical Studies ....................................................................................................30 
2. 
HYPOTHESIS, SCIENTIFIC RATIONALE, OBJECTIVES AND STUDY DESIGN .......... 30 
2.1. 
Study Hypotheses ................................................................................................30 
2.2. 
Scientific Rationale ..............................................................................................31 
2.3. 
Overall Clinical Development Strategy ...............................................................31 
2.4. 
Study Design ........................................................................................................31 
2.4.1. 
Discussion of Study Design ....................................................................... 32 
2.4.2. 
Primary Objective ...................................................................................... 32 
2.4.3. 
Secondary Objective ................................................................................. 32 
2.4.4. 
Primary Endpoints ..................................................................................... 32 
2.4.5. 
Secondary Endpoints ................................................................................ 32 
2.4.6. 
Exploratory Endpoints ............................................................................... 33 
2.4.7. 
Randomization and Vaccination ................................................................ 33 
3. 
STUDY PRODUCTS ....................................................................................................... 33 
3.1. 
Test Vaccine (MCV-5) ...........................................................................................33 
3.1.1. 
Product Description ................................................................................... 33 
3.1.2. 
Manufacturer ............................................................................................. 34 
3.1.3. 
Presentation and Formulation ................................................................... 34 
3.1.4. 
Stability and Storage ................................................................................. 34 

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3.2. 
Diluents .................................................................................................................34 
3.2.1. 
Adjuvanted Diluent .................................................................................... 34 
3.2.2. 
Non-Adjuvanted Diluent ............................................................................ 35 
3.3. 
Reference Vaccine (Menactra®)26 ........................................................................35 
3.3.1. 
Product Description ................................................................................... 35 
3.3.2. 
Manufacturer ............................................................................................. 35 
3.3.3. 
Presentation and Formulation ................................................................... 35 
3.3.4. 
Stability and Storage ................................................................................. 35 
3.4. 
Preparation and Administration ..........................................................................36 
3.4.1. 
Adjuvanted MCV-5 .................................................................................... 36 
3.4.2. 
Non-Adjuvanted MCV-5 ............................................................................ 37 
3.4.3. 
Menactra® ................................................................................................. 37 
3.5. 
Accountability and Disposal ...............................................................................37 
4. 
STUDY POPULATION .................................................................................................... 39 
4.1. 
Clinical Trial Site ..................................................................................................39 
4.2. 
Study Population ..................................................................................................39 
4.3. 
Eligibility ...............................................................................................................39 
4.3.1. 
Inclusion Criteria ....................................................................................... 39 
4.3.2. 
Exclusion Criteria ...................................................................................... 40 
5. 
STUDY PROCEDURES .................................................................................................. 41 
5.1. 
Recruitment ..........................................................................................................41 
5.2. 
Screening, Randomization, Masking Procedures, Study Visits ........................41 
5.2.1. 
Initial and Continuing Informed Consent .................................................... 41 
5.2.2. 
Screening, Visit 1 (Day -28 to -1) ............................................................... 42 
5.2.3. 
Randomization .......................................................................................... 42 
5.2.4. 
Vaccination, Visit 2 (Day 1) ....................................................................... 43 
5.2.5. 
Visit 3 (Day 8 +3 days) .............................................................................. 44 
5.2.6. 
Visit 4 (Day 29 +14 days) .......................................................................... 44 
5.2.7. 
Visit 5 (Day 85 +14 days) .......................................................................... 45 
5.2.8. 
Final Study Contact (Day 180 ±21 days) ................................................... 45 
5.3. 
Unscheduled Visits ..............................................................................................45 
5.4. 
Early Termination .................................................................................................45 
5.5. 
Procedure Methods ..............................................................................................45 
5.5.1. 
Vital Signs ................................................................................................. 45 
5.5.2. 
Height and Weight ..................................................................................... 46 
5.5.3. 
Physical Examination ................................................................................ 46 
5.5.4. 
Medical History .......................................................................................... 46 
5.5.5. 
Injection Site Examination ......................................................................... 46 
5.5.6. 
Assessment of Reactogenicity .................................................................. 46 
5.5.7. 
Concomitant Therapy ................................................................................ 47 
5.5.8. 
Clinical Laboratory Testing ........................................................................ 47 
5.5.9. 
Early Termination from Study .................................................................... 47 
5.5.10. Contraception and Pregnancy ................................................................... 48 
6. 
LABORATORY EVALUATIONS ..................................................................................... 48 
6.1. 
Sample Collection, Distribution and Storage .....................................................48 
6.2. 
Safety Clinical Laboratory Assays ......................................................................48 
6.3. 
Immunological Assays ........................................................................................48 

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6.4. 
Assay Qualification, Standardization and Validation ........................................49 
6.5. 
Biohazard Containment .......................................................................................49 
7. 
STATISTICAL DESIGN AND ANALYSIS ....................................................................... 49 
7.1. 
Overview and General Design .............................................................................49 
7.2. 
Randomization and Blinding Procedures ...........................................................49 
7.3. 
Objectives and Endpoints ...................................................................................50 
7.3.1. 
Primary ...................................................................................................... 50 
7.3.2. 
Secondary ................................................................................................. 50 
7.3.3. 
Exploratory ................................................................................................ 51 
7.4. 
Sample Size Justification ....................................................................................51 
7.5. 
Analytical Methodology .......................................................................................51 
7.5.1. 
Analysis Population ................................................................................... 51 
7.5.2. 
Statistical Method ...................................................................................... 52 
8. 
SAFETY ASSESSMENT AND REPORTING .................................................................. 53 
8.1. 
Safety Events ........................................................................................................53 
8.2. 
Reporting Period ..................................................................................................54 
8.3. 
Definitions ............................................................................................................54 
8.3.1. 
Adverse Event (AE) ................................................................................... 54 
8.3.2. 
Serious Adverse Events (Defined as Serious Adverse Events, Serious 
Suspected Adverse Reactions or Serious Adverse Reactions).................. 54 
8.3.3. 
Unexpected Adverse Event ....................................................................... 54 
8.4. 
Severity Grading ..................................................................................................55 
8.5. 
Guidelines for Determining Causality of an Adverse Event ..............................55 
8.6. 
Assessment of Outcome of Adverse Event ........................................................55 
8.7. 
Adverse Event Identification, Resolution and Reporting ..................................55 
8.7.1. 
AE Resolution ........................................................................................... 57 
8.7.2. 
General Recording and Reporting Procedures .......................................... 57 
8.7.3. 
SAE Recording and Reporting Procedures ............................................... 57 
8.7.4. 
Site Reporting of Events ............................................................................ 58 
8.8. 
Serious Adverse Event Notification ....................................................................59 
8.8.1. 
Notifications and Review ........................................................................... 59 
8.8.2. 
Expedited Reporting .................................................................................. 59 
8.8.3. 
Notifying the Safety Review Committee ..................................................... 60 
8.8.4. 
Notifying the Institutional Review Board .................................................... 60 
9. 
SAFETY MONITORING .................................................................................................. 60 
9.1. 
Safety Review Committee ....................................................................................60 
9.2. 
Study Pause Rule .................................................................................................61 
9.2.1. 
Pause Procedure ...................................................................................... 61 
10. 
DATA MANAGEMENT .................................................................................................... 62 
10.1. Case Report Form Development and Completion .............................................62 
10.2. Details of Data Management ................................................................................62 
10.2.1. Coding....................................................................................................... 62 
10.2.2. Data Validation .......................................................................................... 63 
10.2.3. Source Data Verification ............................................................................ 63 
10.2.4. Definition of Source Data........................................................................... 63 
10.2.5. Definition of Source Document .................................................................. 63 

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10.3. Database Locking Procedures ............................................................................63 
10.4. Record Archival ....................................................................................................63 
10.5. Screen Failures ....................................................................................................64 
10.6. Protocol Deviations ..............................................................................................64 
11. 
STUDY MONITORING .................................................................................................... 64 
11.1. Independent Auditing ..........................................................................................65 
11.2. Regulatory Agency Auditing ...............................................................................65 
12. 
OBLIGATIONS AND ROLES OF THE SPONSOR, PI AND STUDY PERSONNEL ........ 65 
13. 
ETHICAL CONSIDERATIONS AND INFORMED CONSENT ......................................... 66 
13.1. Informed Consent Process ..................................................................................66 
13.2. Risk/Benefit ..........................................................................................................66 
13.3. Protocol Review Process .....................................................................................67 
13.4. Participant Confidentiality ...................................................................................68 
13.5. Reimbursement ....................................................................................................68 
13.6. Storage of Specimens ..........................................................................................68 
14. 
APPENDICES ................................................................................................................. 69 
14.1. APPENDIX I: Schedule of Events ........................................................................69 
14.2. APPENDIX II: Toxicity Grading Scale ..................................................................70 
14.3. APPENDIX III: References .................................................................................. 104 
 
 
 

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LIST OF ABBREVIATIONS AND ACRONYMS 
 
ABBREVIATION 
/ ACRONYM 
DEFINITION 
µg or mcg 
Microgram 
4-PP  
4-Pyrrolidinopyridine 
AE  
adverse event 
Alum 
Aluminum phosphate 
CDC  
Centers for Disease Control 
CI 
Confidence interval 
cm 
Centimeter 
CMV 
conjugated meningococcal vaccines 
CPCSEA 
Committee for the Purpose of Control and Supervision of Experiments on Animals 
CPPT  
1-cyano-4 pyrrolidinopyridinium tetrafluoroborate 
CRF 
Case report form 
CRM 
cross reactive material 
CRO 
Contract research organization 
CVD 
Centre for Vaccine Development 
DAIDS 
Division of AIDS 
DSMB  
Data Safety Monitoring Board 
ELISA 
Enzyme linked immunosorbent assay 
FDA  
Food and Drug Administration (US) 
FIH  
first in human 
GCP 
Good Clinical Practices 
GLP  
Good Laboratory Practices 
GMTs  
geometric mean titers 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
ICD 
Informed consent document 
ICF 
Informed consent form 
Ig 
Immunoglobulin 
IM  
Intramuscular 
IMD 
invasive meningococcal disease 
INDA  
Investigational New Drug Application 
IRB 
Institutional review board 
kg 
Kilogram 
mL 
Milliliter 
MedDRA 
Medical Dictionary for Regulatory Activities 
NIBSC  
National Institute for Biological Standards and Control 
NMT 
Not more than 

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ABBREVIATION 
/ ACRONYM 
DEFINITION 
PCR 
Polymerase chain reaction 
PHE 
Public Health England 
PI 
Principal Investigator 
PS  
Polysaccharide 
PT 
Preferred term 
q.s. 
Quantum satis 
rSBA  
rabbit complement serum bactericidal activity 
SAE  
serious adverse event 
SBA  
serum bactericidal activity 
SIIPL  
Serum Institute of India Private Limited. 
SOC 
System organ class 
SOP  
Standard Operating Procedure 
SRC 
Safety Review Committee 
TCMV 
Tetravalent conjugate meningococcal vaccines 
TT  
tetanus toxoid 
UK 
United Kingdom 
UMB 
University of Maryland, Baltimore 
USA  
United States of America 
w/v 
Weight by volume 
WHO  
World Health Organization 
 
 

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PROTOCOL SIGNATURE PAGE 
 
 
PATH, the study Sponsor, will keep a list of Investigator(s), who must provide a Curriculum Vita 
(CV) and a copy of their medical licenses to the Sponsor or Sponsor representatives. The Sponsor 
will keep a list and qualification records of all relevant Sponsor study personnel. 
 
The Emmes Corporation will conduct site monitoring and provide medical monitoring, data 
management, statistical analysis, quality assurance, safety and pharmacovigilance services. 
 
Site Contact 
Phone Number 
Email Address 
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 
Wilbur H. Chen, MD, MS 
(Principal Investigator) 
410-706-1188 
wchen@medicine.umaryland.edu 
Kathleen M. Neuzil, MD, MPH 
410-706-5328 
kneuzil@medicine.umaryland.edu 
James D. Campbell, MD, MS 
410-706-7284 
jcampbel@medicine.umaryland.edu 
 
 
SIGNATURE OF SITE Principal Investigator (PI):  
 
“I have read the foregoing protocol and agree to conduct the study as outlined herein.”  
 
 
 
_____________________________________  
____________________ 
Principal Investigator   
 
 
 
DD/MM/YY 
 

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PARTICIPATING INSTITUTIONS 
Sponsor 
PATH 
2201 Westlake Avenue, Suite 200 
Seattle, WA 98121 USA 
Clinical Trial Site 
Center for Vaccine Development 
University of Maryland 
685 West Baltimore Street, Room 480 
Baltimore, MD 21201-1509 USA 
Phone: 410-706-5328  
Fax: 410-706-6205 
Research Laboratory 
Vaccine Evaluation Unit, Public Health England (PHE), 
Manchester, United Kingdom 
Collaborating Partner & Vaccine 
Manufacturer 
Serum Institute of India Private Limited (SIIPL) 
212/2 Hadapsaar, Pune – 411028, India 
Phone: +91 206 993 900 ext. 2384  
Fax: +91 206 993 945 
Site Monitoring 
The Emmes Corporation 
401 N. Washington St., Suite 700 
Rockville, MD 20850 
USA 
Medical Monitoring 
The Emmes Corporation 
401 N. Washington St., Suite 700 
Rockville, MD 20850 
USA 
Data Center and  
Statistical Support 
The Emmes Corporation 
401 N. Washington St., Suite 700 
Rockville, MD 20850 
USA 
 
 

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STUDY SYNOPSIS 
TITLE 
A Phase 1, double blind, randomized, controlled study to evaluate the safety and 
immunogenicity of a new Meningococcal Conjugate Vaccine containing serogroups A,C,Y,W 
and X in healthy adults 
NAME OF THE STUDY VACCINE 
Meningococcal (A, C, Y, W, X) Polysaccharide Conjugated Vaccine (freeze-dried), also 
referred to as MCV-5 
STUDY NUMBER 
ACYWX-001/ VAC-046 
PROJECT PHASE 
Phase 1 
SPONSOR 
PATH 
COLLABORATING PARTNER AND VACCINE MANUFACTURER 
Serum Institute of India Private Limited (SIIPL) 
PRINCIPAL INVESTIGATOR 
Dr. Wilbur H. Chen, MD, MS 
Chief, Adult Clinical Studies section 
Center for Vaccine Development 
University of Maryland School of Medicine 
685 W. Baltimore Street, Suite 480 
Baltimore, MD 21201 
Tel: 410-706-1188 
Fax: 410-706-6205 
Email: wchen@medicine.umaryland.edu 
SPONSOR MEDICAL OFFICER 
Dr. Igor Smolenov, MD 
Vaccine Development Global Program – PATH 
2201 Westlake Ave #200 
Seattle, WA 98121, USA 
Email: ismolenov@path.org 
VACCINE MANUFACTURER MEDICAL EXPERT 
Dr. Prasad Kulkarni, MD 
Medical Director, 
Serum Institute of India Private Ltd. Pune 
Tel: 91-20-26602384  
Fax: 91-20-26993945 
Email: drpsk@seruminstitute.com 
 
 

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VACCINE MANUFACTURER MEDICAL OFFICER 
Dr. Amol Chaudhari, MD 
Senior Manager (Clinical Trials & Pharmacovigilance) 
Serum Institute of India Private Ltd. Pune 
Tel: 91-20-26602869 
Fax: 91-20-26993945 
Email:amol.chaudhari@seruminstitute.com 
EMMES MEDICAL MONITOR 
Robert Lindblad, MD 
The Emmes Corporation 
401 N. Washington St., Suite 700 
Rockville, MD 20850 
PATH CLINICAL OPERATIONS MANAGER  
Lionel Martellet 
207 Rte de Ferney, Geneva, 1218 Switzerland  
Office: +41 22 747 1055 / Mobile: +33 699 872 551 
Email: lmartellet@path.org 
CONTRACT RESEARCH ORGANIZATION 
The Emmes Corporation 
401 N. Washington St., Suite 700 
Rockville, MD 20850 
RESEARCH LABORATORY 
Vaccine Evaluation Unit, Public Health England (PHE), Manchester, United Kingdom 
INVESTIGATIONAL PHARMACY 
University of Maryland Medical Center 
Investigational Drug Service (IDS) Pharmacy 
22 South Greene Street 
Room N9E14 
Baltimore, MD 21201 
Prashant Patel, PharmD 
Manager, IDS Pharmacy 
Tel: 410-328-5468/5160 
Fax: 410-328-7326 
Email: ppatel13@umm.edu 
 
 
 

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STUDY OBJECTIVES 
 
Primary Objective: 
To evaluate the safety of adjuvanted and non-adjuvanted formulations of MCV-5 vaccine. 
Secondary Objectives: 
To assess the immune response of adjuvanted and non-adjuvanted formulations of MCV-5 
vaccine. 
STUDY ENDPOINTS 
 
Primary Endpoints 
 
1. The occurrence and severity of solicited local and systemic post immunization reactions 
within seven days following vaccination. 
2. The occurrence, severity, and relatedness to vaccination of unsolicited adverse events 
(AE) for 28 days following vaccination, and serious adverse events (SAE) for 6 months 
following vaccination. 
 
Secondary Endpoints 
 
1. The percentage of participants who show a seroconversion for Meningococcal 
Polysaccharide A, C, Y, W, and X specific antibodies, i.e. a ≥4-fold increase in post-
immunization rabbit complement serum bactericidal activity (rSBA) titer with respect to 
pre-immunization rSBA titer, at 28 days after a single vaccine dose.  
2. The percentage of participants who show a post-immunization seroprotection titer for 
Meningococcal Polysaccharide A, C, Y, W and X specific antibodies defined as rSBA 
titer of 1:8 and 1:128 at 28 days after a single vaccine dose. 
3. Geometric mean titers (GMTs) of Meningococcal Polysaccharide A, C, Y, W, and X 
specific antibodies at 28 days after a single vaccine dose, as measured by rSBA assay. 
STUDY HYPOTHESES 
Primary hypothesis: Two formulations (adjuvanted and non-adjuvanted) of MCV-5 vaccine 
when given to healthy adults will be safe and well tolerated. 
Secondary hypothesis: Two formulations (adjuvanted and non-adjuvanted) of MCV-5 vaccine 
when given to healthy adults will induce immune response to all the five serogroups of the 
vaccines. 
STUDY DESIGN  
This is a Phase 1, single center, double-blind, randomized, controlled clinical trial to be 
performed in 18 to 45 year old healthy volunteers.  
The study will have three arms with three vaccines given in a 1:1:1 ratio: adjuvanted MCV-5, 
non-adjuvanted MCV-5 and Menactra®.  
Each participant will receive a single intramuscular (IM) injection of one of the three vaccines 
and will be followed up for six months after the vaccination. 

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Safety evaluation will include safety laboratory parameters at baseline and seven days after 
vaccination, local and systemic post-immunization reactions for seven days after vaccination. 
Adverse events for one month after vaccination and serious adverse events for the entire study 
period (six months) will be collected. 
The vaccinator will be aware of treatment allocation, although he/she will neither be able to 
influence or decide this allocation nor be part of the safety assessment. The study team involved 
in assessment of safety outcome as well as participants will be unaware of the group allocation. 
STUDY RATIONALE 
Currently, three polyvalent conjugate vaccines are available to protect against meningococcal 
disease. All three are tetravalent (serogroups A, C, W, and Y) vaccines; Menactra® (Sanofi 
Pasteur Inc.), Menveo® (Novartis) and Nimenrix® (GlaxoSmithKline Biologicals). There is vast 
experience with the use of these vaccines, which are generally well tolerated in all age groups. 
At this time,there is no licenced vaccine giving protection against meningococcal serogroup X 
which has caused many outbreaks in Africa and Europe in the recent past.  
 
Following the MenAfriVac® MenA monovalent conjugate vaccine development experience, 
SIIPL has developed a candidate polyvalent conjugate vaccine composed of serogroups A, C, 
Y, W, and X Neisseria meningitidis capsular polysaccharides. The individual polysaccharides 
are conjugated to protein carriers, cross reactive material (CRM) or tetanus toxoid (TT), and 
formulated with or without aluminum phosphate (alum) as an adjuvant. The vaccine is intended 
for the prevention of meningitis and/or septicemia caused by serogroups A, C, Y, W, and X 
N. meningitidis in countries where the disease is endemic and causes large epidemics such as 
the countries in the African meningitis belt. The target population consists of infants, children 
and adults covering an age group of 9 months to 55 years. 
 
This first-in-human (FIH) Phase 1 clinical study is designed to evaluate primarily the safety of 
the study vaccine. The three-group design will allow safety evaluation of the adjuvanted and 
non-adjuvanted MCV-5 formulations. The quadrivalent (ACYW) Menactra® vaccine has been 
chosen as a control vaccine comparator given the large safety database accumulated since the 
vaccine was introduced in the US in 2005, prequalified by World Health Organization (WHO) 
and progressively introduced in other countries. 
The secondary objective of the study is immunologic evaluations of both adjuvanted and 
non-adjuvanted vaccine formulations. 
 
 

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STUDY VACCINES 
MCV-5: 
Two formulations (adjuvanted and non-adjuvanted) of the MCV-5 meningococcal conjugate 
vaccine will be used in the study. MCV-5 will be available as lyophilized product in a five dose 
vial containing meningococcal A and X polysaccharides conjugated to tetanus toxoid and 
meningococcal C, Y, and W polysaccharides conjugated to CRM.  
The vaccine will be reconstituted with either normal saline (non-adjuvanted) or saline containing 
aluminum phosphate at 125 µg Al3+ /dose (adjuvanted) just prior to administration. 
Composition of reconstituted final solution of one single 0.5 mL 
dose of adjuvanted MCV-5 vaccine 
Vaccine component 
Per 0.5 mL dose 
Meningococcal A polysaccharide* 
5 g 
Meningococcal C polysaccharide# 
5 g 
Meningococcal Y polysaccharide# 
5 g 
Meningococcal W polysaccharide# 
5 g 
Meningococcal X polysaccharide* 
5 g 
Sucrose 
2.42 mg 
Sodium Citrate 
0.40 mg 
Tris (Trometomol) 
0.098 mg 
Al3+adjuvant  
125 g /dose 
0.9% Sodium Chloride 
q. s.  
Tetanus Toxoid 
7.8 to 33.4 µg. 
CRM 
11.7 to 50.1 µg 
* - Each conjugated to Tetanus Toxoid (TT);  
# - Each conjugated to CRM, 
q.s. - Quantum satis 
 
Composition of reconstituted final solution of one single 0.5 mL  
dose of non-adjuvanted MCV-5 vaccine 
Vaccine component 
Per 0.5 mL dose 
Meningococcal A polysaccharide* 
5 g 
Meningococcal C polysaccharide# 
5 g 
Meningococcal Y polysaccharide# 
5 g 
Meningococcal W polysaccharide# 
5 g 
Meningococcal X polysaccharide* 
5 g 
Sucrose 
2.42 mg 
Sodium Citrate 
0.40 mg 
Tris (Trometomol) 
0.098 mg 
0.9% Sodium Chloride 
q. s.  
Tetanus Toxoid 
7.8 to 33.4 µg 
CRM 
11.7 to 50.1 µg 
* - Each conjugated to Tetanus Toxoid (TT); 
#- Each conjugated to CRM, 
 q.s. - Quantum satis 
 

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Menactra®: 
Menactra® is a sterile, clear to slightly turbid liquid and each 0.5 mL dose is formulated in sodium 
phosphate buffered isotonic sodium chloride solution to contain four mcg each of 
meningococcal A, C, Y, and W polysaccharides conjugated to approximately 48 mcg of 
diphtheria toxoid protein carrier and residual amounts of formaldehyde of less than 2.66 mcg 
(0.000532%), by calculation.  
STUDY PROCEDURES & VISIT SCHEDULE 
After volunteers have signed the written informed consent, they will be screened for eligibility 
into the study. Screening will take place within 28 days prior to vaccination (Visit 1; Screening). 
A blood sample (up to 18 mL) will be taken at the screening visit for laboratory testing. 
The following assessments will be conducted during the screening visit: medical history, 
physical examination, vital signs measurement and laboratory evaluation including hematology, 
serum chemistry and viral serology for Human immunodeficiency virus (HIV), Hepatitis B virus 
(HBV), and Hepatitis C virus (HCV). A test for pregnancy will be performed among females of 
child bearing potential. Inclusion/exclusion criteria will be assessed for eligibility. 
At Visit 2 (Vaccination), eligible volunteers will be randomized in a 1:1:1 ratio to either one of 
the following groups: 
Group 
Vaccine 
1 (n=20) 
Adjuvanted Study vaccine (MCV-5) 
2 (n=20) 
Non-adjuvanted Study vaccine (MCV-5) 
3 (n=20) 
Reference vaccine (Menactra®, ACYW) 
 
Baseline blood sample (20 mL) for immunogenicity testing will be collected before 
randomization on the day of vaccination and thereafter vaccine will be given as a single 
intramuscular injection of 0.5 mL in the deltoid. The day of vaccination will be considered as 
Day 1. After vaccination, participants will be observed for 60 minutes at the clinic to detect any 
immediate reactions or any other AE. All relevant information will be reported in the Case Report 
Form (CRF). A Memory Aid will be distributed and participants will be instructed to record post-
immunization reactions, adverse events and concomitant medications. Participants will be 
informed to return to study centre for Visit 3 (Day 8).  
At Visit 3 (Day 8), participants will undergo a targeted physical examination, vital sign 
measurement and a blood sample will be collected (up to 8 mL) to repeat the safety laboratory 
evaluations. Memory Aid records will be discussed with the participants, if needed, reconciled 
by the investigator/designee before recording in source document and transcribed into the CRF.  
At Visit 4 (Day 29), the participants will undergo a targeted physical examination, vital sign 
measurement and review of interim health history, medication use and any report of adverse 
event through personal interview. A blood sample (30 mL) will be collected for immunogenicity 
evaluations. All the relevant information will be recorded into the CRF. The participant will be 
informed of the Visit 5 schedule.  
At Visit 5 (85 days after vaccination), the participants will undergo targeted physical examination 
and review of interim medical history including medication use. All serious adverse events will 
be recorded into the CRF by the investigator/designee. 
At Final study contact (180 ± 21 days after vaccination), the participant will be contacted by 
telephone to assess any serious adverse events that may have occurred. 

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STUDY DURATION 
Participants will be followed for approximately six months after vaccination. 
STUDY POPULATION 
60 healthy male and female adult participants aged 18 to 45 years of age.  
SAFETY ASSESSMENTS 
Safety will be assessed during the study via the following parameters: 
- 
Solicited local and systemic reactions for 7 days post-vaccination. 
- 
Adverse events will be recorded for 28 days post vaccination. 
- 
SAEs will be recorded for the study period of 180 days. 
SAFETY MONITORING: 
A Safety Review Committee (SRC) comprised of the Principal Investigator (PI), a medical 
expert with experience in vaccine pharmacovigilance not involved with the study, the Emmes 
medical monitor, Sponsor medical officer and SIIPL medical expert will be established to 
monitor participant safety throughout the duration of the study. The Emmes study statistician, 
with assistance of the data management staff, will prepare safety reports as needed for SRC 
discussions.  
 
During the vaccination period, the SRC will review weekly the safety data. At any time during 
the study, the Emmes Coordinating Center will notify the SRC of ad hoc review if pause criteria 
may have been met.  
 
The SRC reviews will be summarized with consensus recommendations to the study Sponsor 
as to whether there are safety concerns and whether the study should continue without change, 
be modified, paused or stopped. The SRC may request review of unblinded safety data by the 
vaccine pharmacovigilance expert in its deliberation. SRC consensus recommendations 
regarding modifying or stopping further enrolment may involve Sponsor consultation with the 
local regulatory authorities. 
 
If at any time, a decision is made to discontinue administration of study product to all volunteers, 
expeditious notification will be provided by the sponsor to the US Food and Drug Administration 
(FDA), and by the PI to the University of Maryland, Baltimore (UMB) Institutional Review Board 
(IRB). 
The following study pause rules will automatically pause or halt further vaccinations. However, 
volunteers already enrolled will continued to be followed for safety during the pause. These 
pause rules refer to suspected adverse reactions and will be triggered automatically if any of 
the event described below are met during the conduct of the study: 
• One or more participants experience a serious adverse reaction. 
• One or more participants experience a grade four injection site reaction. 
• Two or more participants experience the same grade three injection site reaction.  
• Two or more participants with the same severe (grade three) systemic reactogenicity 
signs or symptoms, within seven days following injection. 
• Two or more participants experience the same vaccine-related grade three or higher 
clinical (including fever) or laboratory abnormality.  

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STATISTICAL CONSIDERATION: 
 
Since this study is a Phase 1 trial, the sample size is designed to provide preliminary safety 
and immunogenicity data that may support testing the study product in larger adult cohorts or 
in age-descending studies. 
 
With 20 vaccine recipients per group, this study’s design allows a greater than 90% chance of 
observing an AE that has an 11% chance of occurrence. Conversely, if no AEs are observed 
in 20 vaccine recipients, the study will be able to rule out AEs occurring at a rate of 
approximately 14% based on the upper bounds of the one-sided 95% Confidence Interval (CI).  
 
 

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1. BACKGROUND AND INTRODUCTION 
1.1. 
Pathogen 
Among several different bacteria that can cause meningitis, Neisseria meningitidis (a gram-
negative aerobic capsular bacterium, also referred as meningococcus), is known to cause large 
epidemics. Neisseria meningitidis otherwise a harmless commensal of human nasopharynx, 
under appropriate conditions is responsible for invasive meningococcal disease (IMD)–a 
spectrum of diseases that includes most commonly meningitis and fulminant septicaemia. 
Pneumonia, myocarditis, or pericarditis may also occur in IMD, albeit less commonly.1, 2 
Once acquired, meningoccocci colonize the nasopharynx and patient may develop between the 
spectrum of an asymptomatic carrier state to a full blown IMD.1 
Meningocci are classified into serogroups based on their capsular polysaccharides. Six of these 
serougroups viz. A, B, C, W, X, and Y are known to cause majority of IMD cases.2 
These serogroups have the potential to cause large epidemics but this potential varies in each 
serogroup with respect to time and geographic location.3 Serogroup A for example has been the 
most important cause of meningitis in sub-Saharan Africa and its outbreaks are commonest 
during December to June. On the other hand majority of IMD cases in Europe and USA are 
caused most commonly by serogroup B, followed by C and Y (Figure 1). Most recently cases of 
serogroup X are on the rise especially in Africa.2, 4 
 
Figure 1: Global serogroup distribution of invasive meningococcal disease.2 
1.2. 
Burden of Disease 
Apart from serogroup variability, IMD also shows variation with respect to age groups with peak 
incidence occuring among children less than 2 years of age and adolescents between 16 and 
21 years. During epidemics, disease rates show a shift towards older age groups.2 

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Meningococcal disease commonly alternates between an endemic situation of few isolated cases 
and fatal unpredictable epidemics in the African meningitis belt (a large area that spans 
sub-Saharan Africa from Senegal in the west to Ethiopia in the east).5 This region has the highest 
annual incidence of IMD and is plagued with problem of recuring epidemics of large proportions. 
The incidence has been known to reach rates of up to 1000 cases per 100,000 people or 1% of 
the entire population.3 This was seen during the large epidemics of 1996 and 2000 through 2001. 
In 1996 and 1997 there were > 250,000 cases, an estimated 25,000 deaths, and disability in 
50,000 people. It is believed to be the largest epidemic in history. Similarly in the 2006 to 2007 
epidemic season, there were 53,438 suspected cases and 3,816 deaths were reported to WHO 
from 15 African countries.4 
Outside of the African meningitis belt, the incidence of IMD is significantly low, although there 
have been reports of outbreaks. In such areas any substantial increase in IMD cases above that 
which is expected at that place and time is considered as outbreak.3, 4 
Respiratory droplets are the main source of meningococcal transmission and occurs most 
commonly due to close contacts with asymptomatic carrier.6 Symptoms of IMD mainly include 
fever, loss of appetite, lethargy, vomiting, diarrhoea, photophobia and convulsions, and usually 
manifest 1 to 14 days after acquiring the pathogen.1 
Meningococcal meningitis and fulminant septicemia—the two most serious presentations of 
IMD—may prove fatal in 50% of cases if untreated within 24 to 48 hours. Even when adequately 
treated, the mortality is close to 10%. Among the survivors of meningitis, it may cause in 10 to 
20% of cases, severe permanent brain damage and sequelae such as mental retardation, 
deafness, epilepsy, or other neurological disorders.2, 4 
1.3. 
Meningococcal Vaccines 
The increasing resitance to antibiotics and associated escalation in healthcares costs makes 
vaccination as the best strategy to tackle invasive meningococcal disease.2, 7 
1.3.1. 
Polysaccharide Vaccines 
As depicted in Figure 2, the earliest vaccines against meningococci were discovered in the 1970s. 
The first ever meningococcal vaccine was developed against serogroup C as a response to 
recurring epidemics among military recruits in the USA. Eventually, further research led to 
availibility of vaccines against serogroups A, W, and Y. These were purified bacterial 
polysaccharide vaccines or “plain” polysaccharide vaccines that lacked conjugation.8, 9 
Polysaccharide vaccines have an excellent safety profile and they have more than served their 
purpose of controlling outbreaks in military and other similar confined set ups. Later these 
vaccines were also used in endemic regions for prophylaxis.2 Subsequently it was noted that the 
polysaccharide vaccines also showed good efficacy (> 85%) in older children and adults, 
however, they produced variable response among younger children (below 24 months of age) 
and often failed to provide protection in this population.2, 8 
 

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Figure 2: Timeline of meningococcal vaccine development.8 OMV, outer membrane vesicle.  
* Two serogroup B vaccines were approved in USA in late 2014 and early 2015. 
Further, polysaccharide vaccines do not provide long term protection or immune memory. Instead 
they may induce immune hyporesponsiveness, particularly for serogroup C, on repeated 
administration. This is because of lack of T-cell induction by these vaccines, as a result of which 
the protection lasts for no more than three to five years post-vaccination.7, 8 These vaccines also 
lack the ability to prevent organism transmission as they have no effect on pharyngeal carriage 
and do not confer herd immunity.10-12 
Today, polysaccharide vaccines are licensed as bivalent (serogroups A and C), trivalent 
(serogroups A, C, and W-135), or quadravalent (serogroups A, C, Y, and W-135), although their 
availibility is very limited in most countries.2 The drawbacks listed above made polysaccharide 
meningococcal vaccines unsuitable for use in population-scale interventions outside of epidemics 
and for infant immunization.9 They are recommended in developed world for use in outbreaks 
related to specific strains, and as prophylaxis in susceptible travellers above 55 years of age as 
well as for military recruits.13 
1.3.2. 
Conjugate Vaccines 
The problems associated with the use of polysaccharide vaccines were overcome by the process 
of conjugation, wherein the capsular polysaccharide is conjugated to a highly immunogenic T-cell 
stimulating antigens such as CRM, diphtheria or tetanus toxoids. Vaccine against serogroup C 
was the first conjugated vaccine against meningococcal disease, that was developed in the 1990s 
in the United Kingdom.9 
With their widespread use thereafter, conjugated meningococcal vaccines (CMV) proved superior 
to polysaccharide vaccines in eliciting T-cell responses and, thus, protected children less than 

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two years of age and induced immunologic memory. The advantage of immunologic memory is a 
booster response to subsequent doses of conjugate vaccines, a phenomena seen in all age 
groups. These vaccines also induce higher levels of protective titers and confer long-lasting 
protection. CMVs were also shown to overcome the problem of nasopharyngeal colonization and 
provide herd immunity. Furthermore, CMVs have not shown any hyporesponsiveness after 
repeated doses.10, 11 
Currently, monovalent (A or C), and tetravalent (A, C, W-135 and Y) conjugate meningococcal 
vaccines are available to protect against IMD.  
1.3.3. 
Monovalent Conjugated Vaccine against Meningococcal Serogroup C 
(MenCCV) 
The monovalent vaccine against C serogrouop contains polysaccharide conjugated to the carrier 
diphtheria toxoid, CRM, or tetanus toxoid without preservatives. It is licensed for children aged > 
two months, adolescents and adults. Infants aged two to eleven months are given two doses (0.5 
mL per dose) with at least two months between the doses, followed by a booster dose about one 
year later.4 
The introduction of MenCCV in the routine infant immunization and a school-based “catch-up” in 
individuals up to 18 years of age in the United Kingdom (UK) resulted in reduction of 86.7% in the 
incidence of serogroup C within two years from 1999 to 2001. Number of associated deaths also 
fell from 67 in 1999 to 5 in 2001, thanks to MenCCV.14 This prompted many other countries to 
introduce MenCCV in their immunization schedule with similar succes in controlling the sergroup 
C disease incidence.9 
1.3.4. 
Monovalent Conjugated Vaccine against Meningococcal Serogroup A 
(MenAfriVac®) 
The majority of the meningococcal epidemics in the African meningitis belt over the years have 
been caused by serogroup A with incidence rates as high as 500 cases per 100,000 population. 
In an effort to overcome this problem in a cost-effective way, the Meningitis Vaccine Project 
(MVP), a partnership between the WHO and PATH, was established with funding from the Bill 
and Melinda Gates Foundation.15 The resultant product was a monovalent vaccine against A 
serotype called MenAfriVac® manufactured by Serum Institute of India Private Limited, and 
developed specifically to tackle the MenA epidemics in African Meningtis belt.10 
MenAfriVac® is a lyophilized vaccine containing purified meningococcal A polysaccharide 
conjugated to tetanus toxoid.2 The vaccine underwent an elaborate clinical development process 
that included a Phase 1 study in India, followed by seven Phase 2 and 3 studies conducted in 
India and the African meningitis belt.16, 17 
The Phase 1 clinical study was conducted among 74 Indian adults (24 received MenAfriVac®, 25 
a meningecoccal polysaccharide A and C vaccine, and 25 a tetanus toxoid vaccine) which 
involved a total of 48 weeks follow up for safety evaluation and four blood draws for testing 
immunogenicity (pre-immunization, and at 4 weeks, 24 weeks and 48 weeks post immunization). 
In the three vaccine groups, solicited reactions were mild and transient and resolved without 
sequelae with commonest being pain, redness, and swelling. All other adverse events resolved 

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without sequelae and were unrelated to the vaccines. Four weeks after vaccination 83% of 
subjects in MenAfriVac® group had a ≥ 4-fold increase in rSBA titers, 72% in the A/C group, and 
12% in the tetanus toxoid only vaccine group. rSBA GMTs and group A specific IgG Enzyme 
linked immunosorbent assay (ELISA) geometric mean concentrations (GMCs) were also higher 
in MenAfriVac® groups as compared to A/C vaccine group (8,192 vs. 5,257 & 110 vs. 44 
respectivley). Furthermore all subjects in the MenAfriVac® group who had initial four-fold increase 
in rSBA titers four weeks after vaccination remained four-fold responders one year later thus 
showing persistence in antibody response. In summary the vaccine was found to be safe and 
immunogenic.18 
One of the Phase 2 clinical trials conducted among 12 to 23 month olds in Africa enrolled 601 
subjects to receive either MenAfriVac® (n = 201), polysaccharide ACWY (Mencevax®) vaccine (n 
= 200) or Haemophilus inlluenza type b tetanus toxoid conjugated (Hib-TT) control vaccine (n = 
200). There was no immediate safety issue at week four post-primary immunization, with all the 
local reactions reported being transient and resolved without sequelae. More indurations were 
reported in the MenAfriVac® group vs. the Mencevax® group (p = 0.01). Rates of other adverse 
events were similar between vaccine groups and they were unrelated to the study vaccines. Four 
weeks after vaccination 96% of subjects in the MenAfriVac® group had a ≥ 4-fold increase in Men 
A rSBA titer, 64% in the Mencevax® group and 36% in the Hib-TT vaccine group, whereas GMTs 
(rSBA) were 16 times greater after MenAfriVac® when compared with Mencevax® vaccine 
recipients. All but one subject in the MenAfriVac® group had a ≥ 4-fold increase in ELISA IgG 
concentrations, as compared to 78% in the Mencevax® group, and 4% in the Hib-TT group. 
Overall, the study MenAfriVac® showed antibody responses that are not inferior to those achieved 
by the Mencevax® vaccine.  
Some of the subjects in this Phase 2 study were further followed up for 40 weeks, and 82% 
subjects in the MenAfriVac group still showed a ≥ 4-fold increase in rSBA titer vs. 38% in each of 
the other two groups. rSBA GMTs and ELISA GMCs were also higher in the MenAfriVac® group 
than the other two groups. MenAfriVac® group also had higher number of subjects with Men A 
rSBA titers ≥ 1:128 and 4-fold increase in ELISA specific IgG concentrations at 40 weeks. It was 
also found that the MenAfriVac® induced immunological memory since the subjects receiving 
booster at 40 weeks with either MenAfriVac® or polysaccharide vaccine showed highr GMTs 
(rSBA) if they were previously immunized with MenAfriVac®.  
MenAfriVac® vaccine was thus found to be safe and it showed the characteristics of a conjugate 
vaccine with superior immunogenicity, effective inducement of immunological memory and 
inducement of bactericidal antibodies persisting at sustained levels after a single vaccine dose.15 
Another Phase 2/3, among 900 healthy children and adults was conducted in Mali, The Gambia 
and Senegal to compare safety and immunogenicity of MenAfriVac® (n = 604) with that of 
Mencevax® vaccine (n = 296). Age of subjects at mmunization was 2 to 10 years (n = 302), 11 to 
17 years (n = 301) and 18 to 29 years (n = 297). Safety evaluation at four weeks did not show 
any SAEs or deaths. Local and systemic reactions, AEs and SAEs were similar between vaccine 
groups overall as well as within each age group. Majority of the reactions were of mild or moderate 
intensity, transient and resolved without sequelae. During an additional one-year follow up, a total 
of five SAEs were reported and they were unrelated to study vaccines. A ≥ 4-fold increase in rSBA 
titer at four weeks post-immunization was seen in 78% in MenAfriVac® group vs. 46% in the 

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Mencevax® group. This remained consistent within each of the three age sub-groups. Even over 
a one year follow up MenAfriVac® group had a significantly higher sustained MenA antibody 
persistence. 15 
Another trial comparing the immunogenicity and safety of a single dose MenAfriVac® against the 
meningococcal group A component of polysaccharide vaccine (Mencevax®) at 28 days was 
conducted among 340 Indian children (169 in MenAfriVac® group) aged 2 to 10 years. Results 
showed 95.2% of children in MenAfriVac® group had a ≥4-fold response in rSBA as compared to 
78.2% in the Mencevax® group. Almost all children in both vaccine groups had a ≥4-fold response 
in group A-specific IgG concentration but the IgG GMC was significantly greater in the 
MenAfriVac® group. Local and systemic reactions during the four days after immunization were 
similar for both vaccine groups except for tenderness (30.2% in MenAfriVac® group vs. 12.3% in 
Mencevax® group). None of the adverse events or serious adverse events were related to the 
study vaccines.19 
The vaccine was subsequently licensed in 2009 and was prequlaified by WHO in 2010. Since 
then it has been widely used in over 217 million individuals of 1 to 29 years of age and has been 
found to be highly effective and safe.3, 20-23 
Use of MenAfriVac® has been highly effective at preventing IMD of serogroup A, reducing it by 
nearly 100%, eliminating outbreaks as well as decreasing carrier states.20, 24 It also reduced the 
incidence in those too young or too old to have been vaccinated, demonstrating an additional 
indirect herd effect. In the data generated for two years since its use started in three African 
countries viz. Burkina Faso, Mali and Niger, there have been no cases of MenA disease reported 
in vaccinated population.10 
1.3.5. 
Tetravalent Conjugate Meningococcal Vaccines (TCMV) 
Today, three different brands of TCMV are available viz. Menactra® (Sanofi), Menveo® (Novartis) 
and Nimenrix® (Glaxo SmithKline Beecham) with each brand having serogroups A, C, W, an Y 
but conjugated to different proteins.2, 25-27 
Menactra®, first ever TCMV uses diphtheria toxoid as conjugate, whereas Menveo® and Nimnerix® 
use CRM and Tetanus Toxoid respectively for conjugation of polysaccharides. Menactra®, 
Menveo® and Nimenrix® are licensed for use in individuals upto 55 years of age. The lower limit 
of age for Menactra® is 9 months, Menveo® is 2 months and Nimenrix® is 12 months.25-27 
For individuals aged 11 years and above, a single dose of either Menactra® or Menveo® should 
be administered at age 11 or 12 years, with a booster dose at age 16 years of age. Booster dose 
of Nimenrix® is not recommended. Those aged 2 to 23 months are given Menveo® as four-dose 
series till six months of age or a two-dose series if above that age. Whereas Menactra® should 
be used as a two dose series starting at nine months with a minimun three months before the 
second dose.25-27 
Use of TCMV has been associated with excellent safety and immunogenicity profile, with 
reduction in incidence of meningococcal diseases in regions where they have been introduced 
for routine immunization.4 

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1.3.6. 
Overall Impact of Meningococcal Vaccines 
The widespread use of conjugate meningococcal vaccines especially in higly endemic settings 
and at population level has reduced the burden of IMD drastically since pre-vaccination era. 
Inspite of this, the use of conjugate vaccine is still a big hurdle in developing world due to its high 
cost. Unlike Men A vaccine which was specifically developed for the Meningitis belt in Sub-
Saharan Africa and hence was very cost effective, the tetravalent vaccine still remains elusive for 
that kind of application in this region.9, 28 
1.3.7. 
Vaccine against B Serogroup 
Serogroup B meningococcus has a poorly immunogenic capsule and contains epitopes that 
potentially cross-react with human antigen, which has hindered progress on developing a 
polysaccharide vaccine effective against it.4, 29 
Recently, though, the FDA of USA has licensed two serogroup B meningococcal vaccine viz. 
Trumenba® and Bexsero® for use in people 10 to 25 years of age as a three-dose series and two-
dose series respectively.30-32 
1.3.8. 
Vaccine against X Serogroup 
There is no vaccine available which gives protection against serogroup X which has caused many 
outbreaks in Africa and Europe in recent past.33 The WHO has expressed concerns over the lack 
of such a vaccine and has encouraged more research into it.4 
1.4. 
Study Vaccine 
Currently, there is no vaccine available against serogroup X of N. meningitidis. This bacterium 
has caused many outbreaks in Africa and Europe in recent past. The serogroup X has been 
responsible for outbreaks between 2006 and 2010 in Kenya, Niger, Togo, Uganda, and Burkina 
Faso, the latter with at least 1,300 cases of serogroup X meningitis among the 6,732 reported 
annual cases.33 
As a result, SIIPL has developed the candidate vaccine MCV-5, which is a polyvalent conjugate 
vaccine composed of serogroups A, C, Y, W, and X of Neisseria meningitidis capsular 
polysaccharides, conjugated to protein carriers, CRM and tetanus toxoid, with aluminum 
phosphate as an adjuvant. It is intended for the prevention of meningitis and/or septicemia caused 
by serogroups A, C, Y, W, and X N. meningitidis in countries where the disease is endemic and 
causes large epidemics such as the countries in the African meningitis belt. The target population 
consists of infants and children and adults aged 1 to 55 years. 

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1.5. 
Summary of Nonclinical Studies 
Table 1: 
Preclinical Studies 
Study Title 
Study Site 
Study Type & 
Compliance 
Animal 
Model 
Sections 
in the 
protocol 
A 5-week subcutaneous dose-ranging 
immunogenicity study of monovalent 
meningococcal serotype X 
polysaccharide conjugate (MenX-TT) 
with and without aluminum phosphate 
adjuvant in mice 
SIIPL 
Immunogenicity 
Non-GLP 
Swiss albino 
mice 
1.5.3.1 
A 7-week subcutaneous 
immunogenicity study of the MenX-TT 
component in the MCV-5 presentation 
with and without aluminum phosphate 
adjuvant in mice. 
National Institute for 
Biological Standards 
and Control, London 
(NIBSC), 
United Kingdom 
Immunogenicity 
Non-GLP 
BALB/c mice 
1.5.3.2 
A 5-week intramuscular 
immunogenicity study of candidate 
SIIPL MCV-5 vaccine formulations in 
comparison to commercial vaccine in 
rabbits 
SIIPL 
Immunogenicity 
Non-GLP 
New Zealand 
white rabbits 
1.5.3.3 
A 5-week intramuscular dose-ranging 
immunogenicity study of pentavalent 
SIIPL MCV-5 vaccine (tox formulation) 
with and without aluminum phosphate 
adjuvant in rabbits 
SIIPL 
Immunogenicity 
Non-GLP 
New Zealand 
white rabbits  
1.5.3.4 
A 7-week intramuscular toxicity study 
of [pentavalent] meningococcal 
(A,C,Y,W,X) polysaccharide conjugate 
vaccine (freeze-dried) in New Zealand 
white rabbits with a 6-week recovery 
MPI Research, Inc., 
54943 North Main Street 
Mattawan, MI 
49071-8353, U.S.A.  
Toxicity & 
immunogenicity 
study. 
GLP  
New Zealand 
white rabbits  
1.5.2.1 & 
1.5.3.5 
Series of toxicology studies of 4-
Pyrrolidinopyridine (4-PP, a byproduct 
of CPPT conjugation chemistry)  
MPI Research, Inc., 
54943 North Main Street 
Mattawan, MI  
49071-8353, U.S.A.  
and 
BioReliance,  
Rockville, MD, U.S.A. 
Byproduct 
toxicology. 
Mutagenicity 
GLP  
Rats,  
guinea pigs, 
prokaryotic & 
eukaryotic 
cells 
1.5.2.2 
 
 
1.5.1. 
Non-Good Laboratory Practice (GLP) Nonclinical Pharmacology/Proof of 
Concept Studies 
Not Applicable 

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1.5.2. 
Toxicology Studies 
Pre-clinical GLP toxicology study 
A repeated dose GLP toxicology study was conducted in 60 rabbits at a GLP certified testing 
facility, MPI Research, Inc, 54943 North Main Street, Mattawan, MI, 49071-8353, USA. The study 
comprised of three groups of animals receiving 4 doses of either MCV-5 vaccine (5 µg of each 
serogroup antigen) with aluminum phosphate adjuvant, MCV-5 vaccine without adjuvant, or saline 
control administered 2 weeks apart. All animals survived to the scheduled necropsy. There were 
no test article-related effects noted for clinical observations, ophthalmoscopic findings, body 
weights, body weight gains, food consumption, or body temperatures. No test article-related 
alterations were observed in hematology, coagulation, or urinalysis parameters. There were no 
clear and consistent organ weight changes seen in terminal or recovery animals. Mild injection 
site reactions included very slight edema and very slight erythema. These were consistent with 
injection of a vaccine and comparable to control animals injected with normal saline. Test article-
related microscopic findings were seen at the injection sites for all terminal and recovery groups. 
The injection site findings were not considered to be adverse, given the low severity, lack of 
systemic findings, limited serum chemistry findings, and lack of associated clinical findings. At 
recovery, at all injection sites, there was a strong trend towards recovery in all groups, with 
generally reduced incidence and severity of most findings compared to terminal groups. At 
recovery, at all injection sites, there was a strong trend towards recovery in all groups, with 
generally reduced incidence and severity of most findings compared to terminal groups. 
Toxicology study of 4-PP (a byproduct of CPPT conjugation chemistry [in progress]) 
A set of toxicology studies, of 4-PP, a residual in 1-cyano-4 pyrrolidinopyridinium tetrafluoroborate 
(CPPT) conjugation, was also conducted at MPI Research, Inc and BioReliance under 
subcontract to MPI. These included: 
a) Oral single dose in rats 
b) IM single dose in rats  
c) In vitro mutagenicity, prokaryotic cells 
d) In vitro mutagenicity, eukaryotic cells (mouse lymphoma) 
e) Skin sensitization study in guinea pigs 
The studies on 4-PP suggest that this by-product is not mutagenic or clastogenic in standard 
genotoxicity assays, is well tolerated after a single intramuscular injection in rats and does not 
cause dermal sensitization in guinea pigs.  
Test article related clinical observations at oral doses of 10 and 50 mg/kg included piloerection, 
audible breathing, and vocalization whereas decreased activity, ataxia, tremors, and low carriage 
at dose of 50 mg/kg. Animals in 200 mg/kg oral dose were either euthanized in extremis or found 
dead on Day 1. 
The No-Observed-Adverse-Effect-Level (NOAEL) of 4-PP is considered to be 10 mg/kg following 
oral administration and 0.2 mg/site following intramuscular administration. In comparison, the 
content of 4-PP in MCV-5 vaccine is estimated to be less than 500 nanogram per dose of vaccine. 
This value is considerably lower than the NOAEL.  
Additional details of these toxicology studies are available in the investigator’s brochure (IB). 

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1.5.3. 
Immunogenicity Studies  
Immunogenicity study of monovalent MenX tetanus toxoid conjugate vaccine (MenX-TT) 
in mice 
This study was conducted in Swiss albino mice at SIIPL, India. The study results presented in 
Table 2 show that immunization with MenX-TT PS conjugate elicits antibody responses to 
MenX PS, as measured by both IgG immunoassay and rSBA. IgG responses were low and rSBA 
antibody responses were undetectable for the group of mice immunized with adjuvanted native 
MenX PS (Group 1, Table 2). Immunization with either 0.5 µg or 1.0 µg of MenX-TT conjugate 
was highly immunogenic and generated strong bactericidal activity after three doses (Days 0, 14, 
28), suggestive of a T-cell dependent immune response. The addition of aluminum phosphate 
adjuvant further improved IgG and rSBA titers, particularly at the 0.5 dose level (Groups 3 and 4, 
Table 2). These data suggest that that the MenX-TT conjugate is immunogenic and could be 
included in a polyvalent meningococcal conjugate vaccine.  
Table 2: Day 35 Serum IgG Titers to MenX after Three Immunizations with MenX-TT 
Group 
Treatment 
Amount per 
dose (µg) 
IgG titer 
(GMT) 
rSBA titer 
(GMT) 
1 
Saline 
- 
50 
<4 
2 
Native MenX PS + aluminum phosphate 
0.5 + 125 
1,600 
4 
3 
MenX-TT conjugate 
0.5 
6,400 
42 
4 
MenX-TT conjugate + aluminum phosphate 
0.5 + 125 
40,637 
128 
5 
MenX-TT conjugate 
1.0 
51,200 
341 
6 
MenX-TT conjugate + aluminum phosphate 
1.0 + 125 
51,200 
512 
 
Immunogenicity of the MenX-TT Component of MCV-5 Vaccine in BALB/c Mice 
This study was conducted in BALB/c mice at National Institute for Biological Standards and 
Control (NIBSC), UK, to confirm and further evaluate the immunogenicity of the MenX-TT PS 
conjugate antigen, with and without aluminum phosphate adjuvant, when combined with the other 
four meningococcal PS conjugates (MenA-TT, MenC-CRM, MenY-CRM and MenW-CRM) 
intended to be included in the pentavalent SIIPL MCV-5. Groups of 20 young adult female BALB/c 
mice were immunized subcutaneously with either MCV-5 with aluminum phosphate or MCV-5 
without adjuvant or licensed quadrivalent Menveo® PS conjugate vaccine as a control. 
Vaccination was on days 0, 14, 28 with each mouse receiving 1/10th of a human dose of the test 
vaccines at each time point 
As expected, the antibody titers to MenX for the animals that were immunized with Menveo®, 
which does not contain a MenX PS conjugate component, were low at all bleed time points (Study 
Days 14, 28, and 42) and reached a maximum relative log GMT of 1.45 units/mL at study day 42 
(2 weeks post-3rd dose) as presented in Table 3. An increase in MenX-specific antibody titers 
was observed in animals immunized with MCV-5 and without aluminum phosphate following the 
second dose, and additional increases were observed after the third dose. Additionally, the MenX-
specific antibody responses to MCV-5 with aluminum phosphate adjuvant were higher than those 
to MCV-5 without adjuvant, and this difference was most pronounced at study day 42 (post 

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dose 3). Taken as a whole, these results clearly demonstrate that the MenX-TT antigen is robustly 
immunogenic when combined with the other four polysaccharide conjugate antigens (MenACYW) 
in MCV-5 and that addition of aluminum phosphate adjuvant improves its immunogenicity.  
Table 3: Geometric Mean Serum IgG Titers to MenX 
Group 
Vaccine Treatment 
Day 14 
Day 28 
Day 42 
GMT 
(95% CI) 
GMT 
(95% CI) 
GMT 
(95% CI) 
1 
MCV-5 
(Adjuvanted) 
0.29 
(0.11 – 0.82) 
43.89 
(19.31-99.75) 
140.23 
(96.49-203.81) 
2 
MCV-5 
(Unadjuvanted) 
0.33 
(0.17-0.65) 
34.05 
(17.19-67.45) 
63.39 
(47.60-84.42) 
3 
Menveo® 
0.02 
(0.02-0.04) 
0.74 
(0.29-1.89) 
1.45 
(1.11-1.89) 
 
Immunogenicity of Candidate SIIPL MCV-5 Formulations in New Zealand White Rabbits 
The immunogenicity of three different candidate formulations of adjuvanted SIIPL MCV-5 were 
evaluated in New Zealand white rabbits in a study conducted at SIIPL. The adjuvanted F3 
formulation selected for clinical development had the best immunogenicity profile compared to 
the other two adjuvanted formulations (F2 and F4). Additionally, the adjuvanted F3 formulation 
elicited comparable or better immune responses to serotypes MenA, C, Y and W than did 
Menveo® (Tables 4 and 5). Additional details of this study are available in the IB. 
Table 4: Geometric mean IgG titers to MenA,C,Y,W and X 
Vaccine Treatment 
Study 
Day 
rSBA antibody responses 
(GMTs) 
MenA 
MenC 
MenY 
MenW 
MenX 
Menveo® 
0 
50 
50 
50 
50 
n.d. a 
35 
44,572 
25,600 
38,802 
29,047 
n.d. a 
SIIPL MCV-5 F2 with 
aluminum phosphate 
adjuvant 
0 
50 
50 
50 
50 
50 
35 
72,408 
51,200 
72,408 
60,887 
60,887 
SIIPL MCV-5 F3 with 
aluminum phosphate 
adjuvant 
0 
50 
100 
50 
50 
200 
35 
58,813 
58,813 
117,627 
89,144 
51,200 
SIIPL MCV-5 F4 with 
aluminum phosphate 
adjuvant 
0 
50 
100 
50 
50 
50 
35 
33,779 
9,701 
29,407 
25,600 
51,200 
a No data (n.d.) because Menveo® does not contain a MenX component.  

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Table 5: Geometric mean bactericidal antibody titers to MenA,C,Y,W and X 
Vaccine Treatment 
Study 
Day 
rSBA antibody responses 
(GMTs) 
MenA 
MenC 
MenY 
MenW 
MenX 
 Menveo® 
0 
2 
2 
4 
2 
n.d.a 
35 
446 
223 
256 
223 
n.d.a 
SIIPL MCV-5 F2 with aluminum 
phosphate adjuvant 
0 
2 
2 
2 
2 
16 
35 
724 
215 
152 
256 
1,024 
SIIPL MCV-5 F3 with aluminum 
phosphate adjuvant 
0 
2 
2 
2 
2 
8 
35 
676 
512 
388 
588 
1,024 
SIIPL MCV-5 F4 with aluminum 
phosphate adjuvant 
0 
2 
2 
2 
2 
2 
35 
338 
64 
111 
147 
676 
a No data (n.d.) because Menveo® does not contain a MenX component. 
 
Immunogenicity of the SIIPL MCV-5 vaccine in New Zealand White Rabbits 
The immunogenicity of the first cGMP lot of the pentavalent SIIPL MCV-5 vaccine was also 
evaluated in New Zealand white rabbits at SIIPL. Groups of adult New Zealand white rabbits were 
dosed with either MCV-5 reconstituted with diluent with and without 125 µg aluminum phosphate 
adjuvant, the licensed quadrivalent vaccine Menactra® or the licensed quadrivalent vaccine 
Menveo®. The dose of MCV-5 was 5 µg per PS conjugate component in the vaccine. The dose 
of Menactra® was 4 µg per PS conjugate component in the vaccine. The dose of Menveo® was 
10 µg of MenA PS conjugate and 5 µg each for the MenC, Y and W PS conjugate components in 
the vaccine. Animals were immunized by intramuscular injection on Days 0, 14 and 28. 
In summary, the IgG and bactericidal (rSBA) antibody response results from this study clearly 
demonstrate that MCV-5 was strongly immunogenic for all 5 meningococcal serotypes (A, C, Y, 
W and X) represented in the vaccine and that addition of aluminum phosphate adjuvant improved 
its immunogenicity. Additionally, adjuvanted MCV-5 had comparable or better immunogenicity for 
the meningococcal serotypes A, C, Y, and W than the licensed vaccines Menveo® and Menactra®. 
Additional details of this study are available in the IB. 
MPI rabbit immunogenicity study of all five serogroups 
This GLP study evaluated the immunogenicity of adjuvanted and non-adjuvanted MCV-5 vaccine 
in adult New Zealand White rabbits following four bi-weekly intramuscular doses given for seven 
weeks in rabbits and after a six-week recovery period. Immunogenicity was measured by rSBA 
with regards to titers of IgG antibodies against all five serogroups in serum samples collected on 
Days 1 and 43. A third group of rabbits received saline as control. The sample size in each of the 
groups was 20 (10 males and 10 females). 
For all three groups, no IgG responses were seen from the Day 1 pre-immune sera against any 
of the meningococcal serogroups. The Day 43 saline control Group 1 had similar geometric mean 
IgG concentrations to those obtained in the Day 1 pre immune sera across all serogroups. The 
Day 43 group immunized with MCV-5 vaccine with or without adjuvant gave a response against 
all serogroups that was significantly greater than the saline control group.  

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Higher antibody concentrations were observed in sera when aluminum phosphate was used as 
an adjuvant, with increases ranging from 49% to 165%. Serogroups A, Y, and X all showed a 
statistically significant increase in antibody concentration compared to the group without adjuvant. 
However, for serogroups C and W, this observed difference between the two groups did not reach 
statistical significance. Additional details of this study are available in the IB. 
In summary, this study showed that the MCV-5 pentavalent vaccine formulation produced a strong 
immune response against all five serogroups. The addition of adjuvant resulted in an increase in 
immune response for all five serogroups with a statistically significant increase for three 
serogroups.  
1.6. 
Clinical Studies 
No human data is available as of now and the present first-in-human study on MCV-5 vaccine is 
being conducted with primary objective of assessing the vaccine’s safety in an adult population.  
There is no clinical data available on potential safety risks, although it is anticipated that the 
vaccine will have a safety profile similar to that of currently licensed vaccines against 
meningococci including Menactra® (reference vaccine in present study) and MenAfriVac®. 
Apart from local solicited reactions such as pain, erythema, induration and swelling, other 
common (≥10%) solicited systemic reactions in adults (18 to 55 years) who received Menactra® 
included headache, malaise, fatigue, arthralgia, diarrhea and anorexia.26 Solicited reactions were 
considered those occurring within seven days of vaccination. 
Clinical trial of MenAfriVac® conducted in 18 to 29 year olds showed post vaccination local and 
systemic reactions to be comparable to Menveo® with headache as the most commonly reported 
reactions (12%) followed by tenderness (6%). Other reactions such as fever, vomiting, fatigue, 
myalgia and arthralgia were infrequent (2.5% to less than 1%).34 
2. HYPOTHESIS, SCIENTIFIC RATIONALE, OBJECTIVES AND STUDY DESIGN 
2.1. 
Study Hypotheses 
The proposed Phase 1 study will test the following hypotheses: 
a. Primary hypothesis: Two formulations (adjuvanted and non-adjuvanted) of MCV-5 vaccine 
when given to healthy adults will be safe and well tolerated. 
b. Secondary hypothesis: Two formulations (adjuvanted and non-adjuvanted) of MCV-5 
vaccine when given to healthy adults will induce immune response to all the five 
serogroups of the vaccines. 
 
 

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2.2. 
Scientific Rationale 
Currently, three conjugate polyvalent vaccines are available to protect against meningococcal 
disease. All three are tetravalent (serogroups A, C, W and Y) vaccines; Menactra® (Sanofi Pasteur 
Inc.), Menveo® (Novartis) and Nimenrix® (Glaxo SmithKline Beecham). There is large experience 
with the use of these vaccines, which are generally well tolerated in all age groups. At this time, 
there is no licenced vaccine giving protection against serogroup X which has caused many 
outbreaks in Africa and Europe in recent past.  
Following the MenAfriVac® MenA monovalent conjugate vaccine development experience, SIIPL 
has developed a candidate polyvalent conjugate vaccine composed of serogroups A, C, Y, W and 
X Neisseria meningitidis capsular polysaccharides. This candidate MCV-5 is conjugated to protein 
carriers, CRM and tetanus toxoid, and formulated with or without aluminum phosphate as an 
adjuvant. It is intended for the prevention of meningitis and/or septicemia caused by serogroups 
A, C, Y, W, and X N. meningitidis in countries where the disease is endemic and causes large 
epidemics such as the countries in the African meningitis belt. The target population consists of 
infants, children and adults aged 1 to 55 years. 
This first Phase 1 clinical study is designed to evaluate primarily the safety of the study vaccine. 
The three-group design of the study will allow safety evaluation of the adjuvanted and non-
adjuvanted MCV-5 formulations. The Menactra® vaccine has been chosen as control vaccine for 
the large safety database accumulated since the vaccine has been introduced in the USA in 2005 
and progressively in other countries.9, 35 
In addition, secondary immunogenicty evaluation is planned on both adjuvanted and 
non-adjuvanted formulations. 
This Phase 1 study will be performed in adult healthy volunteers aged 18 to 45 years of age. 
2.3. 
Overall Clinical Development Strategy 
SIIPL has developed MCV-5 with an aim to license and make it available particularly in developing 
markets including Africa. Once the results of current study are available, both the adjuvanted and 
non-adjuvanted formulations will further be compared for immune response in a Phase 2 clinical 
trial among toddlers. Results of this Phase 2 study will help decide which one of the formulations 
to be carried into the next phases of clinical development.  
2.4. 
Study Design 
This is a Phase 1, single center, double-blind, randomized, controlled clinical trial to be performed 
in 18 to 45 year old healthy volunteers.  
The study will have three arms with three vaccines given in a 1:1:1 ratio: adjuvanted MCV-5, non-
adjuvanted MCV-5 and Menactra® given as a single intramuscular injection. All participants will 
be followed up for six months after the vaccination.  

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2.4.1. 
Discussion of Study Design  
The three-group design of the study will allow comparison of the adjuvanted and non-adjuvanted 
ACYWX safety profile with that of a licensed ACYW conjugate vaccine (reference vaccine group).  
The vaccinator will be aware of group allocation, although he/she will not be able to influence or 
decide this allocation nor be part of the safety assessment. This will ensure that the study team, 
involved in assessment of safety outcome as well as participants, are unaware of the identity of 
study vaccine administered to them. This will help rule out the bias at the time of assessment.  
As the reference product and study vaccines are different in appearance and composition, the 
vaccinator blind cannot be maintained in this study. However the vaccinator is not involved in 
safety assessment. 
In addition, immunogenicity assessments are planned to evaluate any difference in the immune 
responses induced by the adjuvanted and non-adjuvanted study vaccines and to compare against 
the reference vaccine. The study, however, is not statistically powered to determine significance 
of any difference. There is neither any formal sample size calculation as this is a Phase 1 trial. 
As this is the first clinical study with the study vaccine, the study will be initially performed in adult 
healthy volunteers. 
2.4.2. 
Primary Objective 
To evaluate the safety of adjuvanted and non-adjuvanted formulations of MCV-5 vaccine. 
2.4.3. 
Secondary Objective 
To assess the immune response of adjuvanted and non-adjuvanted formulations of MCV-5 
vaccine. 
2.4.4. 
Primary Endpoints 
 
The occurrence and severity of solicited local and systemic post immunization reactions 
within seven days following vaccination.  
 
The occurrence, severity, and relatedness of unsolicited adverse events for 28 days 
following vaccination, and serious adverse events for 6 months following vaccination. 
2.4.5. 
Secondary Endpoints 
 
The percentage of participants who show a seroconversion for Meningococcal 
Polysaccharide A, C, Y, W and X specific antibodies, i.e. a ≥4-fold increase in post-
immunization rSBA titer with respect to pre-immunization rSBA titer, at 28 days after a 
single vaccine dose. 
 
The percentage of participants who show a post-immunization seroprotection titer for 
Meningococcal Polysaccharide A, C, Y, W, and X specific antibodies defined as rSBA titer 
of 1:8 and 1:128 at 28 days after a single vaccine dose. 
 
GMTs of Meningococcal Polysaccharide A, C, Y, W and X specific antibodies at 28 days 
after a single vaccine dose, as measured by rSBA assay. 

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2.4.6. 
Exploratory Endpoints 
Additional immune response of adjuvanted and non-adjuvanted formulations of MCV-5 may be 
assessed by other relevant assays if remaining specimen volume is adequate.  
2.4.7. 
Randomization and Vaccination 
This is a prospective, randomized, parallel group, double blind clinical study. For arm allocation, 
a randomization-blocking scheme (1:1:1) will be used. Each block will be of six participants. The 
vaccine will be supplied to the study site while respecting the randomization block size.  
The vaccine will be administered sequentially depending upon the randomization number by 
unblinded clinical staff not involved with the clinical assessment of study participants. Other 
investigative site personnel will not be aware of which group the participant has been randomized. 
The identity of the same cannot be revealed except in an emergency. Study monitor will verify 
randomization by checking the treatment allocation against the vaccination records at each study 
visit. 
 
3. STUDY PRODUCTS 
3.1. 
Test Vaccine (MCV-5) 
3.1.1. 
Product Description 
Serum Institute of India Private Limited’s candidated vaccine MCV-5 is a sterile pentavalent 
polysaccharide-conjugate vaccine composed of serogroups A, C, Y, W and X Neisseria 
meningitidis capsular polysaccharides, conjugated to two different protein carriers, with aluminum 
phosphate as an adjuvant. Serogroup A & X polysaccharide are separately conjugated to tetanus 
toxoid while C, Y & W are separately conjugated to recombinant CRM (CRM is genetic mutant of 
diphtheria toxin). 
It is intended for intramuscular administration and protects against meningitis and/or septicemia 
caused by serogroups A, C, Y, W, and X N meningitidis. 
N. meningitidis A, C, Y, W, and X polysaccharides are produced by cultivating cells in fed batch 
fermentation and purified after separation. Tetanus toxin is derived from Clostridium tetani grown 
in a modified medium and purified. CRM is expressed by Pseudomonas fluorescens strain and 
used after it is purified. Meningococcal polysaccharides are covalently conjugated to TT or CRM 
and purified to make the final formulated vaccine.  
Screening 
Randomization 
Group 1 (n=20): Study Group 
Adjuvanted MCV-5 conjugate vaccine 
Group 2 (n=20): Study Group 
Non-adjuvanted MCV-5 conjugate vaccine 
Group 3 (n=20): Study Group 
Menactra® 

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3.1.2. 
Manufacturer 
Serum Institute of India Private Limited, Pune 
3.1.3. 
Presentation and Formulation 
The MCV-5 vaccine is provided as a freeze-dried powder in a five-dose vial containing 
meningococcal A, C, Y, W, and X polysaccharides conjugated to tetanus toxoid and CRM protein. 
The vaccine has to be reconstituted with either adjuvant containing diluents or 0.9% Sodium 
Chloride Injection, USP as per sections 3.2 and 3.4. (Further details regarding preparation of 
adjuvanted and non-adjuvanted MCV-5 are provided in the protocol specific Pharmacy Manual.) 
No preservative is added either in vaccine or diluents component during manufacture.  
Vaccine Composition of 5 dose vial of MCV-5 vaccine (freeze dried) 
Component 
Quantity 
Meningococcal A polysaccharide* 
30 g 
Meningococcal C polysaccharide# 
30 g 
Meningococcal Y polysaccharide# 
30 g 
Meningococcal W polysaccharide# 
30 g 
Meningococcal X polysaccharide* 
30 g 
Sucrose 
15 mg 
Sodium Citrate 
2.5 mg 
Tris (Trometomol) 
0.61 mg 
* - Conjugated to Tetanus Toxoid (TT); # - Conjugated to CRM; q.s. - Quantum satis 
 
3.1.4. 
Stability and Storage 
MCV-5 vaccine must be stored between +2°C to +8°C. 
3.2. 
Diluents 
3.2.1. 
Adjuvanted Diluent 
Product Description 
The adjuvanted diluent containing aluminum phosphate used to prepare the adjuvanted MCV-5 
is a sterile white homogeneous suspension presented in a glass ampoule. 
Manufacturer 
Serum Institute of India Private Limited, Pune 

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Presentation and Formulation 
The adjuvant containing diluent is provided in a five-dose glass ampoule containing an actual fill 
volume of 3.1 mL ± 0.1 mL. Each 0.5 mL of adjuvanted diluent contains 125 µg Al3+ formulated 
in 0.9% Sodium Chloride. 
Stability and Storage 
The adjuvanted diluent must be stored between +2°C to +8°C and not to be frozen. 
3.2.2. 
Non-Adjuvanted Diluent 
0.9% Sodium Chloride Injection, USP, will be used to prepare the non-adjuvanted MenACYWX 
vaccine. The research pharmacy at the site will procure enough supply of the same lot of 0.9% 
Sodium Chloride Injection to complete the study. The 0.9% Sodium Chloride Injection will be 
stored at 20°C - 25°C.  
3.3. 
Reference Vaccine (Menactra®)26 
3.3.1. 
Product Description 
Menactra® is a sterile, intramuscularly administered quadrivalent conjugate vaccine composed of 
serogroups A, C, Y, and W Neisseria meningitidis capsular polysaccharides, conjugated to a 
protein carrier, diphtheria toxoid protein, without any adjuvant. It is intended for the prevention of 
meningitis and/or septicemia caused by serogroups A, C, Y, and W N. meningitidis. 
N. meningitidis A, C, Y, and W-135 strains are cultured on Mueller Hinton agar and grown in 
Watson Scherp media containing casamino acid.  
3.3.2. 
Manufacturer 
Sanofi Pasteur Inc. 
3.3.3. 
Presentation and Formulation 
Menactra® vaccine is a clear to slightly turbid solution supplied in 0.5 mL single dose vial. Each 
0.5 mL dose of vaccine is formulated in sodium phosphate buffered isotonic sodium chloride 
solution to contain four mcg each of meningococcal A, C, Y, and W-135 polysaccharides 
conjugated to approximately 48 µg of diphtheria toxoid protein carrier and residual amounts of 
formaldehyde of less than 2.66 µg (0.000532%), by calculation.  
3.3.4. 
Stability and Storage 
Menactra® must be stored between +2°C to +8°C. 
 
 

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3.4. 
Preparation and Administration 
Participants will be randomized 1:1:1 to receive either adjuvanted MCV-5 or non-adjuvanted 
MCV-5 or Menactra®. The vaccination will be administered by a staff not involved with the clinical 
assessment of study participants. 
3.4.1. 
Adjuvanted MCV-5 
The adjuvanted MCV-5 is prepared by reconstituting one vial of MCV-5 with a single ampoule of 
adjuvant containing diluent. For each participant, 0.5 mL dose will be withdrawn from the 
reconstituted five-dose adjuvanted MCV-5 vaccine vial using a sterile needle and syringe. For the 
purpose of this study one vial of reconstituted adjuvanted MCV-5 will be used for only one 
participant. 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. The 
single dose of 0.5 mL vaccine as per randomization schedule will be given via intramuscular 
injection using a needle and syringe in the deltoid muscle.  
The compositions of a single 0.5 mL dose of reconstituted adjuvanted MCV-5 vaccine are: 
Vaccine component 
Per 0.5 mL dose 
Meningococcal A polysaccharide* 
5 g 
Meningococcal C polysaccharide# 
5 g 
Meningococcal Y polysaccharide# 
5 g 
Meningococcal W polysaccharide# 
5 g 
Meningococcal X polysaccharide* 
5 g 
Sucrose 
2.42 mg 
Sodium Citrate 
0.40 mg 
Tris (Trometomol) 
0.098 mg 
Al3+adjuvant  
125 g  
0.9% Sodium Chloride 
q. s.  
Tetanus Toxoid 
7.8 to 33.4 µg 
CRM 
11.7 to 50.1 µg 
*- Each conjugated to Tetanus Toxoid (TT); 
# - Each conjugated to CRM; 
q.s. - Quantum satis 
 
 

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3.4.2. 
Non-Adjuvanted MCV-5 
The non-adjuvanted MCV-5 is prepared by reconstituting one vial of MCV-5 with a 3.1 mL of 0.9% 
Sodium Chloride Injection, USP. For each participant, 0.5 mL dose will be withdrawn from the 
reconstituted five-dose non-adjuvanted MCV-5 vaccine vial using a sterile needle and syringe. 
For the purpose of this study one vial of reconstituted non-adjuvanted MCV-5 will be used for only 
one participant. 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. 
The single dose of 0.5 mL vaccine as per randomization schedule will be given via intramuscular 
injection using a needle and syringe in the deltoid muscle.  
The compositions of a single 0.5 mL dose of reconstituted non-adjuvanted MCV-5 vaccine are: 
Vaccine component 
Per 0.5 mL dose 
Meningococcal A polysaccharide* 
5 g 
Meningococcal C polysaccharide# 
5 g 
Meningococcal Y polysaccharide# 
5 g 
Meningococcal W polysaccharide# 
5 g 
Meningococcal X polysaccharide* 
5 g 
Sucrose 
2.42 mg 
Sodium Citrate 
0.40 mg 
Tris (Trometomol) 
0.098 mg 
Tetanus Toxoid 
7.8 to 33.4 µg 
CRM 
11.7 to 50.1 µg 
* - Each conjugated to Tetanus Toxoid (TT); 
# - Each conjugated to CRM;  
q.s. - Quantum satis  
 
3.4.3. 
Menactra® 
After inspecting and confirming visually for particulate matter and discoloration 0.5 mL dose of 
vaccine is to be withdrawn from the single-dose vial using a sterile needle and syringe. The single 
dose of 0.5 mL vaccine as per randomization schedule will be given via intramuscular injection 
using a needle and syringe in the deltoid muscle. Vaccine must be administered within two hours 
of preparation. 
3.5. 
Accountability and Disposal 
Test vaccine MCV-5 and diluent used for reconstitution of adjuvanted formulation (sodium 
chloride plus aluminum phosphate) will be provided by SIIPL and shipped to the study site in 
validated cold chain boxes. The investigator will acknowledge receipt of products indicating 
shipment content and condition. 
Whereas, site may arrange to directly procure Menactra® as well diluent for non-adjuvanted 
formulation (sodium chloride). In case it is not feasible for site, the same will be arranged by 
sponsor/designee. 

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The SIIPL supplied vaccine will be packed in appropriate package deemed to maintain the 
integrity of the product. The packaging for Menactra® will be the same as that available in market 
at the time of procurement.  
Additional labels will be affixed on all study vaccines and diluents which should specify a statutory 
statement: ‘Caution: New Drug--Limited by Federal law to investigational use’.  
The label should also have following details: 
 
Name of Manufacturer 
 
Protocol number 
 
Store between 2° and 8°C 
A participant identifier will be captured or pre-printed on vaccine labels to ensure accountability 
and traceability to the study subject for which they were used. 
All vaccines used in the study must be accounted for in the Vaccine Accountability Record.  
Investigator or an authorized representative of the investigator will ensure that all vaccines will be 
stored in a secured area, in a light protected, dry place at temperature between +2°C and +8°C. 
Storage temperature should be monitored every day. 
Qualified staff members will administer the vaccine.  
The investigator must maintain a temperature log and an inventory record of vaccines received 
and administered. 
At the end of the study, all vaccine will be destructed at the site, as per site’s standard operating 
procedure or returned to SIIPL, including vaccine not administered to participants. It will be 
ensured that destruction occurs only after study product accountability. 
 
 

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4. STUDY POPULATION 
4.1. 
Clinical Trial Site 
This will be a single site study conducted at the Center for Vaccine Development (CVD), University 
of Maryland, Baltimore USA. 
4.2. 
Study Population 
Healthy adult volunteers, 18 to 45 years of age. 
4.3. 
Eligibility 
4.3.1. 
Inclusion Criteria 
Male and female participants will be eligible for inclusion if ALL of the following apply at the time 
of screening: 
1. 
Age 18 to 45 years of age inclusive  
2. 
Written informed consent of volunteers 
3. 
Healthy as established by medical history, laboratory evaluation and screening evaluations 
including clinical physical examination 
4. 
Participants must have the following laboratory parameters: 
a. Hemoglobin: ≥ 10.5 g/dL for female, ≥ 11.0 g/dL for male 
b. White cell count: 3,300 to 12,000 cells/ mm3 
c. Platelets: 125,000 to 550,000/ mm3 
d. ALT < 1.25 times the institutional upper limit of normal (ULN) 
e. Creatinine and total bilirubin ≤ institutional ULN 
f. Albumin ≥ institutional lower limit of normal 
5. 
Participants are able to understand and comply with planned study procedures and be 
available for all study visits  
6. 
Female subjects must be of non-childbearing potential (defined as surgically sterile or 
postmenopausal for more than 1 year), or if of childbearing potential must be practicing 
abstinence or using an effective licensed method of birth control (e.g., history of 
hysterectomy or tubal ligation; use hormonal or barrier birth control such as implants, 
injectables, combined oral contraceptives, some intrauterine devices (IUDs), cervical 
sponges, diaphragms, condoms with spermicidal agents; or must have a vasectomized 
partner) within one month of vaccination and must agree to continue such precautions for 
84 days after vaccination. A woman is eligible if she is monogamous with a vasectomized 
male. 
 
 

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4.3.2. 
Exclusion Criteria 
Participants with any of the following criteria at study entry will not be eligible for participation: 
1. 
Previous vaccination against Neisseria meningitidis. 
2. 
Known exposure to Neisseria meningitidis in the past. 
3. 
History of meningitis or seizures or any neurological or psychiatric disorder. 
4. 
Administration of any other vaccine within 30 days prior or after administration of study 
vaccines. 
5. 
Use of any investigational or non-registered drug or vaccine within 30 days prior to the 
administration of study vaccines or planned during the study. 
6. 
History of allergic disease or known hypersensitivity to any component of the three study 
vaccines. 
7. 
History of Serious Adverse Reactions following administration of Tetanus Toxoid, Diphtheria 
Toxoid or CRM containing vaccines. 
8. 
History of Guillain-Barré syndrome. 
9. 
Confirmed or suspected immunosuppressive or immune-deficient condition. 
10. A family history of congenital or hereditary immunodeficiency. 
11. Chronic administration (defined as more than 14 days) of immune-suppressants or other 
immune-modifying agents within six months prior to administration of study vaccine. (For 
corticosteroids, this means prednisone, or equivalent, > 0.5 mg/kg/day; topical or inhalable 
steroids are allowed.) 
12. Laboratory confirmed infection of either hepatitis B virus (HBs Ag positive on ELISA), 
hepatitis C virus (anti-HCV positive on ELISA as well as PCR) or human immunodeficiency 
virus (HIV on ELISA). 
13. Major congenital defects or serious chronic illness. 
14. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic, or renal functional 
abnormality, as determined by medical history, physical examination or laboratory screening 
tests.  
15. Known bleeding disorders. 
16. Administration of immunoglobulins and/or any blood products within the three months 
preceding the administration of study vaccines or planned administration during the vaccine 
period. 
17. History (within the past year) or signs of alcohol or substance abuse.  
18. Pregnancy or lactation. A negative pregnancy test will be required before vaccination for all 
women of childbearing potential. 
19. A Body Mass Index (BMI) above 30. 
20. Any other condition, which in the opinion of the investigator, might interfere with the study 
objectives, jeopardize the safety or rights of the participant or making it unlikely the participant 
could complete the protocol. 
 
 

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5. STUDY PROCEDURES 
The study will be started only after the written approval from appropriate regulatory authority and 
the respective site’s ethics committees are obtained. 
The study Principal Investigator (PI) will ensure that the study team adheres to good clinical 
practices (GCP). Study personnel will be required to: 
 
Maintain control and retention of primary source documents and electronic databases with 
passwords, back-up, and restrict the ability to change results. 
 
Avoid coercive means of recruitment. 
 
Avoid excessive compensation that leads to the inclusion of participants who would 
otherwise be ineligible. 
 
Report adverse events and routine data to the external monitoring committee per the 
monitoring plan. 
 
Comply with the local regulatory and GCP requirements for vaccine-related adverse event 
reporting. 
 
Use infection control/biosafety measures to reduce exposure to infectious diseases, 
including during the transport of specimens. 
 
Report any anticipated changes to the protocol (such as randomization plan revisions) to 
the ethics committees and have approvals from such committees prior to initiating 
changes. 
5.1. 
Recruitment 
Participants may be recruited from the CVD volunteer database and by local advertisements and 
flyers. Potential participants who are interested in the study will be informed of the study and if 
they wish to participate, will receive additional study information, including the informed consent 
form. 
5.2. 
Screening, Randomization, Masking Procedures, Study Visits 
5.2.1. 
Initial and Continuing Informed Consent 
Informed consent is the process of ensuring that study participants fully understand the purpose 
of the study and what will and may happen to them while participating in a research study. Initial 
written informed consent is required before performance of any study-related procedures. The 
informed consent process continues throughout the study. Key study concepts are reviewed with 
the participant at designated times and as needed, and the review is documented.  
Additionally, if any new information becomes available that, in the judgment of the Sponsor and/or 
PI, may affect the participant’s decision to continue in the trial, such information will be shared 
with the study participant and may be the basis for requiring a new consent form to be signed. 
A copy of the signed informed consent form (ICF) will be provided to the participant and the 
original ICF will be filed with the participant’s study record. 

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5.2.2. 
Screening, Visit 1 (Day -28 to -1) 
Once informed consent has been obtained the participant will be considered enrolled in the trial. 
The following procedures will be completed during screening to determine study eligibility and 
may occur over multiple screening visits. Additional screening visits may be scheduled for any 
follow up as needed, but are not required. At the screening visit(s), the PI or designee will provide 
prospective volunteers with a detailed description of the study objectives and study participation 
requirements, as well as potential health risks and benefits associated with study participation. 
Baseline data are obtained during screening, which may occur over the course of several 
contacts/visits, between 28 days prior to and on Day 1, the day of vaccination. All 
inclusion/exclusion criteria must be assessed from data obtained within that period, unless 
otherwise specified in the eligibility criteria. After study information has been provided and the 
appropriate informed consent has been obtained, the following procedures are performed by 
PI/designee: 
a) Confirms that written informed consent has been given and solicits and discusses any 
remaining questions the participant may have; 
b) Assign screening number once study specific consent form has been signed; 
c) Obtain demographic and contact (e.g., address, telephone, email) information; 
d) Obtain medical history; including history of any vaccination in the last 30 days and ever 
received vaccination against Neisseria meningitidis, tetanus or diphtheria containing 
vaccines 
e) Obtain history of medication use in the past 30 days; 
f) Measure height & weight; 
g) Perform full physical exam, including vital signs (blood pressure, pulse and temperature – 
section 5.5.1); and 
h) Collect blood samples (18 mL) for screening laboratory testing: hematology (hemoglobin, 
platelet count and WBC), clinical chemistry (creatinine, albumin, ALT and total bilirubin), 
serum HCG pregnancy test (females of childbearing potential only) and screening for HIV, 
HCV and HBV (Appendix I). 
5.2.3. 
Randomization  
Enrollment will be performed online using the enrollment module of AdvantageEDCSM, the Emmes 
Corporation’s electronic data capture (EDC) system. Randomization will occur on the day 
participants are to receive their first study vaccination, after confirmation of eligibility and 
immediately prior to vaccination.  
Participants will be assigned to a coded treatment assignment after demographic and eligibility 
data have been entered into the system. The unblinded pharmacist will be provided with the 
treatment assignment codes for preparation of the vaccine to be given to each participant. The 
research pharmacist will maintain the treatment code list in a secure place. 

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Based on this randomization schedule each participant will be assigned to one of the following 
three treatment groups: 
Group 
Vaccine 
1 
Adjuvanted Study vaccine (MCV-5) 
2 
Non-adjuvanted Study vaccine (MCV-5) 
3 
Reference vaccine (Menactra®, ACYW) 
5.2.4. 
Vaccination, Visit 2 (Day 1) 
Prior to Vaccine Administration 
a) Obtain interim medical and medications history to confirm continued eligibility; 
b) Measure vital signs; 
c) Perform targeted physical exam based on complaints, interval history and to confirm 
absence of abnormality at the injection site (deltoid);  
d) For female participants of child bearing potential, perform urine or serum pregnancy test;  
e) Obtain blood samples (20 mL) for immunological testing; and 
f) Record randomization code for eligible participant 
Vaccine Administration 
a) The prospective injection site will be cleaned with an alcohol swab and allowed to dry 
completely. The study injection will be administered into the deltoid by inserting the needle 
(25 gauge, 25 mm) into muscle at 90°, holding the muscle mass stable with the non-
injecting hand, and slowly depressing the plunger. The needle is removed and the injection 
site gently rubbed with gauze. 
b) An unblinded clinical staff not involved with clinical assessment will administer the 
assigned vaccine to the participant. 
c) Document on the CRF as to timing and location of vaccine administration. 
Post Dose – Observation Period 
a) Participants will remain at the site for at least 60 minutes post-vaccination. 
b) After 60 minutes study staff will assess and record oral temperature, systemic (headache, 
fatigue/malaise, myalgia, arthralgia, diarrhea and anorexia) and local injection site (pain, 
redness/erythema, swelling/induration) reactions. 
c) The PI (or designee) may determine that a participant requires further on-site 
observation; or clinical assessments as needed. 
d) When all study related procedures are complete and the PI (or designee) determines that 
a participant’s condition is acceptable, the participant will be discharged from study site. 
e) Before discharge, the participant will be provided with supplies including a thermometer, 
injection site measuring device, and a Memory Aid; instructed in their use; and provided 
with written materials, follow-up visit information, and contact telephone numbers for study 
staff.  

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5.2.5. 
Visit 3 (Day 8 +3 days) 
On the eighth day after vaccination, the participant will return to the study site for the following 
procedures: 
a) Study staff review and record participant’s interim health history, medication use and self-
assessment experience through personal interview, assisted by the Memory Aid.  
b) Vital signs, injection site, and a targeted physical examination (if indicated) will be 
performed. 
c) Local and systemic reactions and AEs review as recorded in Memory Aid as well as asked 
for by PI (or designee). The highest temperature written in the Memory Aid each day will 
be recorded to source document as peak temperature. 
d) Findings of PI or study staff that suggest inaccuracy of reported self-assessments will be 
clearly documented. 
e) Any topics or new information considered by PI to be important to continued informed 
consent will be shared with the participant. 
f) Blood samples (8 mL) will be obtained for safety laboratory tests (Appendix I). 
g) Study staff will instruct the participant regarding continued self-assessment and need to 
contact study staff (a) in follow-up of specific AEs, (b) if injection site changes worsen or 
do not resolve, (c) if systemic symptoms worsen or do not resolve, and (d) if other AEs 
occur.  
h) The next visit is scheduled. 
5.2.6. 
Visit 4 (Day 29 +14 days) 
On Day 29 (plus 14 calendar days if necessary for participant compliance), the participant will 
return to study site and the following procedures occur:  
a) Obtain interim medical history, including medication use.  
b) Vital signs will be measured. 
c) AEs will be evaluated. 
d) A targeted physical exam will be performed, if indicated. 
e) Urine pregnancy test will be performed. 
f) Blood samples (30 mL) will be obtained for immunological assays (see Appendix I). 
g) The participant will be reminded to contact the study site with any new information about 
chronic illnesses, serious health events, and/or hospitalizations, and the Day 85 follow-up 
contact information will be provided. Every effort should be made to adhere to the protocol 
windows.  

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5.2.7. 
Visit 5 (Day 85 +14 days) 
On Day 85 (plus 14 calendar days if necessary for participant compliance), the participant will 
return to study site and the following procedures occur: 
a) Interim medical history will be obtained, including medication use. 
b) Vital signs will be measured. 
c) SAEs, if any will be recorded and evaluated. 
d) A targeted physical exam will be performed, if indicated. 
e) Urine pregnancy test will be performed. 
5.2.8. Final Study Contact (Day 180 ±21 days) 
The participant will be contacted by telephone to assess any SAEs that may have occurred.  
SAEs, if any will be recorded and evaluated. 
5.3. 
Unscheduled Visits 
Unscheduled visits may be performed at participant’s requests or directly by the study site when 
the PI or staff member considers it necessary for diagnosis and/or management of a finding or 
AE. All unscheduled visits will be documented in participants’ study records and on applicable 
case report forms. 
5.4. 
Early Termination 
If a participant withdraws from the study for any reason prior to the planned study duration, every 
attempt is made to complete a termination visit to include the following. 
a) Report of local and systemic reactogenicity and AEs are reviewed by PI (or designee).  
b) Vital signs are obtained. 
c) Specimens are obtained for chemistry, hematology and immunogenicity analysis if 
withdrawal occurs prior to schedule laboratory testing. 
d) Memory Aid information is reviewed with the participant in detail by site staff, if in use since 
the last visit. 
e) Injection site examination and a targeted physical examination are performed (if 
indicated). 
5.5. 
Procedure Methods 
Study procedures are performed and recorded in source documents as outlined in the Schedule 
of Events and according to the following subsections. 
5.5.1. 
Vital Signs 
 
Temperature in degrees Fahrenheit (recorded to the nearest 0.1 degree) will be measured 
by oral thermometer.  
 
Blood pressure in mm of mercury and heart rate in beats per minute will be measured by 
automated device or manually. 

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5.5.2. 
Height and Weight 
 
Height will be measured in cm and recorded to the nearest 0.1 cm.  
 
Weight will be measured in kg and recorded to the nearest 0.1 kg.  
5.5.3. 
Physical Examination 
Full physical examination will include assessment of vital signs, head, eyes, ears, nose, 
oropharynx, neck, chest (auscultation), heart (auscultation), back, abdomen (auscultation and 
palpation), musculoskeletal, skin (especially injection site), and neurological. Not included are 
breast, genital or anorectal examinations. 
5.5.4. 
Medical History 
 
A comprehensive medical history will be collected at screening including, history of any 
vaccination in the last 30 days and ever received vaccination against Neisseria 
meningitidis, tetanus and diphtheria containing vaccines, current medication and history 
of any chronic or recurrent medical and psychiatric conditions.  
 
An interim medical history will consist of inquiring regarding changes (healthcare events, 
signs, symptoms and changes in use of prescription or nonprescription drugs or herbal 
preparations) since the last medical history discussion.  
5.5.5. 
Injection Site Examination 
Injection site assessment will be done by trained study personnel. Local reactions will be graded 
according to the toxicity grading scale in Appendix II. 
 
Erythema/redness will be examined under standardized lighting conditions and measured. 
Severity of the reaction will be determined by staff on the basis of the severity grading 
table (Appendix II).  
 
Swelling/induration will be examined by palpation and visual inspection under 
standardized lighting conditions; the examiner may temporarily mark skin at margins of 
visible swelling/induration, then measure maximum diameter (as per Appendix II).  
 
Pain will be assessed by (a) inquiring as to whether there is significant discomfort at rest 
and/or (b) whether movement of the injection site causes discomfort, impacts limb 
movement or daily activity (Appendix II).  
5.5.6. 
Assessment of Reactogenicity 
The following parameters for reactogenicity will be assessed during the seven days following 
vaccination. 
Local reactogenicity 
 
Pain  
 
Erythema / redness 
 
Swelling / induration 

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Systemic reactogenicity 
 
Fever (based on oral temperature) 
 
Headache 
 
Fatigue/malaise 
 
Joint pain (arthralgia) 
 
Muscle pain (myalgia) 
 
Diarrhea 
 
Anorexia 
 
Chills 
 
Vomiting 
5.5.7. 
Concomitant Therapy  
Other medications that are considered necessary for participant’s welfare and that will not 
interfere with the vaccine may be given at the discretion of the investigator. At each study visit, 
the investigator/designee should ask the participants about concomitant medication.  
Any of the medication taken at any time during the period starting 30 days before the first study 
vaccination and ending four weeks after the final study vaccination must be captured with trade 
name and/or generic name, indication, start and end dates. 
The following drug/vaccines should not be taken during study participation: 
1. Any investigational or non-registered drug or vaccine within 30 days prior to administration 
of study vaccines as well as during the entire study participation. 
2. Chronic administration (defined as more than 14 days) of immunosuppressant or other 
immune-modifying agents during the vaccine period. For corticosteroids, this means 
prednisone or equivalent  0.5 mg/kg/day. Topical or inhalable steroids will be allowed. 
3. Administration of routinely recommended licensed vaccine within 28 days post vaccination.  
4. Administration of immunoglobulin and/or any blood products during the study period. 
5. Prophylactic antipyretics or analgesics to prevent fever or pain for seven days post 
vaccination. 
5.5.8. 
Clinical Laboratory Testing 
Laboratory evaluations for screening (hematology, chemistry, testing for HIV, Hepatitis B and C, 
and, for women of childbearing potential, pregnancy tests) and safety monitoring (hematology, 
chemistry and pregnancy tests for women of child bearing potential) are detailed in Appendix I, 
Schedule of Events. 
5.5.9. 
Early Termination from Study 
An enrolled/vaccinated participant may be terminated from the study for any of these reasons:  
a) Participant withdraws consent. 
b) The participant fails to comply with the study requirements so as to cause harm to 
him/herself or seriously interfere with the validity of the study results. 
c) Sponsor terminates the study. 

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5.5.10. 
Contraception and Pregnancy 
Contraception status is assessed and documented prior to enrollment and study vaccination for 
female participants who are of childbearing potential. Prior to enrollment and at vaccination visit, staff 
will ask participants to verbally confirm their use of adequate contraception methods if they are able 
to become pregnant. Adequate methods of contraception include double barrier contraception, 
hormonal birth control, IUD, or surgical sterility. If a participant becomes pregnant following 
vaccination, she will be encouraged to complete remaining visits and study procedures unless 
medically contraindicated. Any participant who becomes pregnant during the period between first 
vaccination and Day 180 will continue to be followed for pregnancy outcome, if possible. 
6. LABORATORY EVALUATIONS 
Blood samples will be obtained to examine vaccine safety and immunogenicity. 
6.1. 
Sample Collection, Distribution and Storage 
Samples to evaluate vaccine safety will be obtained at the clinical trial site and transported to the 
site’s designated laboratory for clinical testing. Research specimens collected for the 
immunogenicity time points will be separated into aliquots by the site’s research laboratory or 
study laboratory as per study specific process and sent to the contract laboratories. Samples will 
be stored properly in controlled-temperature refrigerators/freezers. Backup generators are 
available for proper sample storage. 
6.2. 
Safety Clinical Laboratory Assays 
Protocol mandated screening and clinical safety laboratory tests will be conducted in real time as 
per Schedule of Events (Appendix I).The clinical laboratory must maintain proper accreditation 
and subscribes to a proficiency testing program.  
Laboratory results will be reviewed promptly by the PI or designee. Participants will be notified of 
any clinically significant abnormalities. If clinically significant abnormalities are identified during 
screening, participants will be referred to their primary health provider or appropriate medical 
center. If identified during the study, participants may be asked to return to the study site for further 
evaluation, including clinical evaluation and repeat laboratory testing as warranted. 
6.3. 
Immunological Assays 
The immunological assays to be performed are: 
Immunogenicity testing for Meningococcal Polysaccharide A, C, Y, W, and X specific antibodies 
using rSBA assay will be performed on sera collected at baseline (Day 1) and 28 days post 
vaccination. The rSBA assay will be conducted at Vaccine Evaluation Unit at Public Health 
England (PHE) in Manchester UK. Additional immunogenicity assays may be performed by 
research laboratories to further evaluate post-vaccination immune responses. These exploratory 
analyses may be done on a sub-sample of participants’ sera, if remaining specimen volume is 
adequate. 

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6.4. 
Assay Qualification, Standardization and Validation 
The PHE rSBA assay for serogroups A, C, Y, and W is a validated assay. Samples from this study 
will be used for the validation of the PHE rSBA assay for serogroup X. 
6.5. 
Biohazard Containment 
As transmission of blood-borne pathogens can occur through contact with contaminated needles, 
blood, and blood products, appropriate blood and secretion precautions will be employed by all 
personnel in the drawing of blood and shipping and handling of all specimens for this study, as 
recommended by the Centers for Diseases Control and Prevent (CDC). All biological specimens 
will be transported using packaging mandated by 42 CFR Part 72. All dangerous goods materials, 
including diagnostic specimens and infectious substances, must be transported according to 
instructions detailed in the International Air Transport Association (IATA) Dangerous Goods 
Regulations. 
Biohazardous waste will be contained according to institutional, transportation/carrier, and all 
other applicable regulations. 
7. STATISTICAL DESIGN AND ANALYSIS 
7.1. 
Overview and General Design 
This study is a Phase 1 double blinded randomized, controlled clinical trial to assess the safety 
and immunogenicity of the adjuvanted and non-adjuvanted formulation of polyvalent conjugate 
vaccine composed of serogroups A, C, Y, W, and X Neisseria meningitidis capsular 
polysaccharides (MCV-5). The primary objective is to evaluate the safety of adjuvanted and non-
adjuvanted formulations of MCV-5 vaccine. The secondary objective is to assess the immune 
response of adjuvanted and non-adjuvanted formulations of MCV-5 vaccine. 
The primary hypothesis of safety will be fulfilled if no participants develop a vaccine related SAE 
and the vaccine is well tolerated. The second hypothesis of immunogenicity will be fulfilled if the 
two formulations of MCV-5 induce immune response as measured by rSBA to all five serogroups 
of the vaccines. 
A detailed statistical analysis plan for preparation of the final study report will be created and 
made final prior to database lock and unblinding. All statistical analyses will be performed using 
SAS® software Version 9.3 or later. 
Medical history and AEs will be coded using the current version of the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary. The frequency count and percentage of participants 
will be summarized according to the coded terms of system organ class and preferred term. 
Participant-wise data listing will be provided. 
7.2. 
Randomization and Blinding Procedures 
The randomization scheme will be generated and maintained by the Statistical and Data 
Management Group (SDMG) at the Emmes Corporation, Rockville, MD. Participants will be 
enrolled into the study online and randomized using the enrollment module of the Emmes 
Corporation’s AdvantageEDCSM electronic data capture system. Each participant enrolled into the 
trial will be assigned a treatment code after demographic and eligibility data have been entered 
into the system. 

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The pharmacist with primary responsibility for dispensing study products is charged with 
maintaining security of the treatment assignments. 
7.3. 
Objectives and Endpoints 
7.3.1. 
Primary 
Objective: To evaluate the safety of adjuvanted and non-adjuvanted formulations of MCV-5 
vaccine in healthy adults. 
Endpoints:  
Summaries by product received including the number and percentage of participants 
experiencing: 
 
immediate AEs within 60 minutes post-vaccination; 
 
solicited local or systemic post vaccination reactogenicity reactions within seven days 
following vaccination (Days one through seven); 
 
any SAE within six months following vaccination;  
 
any AE within 28 days following vaccination;  
 
any Grade 2 or greater solicited local or systemic post vaccination reactions within seven 
days following vaccination; 
 
any Grade 2 or greater unsolicited AE within 28 days following vaccination;  
 
any unsolicited AE within 28 days following vaccination judged to be related to study 
product; and 
 
any Grade 2 or greater unsolicited AE within 28 days following vaccination judged to be 
related to study product. 
7.3.2. 
Secondary 
Objective: To assess the immune response of adjuvanted and non-adjuvanted formulations of 
MCV-5 vaccine in healthy adults 
Endpoints: 
 
The percentage of participants who show a seroconversion for Meningococcal 
Polysaccharide A, C, Y, W, and X specific antibodies, i.e. a ≥4-fold increase in post-
immunization rSBA titer with respect to pre-immunization rSBA titer, at 28 days after a 
single vaccine dose.  
 
The percentage of participants who show a post-immunization seroprotection titer for 
Meningococcal Polysaccharide A, C, Y, W, and X specific antibodies defined as rSBA titer 
of 1:8 and 1:128 at 28 days after a single vaccine dose. 
 
GMTs of Meningococcal Polysaccharide A, C, Y, W and X specific antibodies at 28 days 
after a single vaccine dose, as measured by rSBA assay. 

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7.3.3. 
Exploratory 
Immune response of adjuvanted and non-adjuvanted formulations of MCV-5 may be assessed 
by other relevant assays, if remaining specimen volume is adequate.  
7.4. 
Sample Size Justification 
Since this study is a Phase 1 trial it is designed to provide preliminary safety and immunogenicity 
data that may support testing the study product in additional larger cohorts in adults and in age-
descending studies. 
With 20 vaccine recipients per vaccine group, this study’s design allows a greater than 90% 
chance of observing an AE that has an 11% chance of occurrence. Conversely, if no AEs are 
observed in 20 vaccine recipients, the study will be able to rule out AEs occurring at a rate of 
approximately 14% based on the upper bounds of the one-sided 95% Confidence Interval.  
No formal statistical hypothesis testing is planned for this first time in human Phase 1 study whose 
objectives are aimed to descriptively evaluate the safety and immunogenicity profile of the study 
vaccines 
7.5. 
Analytical Methodology 
7.5.1. 
Analysis Population 
Definitions of analysis populations to be analyzed are: 
Enrolled Population  
All screened participants who provide informed consent, regardless of the participant’s 
randomization and treatment status in the trial. 
Full Analysis population  
All participants in the enrolled population who were randomized and received a study vaccination. 
All safety analyses will be performed using this population. Treatment groups for safety analysis 
will be assigned according to the actual treatment received at Day 1.  
Per Protocol population  
All participants in the per protocol population who are assigned the study vaccination with no 
major protocol violations that are determined to potentially interfere with the immunogenicity 
assessment of the study vaccine. This population will serve as the primary analysis population for 
the immunogenicity endpoints. 
The criteria for exclusion of participants from the Per Protocol Population will be established 
before breaking the blind and will be based on the blinded review of protocol violations. 

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7.5.2. 
Statistical Method 
When the use of descriptive statistics to assess group characteristics or differences is required, 
the following methods will be used: for categorical variables, the number and percent of 
participants in each category; for continuous variables, the mean, median, standard deviation, 
quartiles and range (minimum, maximum).  
In general all missing data will be treated as missing completely at random and no imputation will 
be performed except for the safety endpoints as described below. Non-analyzable data (e.g., due 
to major protocol violations) will be documented in the deviations.  
If some safety data are available for a subject in the safety population but respective secondary 
endpoint related data are missing then the subject will be included in the safety analysis and data 
will be treated as follows for immediate AEs, solicited AEs, unsolicited AEs and SAEs. 
1. If Severity is missing for any AE then it will be considered as an AE of maximum severity 
(Grade 3) “Severe” unless it’s captured as SAE.  
2. If “Relationship” is missing then it will be considered as “Related” to the vaccine administered. 
3. If, for Start date, the day of event/condition is missing due to any adverse event then it will be 
imputed as the date of last dose of study vaccine. 
4. If, for Start date, the day and month of an adverse event is missing, then it will be imputed as 
the date of first dose of study vaccine. 
5. If the Stop date of an adverse event is missing then it will be treated as ongoing. 
Analysis of Primary Safety Objective 
The primary aim of the study is to assess the safety of the study vaccine. All safety data (solicited 
local and systemic reactions and unsolicited AEs and SAEs) collected after participants are 
exposed to the study product will be included in the primary analysis of safety.  
To assess safety, the number and percentage of participants experiencing at least one AE, and 
the number and percentage of participants experiencing each specific AE, categorized by body 
system and preferred term, will be tabulated by product received along with their corresponding 
two-sided exact 95% confidence intervals.  
Fisher’s exact test will be used to compare the proportion of participants with solicited local and 
systemic reactogenicity events between the MCV-5 group and the Menactra® Group. The primary 
purpose of statistical comparisons is to screen out potential solicited reactogenicity events that 
need further clinical evaluation. Therefore, they are not considered formal statistical hypothesis 
tests and it is acknowledged that there will be inflated Type I errors (i.e. inflated false statistical 
significances) from performing multiple unadjusted comparisons. 
Changes in clinical laboratory values from baseline to end of treatment/follow-up will be analyzed 
descriptively. 

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To facilitate the planning of the follow-up trial, analysis of unblinded primary safety data up to Visit 
4 (Day 29) by treatment groups will be made available to the Sponsor after all participants have 
completed this visit and their data have been cleaned and verified.  
Analysis of Secondary and Exploratory Immunogenicity Objective 
The percentage of participants with a 4-fold response in rSBA titer against serogroups A, C, W, 
Y and X will be defined as: 
 
For participants with a pre-vaccination rSBA titer <8, a post-vaccination titer of ≥32; 
 
For participants with a pre-vaccination rSBA titer ≥8, an increase in rSBA titer of at least 4 
times the pre-vaccination titer. 
For seroresponse rate endpoints, two-sided 95% exact confidence intervals (CIs) for each of the 
proportions will be provided. Two-sided exact 95% CIs for the three pair-wise proportion 
differences between the three treatment groups will be computed using the unconditional exact 
method proposed by Chan and Zhang (1999) or another appropriate method. 
For the purpose of determining GMT antibody titer below 1:8 will be given an arbitrary value of 
half of the assay’s cut-off (4). GMT will be calculated as: GMT = antilog (mean loge-x]) where x is 
the assay result and e is the natural logarithm. GMTs will be summarized by treatment group and 
by visit with corresponding two-sided 95% CIs based on the t-distribution to provide population 
estimates. Two-sided 95% CIs for the ratios of GMTs between treatment groups will be 
constructed using the log normal distribution. The log values will be used to construct a CI using 
the t-distribution for the mean difference between three pair-wise treatment groups. The mean 
difference and the corresponding CI limits will then be exponentiated to obtain the GMT ratio and 
the corresponding CI. If the values deviate from a log normal distribution, a nonparametric method 
may be used for the analysis of GMT. 
Due to the hypothesis generating nature of multiple statistical comparisons for immunogenicity 
associated with multiple endpoints for this early phase first study in human subjects, all 
estimations will be carried out using a two-sided 5% Type I error rate without an adjustment for 
multiple comparisons. 
8. SAFETY ASSESSMENT AND REPORTING 
This section defines the types of safety events that should be reported and outlines the 
procedures for appropriately collecting, grading, recording and reporting them. 
8.1. 
Safety Events 
All safety events observed under this protocol are reported through the AdvantageEDC data 
system throughout the study. Safety events related to vaccine reactogenicity are collected on 
study-specific forms. Reactogenicity will be collected through the visit on Day 7, if a solicited sign 
or symptom has started during the seven days post-vaccination and continues it will continue to 
be reported as a reactogenicity symptom. Only when the reactogenicity event is considered an 
SAE, as defined below, will it be reported on an AE/SAE form set, in addition to the reactogenicity 
form. Any symptom starting after seven days post-vaccination will be recorded as an AE. All other 

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safety events that meet the definition of an AE or SAE that occur throughout the study are reported 
on the AE/ SAE form set. AE's will be collected through study visit Day 28. SAEs will be assessed 
through Day 180 and will be reported on the AE/ SAE form set. 
8.2. 
Reporting Period 
Safety events are reported from the time of the vaccination through completion of the study at 6 
months as described above.  
8.3. 
Definitions 
8.3.1. 
Adverse Event (AE)  
An adverse event is any untoward medical occurrence in humans, whether or not considered 
vaccine related, that occurs after the vaccination during the conduct of a clinical trial. Any change 
from baseline assessment of clinical status, ECGs, routine laboratory tests, X-rays, physical 
examinations, etc., that is considered clinically significant by the PI is considered an AE.  
Suspected adverse drug reaction is any AE for which there is a reasonable possibility that the 
vaccine caused the AE. A reasonable possibility implies that there is evidence to suggest that the 
study product caused the event. 
Adverse reaction is any AE caused by the vaccine.  
8.3.2. 
Serious Adverse Events (Defined as Serious Adverse Events, Serious 
Suspected Adverse Reactions or Serious Adverse Reactions) 
An SAE, including a serious suspected adverse reaction or serious adverse reaction as 
determined by the PI or the Sponsor, is any event that results in any of the following outcomes: 
1. Death. 
2. Life-threatening AE (Life-threatening means that the study participant was, in the opinion 
of the PI or Sponsor, at immediate risk of death from the event as it occurred.)  
3. Inpatient hospitalization or prolongation of existing hospitalization. 
4. Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions.  
5. Congenital abnormality or birth defect. 
6. Important medical event that may not result in one of the above outcomes but may 
jeopardize the health of the study participant or require medical or surgical intervention to 
prevent one of the outcomes listed in the above definition of serious event.  
8.3.3. 
Unexpected Adverse Event 
An AE is “unexpected” when its nature (specificity) or severity is not consistent with applicable 
product information, such as safety information provided in the Investigators’ Brochure (IB), the 
investigational plan or the protocol.  

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8.4. 
Severity Grading 
The study site assigns severity grades to indicate the severity of adverse events and reactions. 
The severity grading criteria provided in Appendix II grade AEs from Mild (Grade 1) to Life 
Threatening (Grade 4). All AEs leading to death are Grade 5 events. AEs are graded with the 
worst severity grade during the illness/symptoms. AE severity will be graded using the attached 
grading scale (Appendix II) based on the Division of AIDS (DAIDS) Table for Grading the Severity 
of Adult and Pediatric Adverse Events, version 2.0, November 2014, of the US National Institute 
of Health. 
8.5. 
Guidelines for Determining Causality of an Adverse Event 
The PI should consider the following question when assessing causality of an AE to study product:  
Is there a reasonable possibility that the study product caused the event? 
Reasonable possibility implies there is evidence to suggest that the study product caused the 
reported event. An affirmative answer designates the event as a suspected adverse reaction, and 
the AE is considered “related”. If the answer is no, then the AE is considered “unrelated”. 
The causality assessment is made on the basis of the available information at the reporting time 
point. Assessment of causality can change according to follow-up information. 
8.6. 
Assessment of Outcome of Adverse Event  
The outcome of adverse event will be assessed as at the time of last observation as per the 
following categories:  
 
Recovered/resolved without sequelae  
 
Recovered/resolved with sequelae 
 
Ongoing at the end of the study 
 
Death 
 
Unknown. The outcome of the AE is not known 
8.7. 
Adverse Event Identification, Resolution and Reporting 
To improve the quality and precision of acquired AE data, the PI should observe the following 
guidelines: 
 
Whenever possible, use recognized medical terms when recording AEs on the AE CRF. 
Do not use colloquialisms and/or abbreviations. 
 
If known, record the diagnosis (i.e., disease or syndrome) rather than component signs, 
symptoms and laboratory values on the AE CRF (e.g., record congestive heart failure 
rather than dyspnea, rales, and cyanosis). However, signs and symptoms that are 
considered unrelated to an encountered syndrome or disease should be recorded as 
individual AEs on the CRF (e.g., if congestive heart failure and severe headache are 
observed at the same time, each event should be recorded as an individual AE). 

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 
AEs occurring secondary to other events (e.g., sequelae) should be identified by the 
primary cause. A “primary” AE, if clearly identifiable, generally represents the most 
accurate clinical term to record on the AE CRF. If a primary serious AE (SAE) is recorded 
on an SAE CRF, events occurring secondary to the primary event should be described in 
the narrative description of the case. 
 
For example: 
Orthostatic 
hypotension 
 
Fainting and 
fall to floor 
 
Head 
trauma 
 
Neck pain 
The primary AE is orthostatic hypotension. 
 
Grade 2 or higher abnormal laboratory test results will be reported as AEs and assessed 
for severity according to severity grading criteria provided in Appendix II and causality 
(related or unrelated) to the study product. Grade 1 abnormal laboratory test results will 
be entered as AEs if the site PI determines them to be clinically significant. 
 
Death is an outcome of an event. The event that resulted in the death should be recorded 
and reported on the SAE CRF. 
 
For hospitalizations for surgical or diagnostic procedures, the illness leading to the surgical 
or diagnostic procedure should be recorded as the SAE, not the procedure itself. The 
procedure should be captured in the case narrative as part of the action taken in response 
to the illness. 
 
Pregnancies that occur in study participants are not considered AEs and will be recorded 
on a separate Pregnancy CRF. Pregnancy outcomes that include stillbirth and any 
congenital anomalies must be reported as SAEs. 
AEs may be discovered through any of these methods. 
 
Observing the participant. 
 
Questioning the participant, which should be done in an objective manner. 
 
Receiving an unsolicited complaint from the participant. 
 
Review of medical records/source documents. 
Each participant will have a scheduled observation following vaccination, including a symptom-
directed physical examination, if indicated. They will be monitored in-house for 60 minutes after 
vaccination. On Days 1 to 7 after vaccination, participants will be instructed to assess and record 
daily in a participant memory aid any signs and symptoms at the injection site, as well as systemic 
signs and symptoms. Follow-up visits will be conducted seven days after vaccination, including 
directed assessment, safety tests and verification of memory aid notes. They will be instructed to 
call the study team if they observe significant injection site or systemic signs or symptoms, and 
then to continue monitoring and reporting their condition. All participants will be followed for safety 
for six months after the vaccination. 

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8.7.1. 
AE Resolution 
All reported AEs should be followed until resolution or stabilization, or until the participant’s 
participation in the study ends. Participants who have an ongoing study product-related SAE at 
study completion or at discontinuation from the study will be followed by the PI or his designee 
until the event is resolved or determined to be irreversible, chronic, or stable by the PI. 
8.7.2. 
General Recording and Reporting Procedures 
A multi-page AE/SAE form set will be used allowing all AEs to be submitted through a single 
reporting mechanism. SAEs will require additional information reported on additional pages within 
the Internet data entry system. As appropriate or per request of the Emmes medical monitor or 
Sponsor medical officer, source documents (e.g., hospitalization discharge summaries) may be 
uploaded to the AE/SAE form set as well. The PI will treat or refer, as appropriate, participants 
experiencing AEs and observe them at suitable intervals until their symptoms resolve or their 
status stabilizes. 
8.7.3. 
SAE Recording and Reporting Procedures 
SAEs will be recorded on the AE CRF. The site is obligated to report SAEs to the Emmes 
Coordinating Center within 24 hours of the site’s knowledge of the event. The Emmes 
Coordinating Center will in turn pass on that information to Sponsor and SIIPL.  
The following attributes will be assigned by the PI or assignment by designee will undergo 
documented review by the PI:  
 
Description 
 
Date of onset and resolution (if known when reported) 
 
Severity 
 
Assessment of relatedness to test article  
 
Action taken 
 
 

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8.7.4. 
Site Reporting of Events 
Figure 3: Reporting Decisions for Adverse Events 
 
 
Notify the PI. 
 
Complete and transmit an AE Form through the Internet data entry system. Information 
regarding a SAE report must be recorded in the participant’s medical chart and entered in 
the Internet data entry system. 
 
SAE follow-up reports should include hospital admittance notes, hospital discharge 
summary, clinical notes, resolution date, treatment, and any other pertinent information 
regarding the event. If not immediately available, reporting should not be delayed to 
provide these documents. 
 
In the event of a death, the SAE Form must be completed and transmitted along with other 
supporting data (e.g., death certificate, medical notes). 
 
 
No 
Yes 
Safety Event requiring AE Form Submission: 
All adverse events and all serious adverse events 
SAE? 
Expedited Reporting 
(Within 24 hours) 
Use the Serious Adverse Event Form 
Submit to Emmes Coordinating Center 
(also notify ethics board/IRB as per 
ethics board/ IRB guidelines) 
Standard Reporting 
(Within 5 to 7 days) 
Use the Adverse Event Form and 
other CRFs 
Submit to Emmes Coordinating Center 

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8.8. 
Serious Adverse Event Notification 
8.8.1. 
Notifications and Review 
The PI will provide the Emmes Coordinating Center with data for all SAEs, as defined per the 
protocol, on a timely manner by entering the information in AdvantageEDC. The Emmes 
Coordinating Center is responsible for notifying the Sponsor and will do so simultaneously with 
the reporting to the clinical database. Notification of reported events will be generated at the time 
of entry into the data system, and all SAEs will be reviewed promptly by the Emmes medical 
monitor within the data system. As noted above, this notification should be within 24 hours of site 
awareness of the event. Site personnel will be trained in reporting AEs and SAEs.  
The Emmes medical monitor will review all unanticipated events involving risk to participants or 
others, SAEs and all participant deaths associated with the protocol and will provide a written 
report. At a minimum, the Emmes medical monitor must comment on the outcomes of the event 
or problem and, in case of an SAE or death, comment on the relationship to participation in the 
study. The Emmes medical monitor must also indicate whether he/she concurs with the details of 
the report provided by the PI. 
Summary review of all reported AEs and SAEs will be compiled on a weekly basis to identify any 
safety trends. Review of safety laboratory tests will also be conducted on a weekly basis. 
8.8.2. 
Expedited Reporting 
The Emmes Coordinating Center will be responsible for expedited IND Safety Reports and IND 
Annual reports to the FDA.  
When expedited reports as defined below are required, the cover memorandum, MedWatch Form 
FDA 3500A, and any pertinent attachments will be processed by the Emmes medical monitor and 
a copy of the completed report will be submitted by fax or courier delivery before the regulatory 
reporting deadline, to the following persons: 
 
FDA medical officer as appropriate (submitted as an amendment to the applicable 
IND) 
 
PI (who is responsible for forwarding the report to the local/central IRB) 
 
Safety Review Committee members 
If relevant follow-up information becomes available, the Emmes medical monitor will be 
responsible for obtaining and reviewing details from the site. A follow-up MedWatch form will be 
completed and forwarded to all parties that received the earlier SAE report. A copy of the safety 
sections for annual FDA reports will be forwarded to PATH.  
Suspected adverse reactions that are serious and unexpected will be reported to the FDA within 
15 days, or for deaths and life threatening events that are both suspected adverse reactions and 
unexpected, within 7 days (per 21 CFR 312.32). The IND Safety Report will be unblinded to 
treatment allocation and determination of relationship to study product based on the assessment 
of the sponsor.  

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Subsequent review by the FDA, the SRC, IRB, or the Sponsor may suspend further study product 
administration or procedures. The FDA and the study Sponsor with consultation with the SRC 
retain the authority to suspend additional enrollment for the entire study as applicable. 
8.8.3. 
Notifying the Safety Review Committee 
The Emmes Coordinating Center will provide the SRC with listings of all SAEs on an ongoing 
basis. Furthermore, the SRC will be informed of expedited reports of SAEs. 
8.8.4. 
Notifying the Institutional Review Board 
The PI will ensure the timely dissemination of required AE information, including expedited 
reports, to the IRB in accordance with applicable local regulations and guidelines. The PI is 
responsible for submitting the IND Safety Report (initial and follow up SAE reports) or other safety 
information (e.g., revised IB) to the site’s IRB and for retaining a copy in the site’s study file. 
University of Maryland, Baltimore (UMB) IRB 
Using the same criteria above, any qualifying SAE will be reported to the UMB IRB, as a reportable 
new information event and within five business days. The contact information for the UMB IRB is 
as follows: 
University of Maryland, Baltimore 
Human Research Protections Office 
Lexington Building 
620 West Lexington Street, Second Floor 
Baltimore, MD 21201 
410-706-5037 
9. SAFETY MONITORING 
Extensive safety monitoring will be provided for this protocol. The PI and/or designated site staff 
will be responsible for continuous close safety monitoring of all study participants and for alerting 
the Sponsor if unexpected concerns arise or pause criteria are met. 
9.1. 
Safety Review Committee 
A Safety Review Committee, comprised of the PI, a medical expert with experience in vaccine 
pharmacovigilance not involved with the study, the Emmes medical monitor, SIIPL and PATH 
medical officer will monitor safety throughout the duration of the study. The Emmes study 
statistician with assistance of the data management staff will prepare safety reports as needed 
for SRC discussions. During the vaccination period the SRC will review weekly the safety data. 
At any time during the study, the Emmes Coordinating Center will notify the SRC of ad hoc review 
if pause criteria may have been met. The SRC reviews will be summarized with consensus 
recommendations to the study Sponsor as to whether there are safety concerns and whether the 
study should continue without change, be modified, or be stopped. The SRC may request review 
of unblinded safety data by the pharmacovigilance expert in its deliberation. SRC consensus 
recommendations regarding modifying or stopping further enrolment may involve Sponsor 
consultation with the local regulatory authority. 

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The SRC members must be satisfied that the timelines, completeness, and accuracy of the data 
submitted to them for review are sufficient. Items reviewed by the SRC may include: study 
participant demographic information; interim/cumulative data for evidence of study-related 
AEs; data quality, completeness, and timeliness; and factors external to the study, such as 
scientific or therapeutic developments that may impact participant safety or the ethics of the study. 
If at any time, a decision is made to discontinue administration of study product in all participants, 
expeditious notification will be provided by the sponsor to the US FDA and by the PI to the site 
IRB.  
9.2. 
Study Pause Rule 
The following study pause rules will automatically pause or halt further vaccinations. However 
participants already enrolled will continued to be followed for safety during the pause. These 
pause rules refer to suspected adverse reactions and will be triggered automatically if any of the 
event described below are met during the conduct of the study: 
 
One or more participants experience a serious adverse reaction. 
 
One or more participants experience a Grade 4 injection site reaction. 
 
Two or more participants experience the same Grade 3 injection site reaction. 
 
Two or more participants with the same severe (Grade 3) systemic reactogenicity signs or 
symptoms, within seven days following vaccination. 
 
Two or more participants experience the same vaccine-related Grade 3 or higher clinical 
(including fever) or laboratory abnormality. 
9.2.1. 
Pause Procedure 
 
The SRC will be notified by the Emmes Coordinating Center and convene ad hoc review 
if pause criteria may have been met. 
 
At scheduled study review, the SRC may also identify adverse events that could potentially 
qualify as pause criteria. 
 
If the PI (or designee), the Emmes medical monitor or any member of the SRC identifies 
that a pause criterion may have been met or propose the study be paused on a 
discretionary basis, all vaccinations and enrollment will be suspended. The SRC will be 
notified and will expeditiously (within 48 hours) convene to review all available, relevant 
information. The SRC may request review of unblinded safety data by the 
pharmacovigilance expert, The SRC reviews will be summarized with consensus 
recommendations to the study Sponsor as to whether there are safety concerns and 
whether the study should continue without change, be modified, or be stopped. 
 
If at any time, a decision is made to discontinue administration of study product in all 
participants, expeditious notification will be provided by the Sponsor to the US FDA and 
by the PI to the IRB within 48 hours. 
 
If the Sponsor re-starts the study after SRC review and recommendation, enrollment and 
vaccination may resume.  

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10. 
DATA MANAGEMENT 
The PI is responsible for ensuring the accuracy, completeness, and timeliness of the data 
reported. Data collection is the responsibility of the clinical trial staff at the study site under the 
supervision of the study PI. The Emmes Corporation is responsible for data management 
activities, including quality review, analysis, and reporting of the study data according to Standard 
Operations Procedure (SOP). 
10.1. Case Report Form Development and Completion 
Electronic Data Capture will be the method of data collection in this study. The electronic Case 
Report Forms (eCRFs) will be developed by the Emmes Corporation and approved by SIIPL and 
PATH. Clinical data (including AEs, concomitant medications, and reactogenicity data) and 
clinical laboratory data will be entered into the 21 CFR Part 11-compliant Internet Data Entry 
System (IDES) provided by The Emmes Corporation. The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that 
appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents.  
Data for each participant will be recorded in the eCRF. It is the PI’s responsibility to ensure the 
accuracy, completeness, legibility, and timeliness of the data reported in the participant’s eCRF 
and any supporting documentation. All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation of data. Source documentation supporting the eCRF 
data should indicate the participant’s participation in the study and should document the dates 
and details of study procedures, AEs and the participant’s status. The PI/institution will maintain 
all information in the eCRFs and all source documents that support the data collected from each 
participant. 
The PI or designated representative should complete the eCRFs as soon as possible but within 
three days after information is collected. Completed eCRFs must be submitted for each screened 
participant who signs the study-specific ICF. The eCRFs will not be completed for participants 
who do not sign the study specific ICF. The PI will retain all essential documents. 
10.2. Details of Data Management 
A Data Management Handbook (DMH) will be written by The Emmes Corporation and contain all 
study-specific requirements.  
10.2.1. 
Coding 
The PI is responsible for ensuring the accuracy, completeness, and timeliness of the data 
reported. Data collection is the responsibility of the clinical trial staff at the study site under the 
supervision of the study PI. The Emmes Corporation is responsible for data management 
activities, including quality review, analysis, and reporting of the study data according to SOPs. 

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10.2.2. 
Data Validation 
The Emmes Corporation will inspect the data entered into the database for completeness and 
consistency.  
10.2.3. 
Source Data Verification 
For source data verification (SDV), the monitor (on behalf of the study Sponsor) must have direct 
access to source documents that support the data recorded, e.g., medical records, original 
laboratory records and ICFs. If source data are electronic, these data must be printed, signed and 
dated by the PI and stored in the participant’s study file. Clinical laboratory data will remain in 
study participant records. Essential documents, including ICFs, must be filed and kept in the study 
files on an ongoing basis. 
10.2.4. 
Definition of Source Data 
Source data are all information in original records or certified copies of original records of clinical 
findings, observations, or other activities in a clinical study. Source data are contained in source 
documents.  
10.2.5. 
Definition of Source Document 
Original source documents include data and records, e.g., hospital records, medical notes, 
laboratory notes, evaluation checklists, pharmacy dispensing records, records kept at the 
pharmacy and at the laboratory, documentation of shipments. Note that, for this protocol, the 
volunteer participant data collection tool (i.e., the Memory Aid) is not considered a source 
document. Data reported in the eCRF derived from source documents should be consistent with 
the source documents or the discrepancies should be explained. 
10.3. Database Locking Procedures 
 
A final database lock for the primary analysis will occur after all participants have 
completed all follow-up visits, a case-by-case review of the severity of any AEs has been 
performed and finalized, all data anomalies have been resolved and monitoring is 
complete.  
 
Remaining immunology data will be maintained in a separate immunology database.  
10.4. Record Archival 
The PI is responsible for retaining study records for a period of two years following the date that 
a marketing application is approved for the product or, if no application is to be filed or, if a file 
application is not approved, until two years after the investigation is discontinued and the FDA is 
notified. The Sponsor will be responsible for providing the site with date of vaccine approval or 
IND withdrawal. 
These records are also to be maintained in compliance with IRB, state, and federal medical 
records retention requirements, whichever is longest. Storage of all trial-related documents will 
be such that confidentiality will be strictly maintained to the extent provided by federal, state, and 
local law.  

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10.5. Screen Failures 
If a participant signs the study-specific ICF, but is not randomized because of non-eligibility (a 
screen failure), the reason for his/her non-eligibility should be entered in the medical 
records/notes/charts. Also, a screening log must be kept. Data from participants who fail 
screening will not be recorded in the eCRF, with the exception of demographic data and the 
reason for screen fail.  
10.6. Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or site SOP 
requirements. The noncompliance may be either on the part of the participant, the PI, or the study 
site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly.  
These practices are consistent with ICH E6: 
 
Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3. 
 
Quality Assurance and Quality Control, Section 5.1.1. 
 
Noncompliance, Sections 5.20.1 and 5.20.2. 
It is the responsibility of the site to exercise continuous vigilance to identify and report deviations 
within five working days after identification of the protocol deviation, or within five working days of 
the scheduled protocol-required activity. All deviations must be promptly reported to Emmes and 
sponsor via the appropriate eCRF within the electronic data system.  
All deviations from the protocol must be addressed in study participant source documents. 
Protocol deviations must be sent to UMB IRB per its guidelines. The site PI/study staff is 
responsible for knowing and adhering to UMB IRB’s requirements. 
11. STUDY MONITORING 
Sponsor monitoring responsibilities will be provided by The Emmes Corporation. A site initiation 
visit will be conducted prior to beginning the study, and monitoring will be conducted at initiation, 
during, and at closeout of the study by the study monitor or designee.  
During the course of the study, the Emmes monitor will visit the clinical site at intervals to verify 
compliance to the protocol; check for completeness, accuracy, and consistency of the data and 
study product accountability; adherence to CFR, and any additional regulations and requirements, 
including GCP, of the conduct of clinical research. The monitor should have access to participant 
medical records, study product accountability and other study-related records needed to verify 
the entries on the eCRFs. 
The PI and the monitor must agree to cooperate to ensure that any problems detected in the 
course of these monitoring visits, including eCRF completion and query resolution, are resolved 
in a predefined timeframe.  

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To ensure the quality of clinical data across all participants at the site, a clinical data management 
review will be performed on volunteer data received at The Emmes Corporation. During this 
review, participant data will be checked for consistency, omissions, and any apparent 
discrepancies. In addition, the data will be reviewed for adherence to the protocol and GCP. To 
resolve any questions arising from the clinical data management review process, data queries 
and/or site notifications will be sent to the site for resolution prior to the site’s last monitoring close-
out visit. 
Essential documents must be filed in the site study file on an ongoing basis and available for 
review by the Emmes monitor. Monitoring visits will be performed according to the Clinical 
Monitoring Plan. 
11.1. Independent Auditing 
The SIIPL or PATH representatives may audit the study to ensure that study procedures and data 
collected comply with the protocol and applicable SOPs at the clinical site and The Emmes 
Corporation, and that data are correct and complete. The PI will permit auditors (employees of 
the Sponsor or an external company designated by the Sponsor) to verify source data validation 
of the regularly monitored clinical study. The auditors will compare the entries in the eCRFs with 
the source data and evaluate the study site for its adherence to the clinical study protocol and 
GCP guidelines and applicable regulatory requirements. 
11.2. Regulatory Agency Auditing 
The PI must be aware that representatives from regulatory authorities or the IRB may wish to 
inspect the eCRFs and associated study records. The PI will notify the Sponsor within 24 hours 
following contact by a regulatory agency. The PI and study coordinator must make the relevant 
records available for inspection and will be available to respond to reasonable requests and audit 
queries made by authorized representatives of regulatory agencies. The PI will provide the 
Sponsor with copies of all correspondence that may affect the review of the current study or his 
qualification as an investigator in clinical studies conducted by the Sponsor. The Sponsor will 
provide any needed assistance in responding to regulatory audits or correspondence. 
12. OBLIGATIONS AND ROLES OF THE SPONSOR, PI AND STUDY PERSONNEL 
This study will be conducted according to GCP and in accordance with all federal regulations 
regarding the protection of human participants in research including US 21 CFR Part 50 and US 
21 CFR Part 312. The PI agrees to perform the research in strict accordance with this protocol, 
the International Council for Harmonisation (ICH) Guideline for Good Clinical Practice (E6), as 
well as in conformity with any federal, state, or local regulations regarding the conduct of clinical 
studies. 
In addition, the PI must follow local and institutional requirements including, but not limited to, 
investigational product, clinical research, informed consent and IRB regulations. The Sponsor will 
provide notification to the PI of protocol and amendment approvals by regulatory authorities when 
applicable. Any modifications to the research protocol, the ICF, and/or the questionnaires or 
change in PI must be submitted to UMB IRB for review and approval prior to implementation. The 

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PI may deviate from the protocol without prior approval only when the deviation is necessary to 
eliminate an apparent immediate hazard to the participant.  
The PI will notify UMB IRB of SAEs and protocol deviations according to UMB IRB requirements. 
Any deviation to the protocol that may have an effect on the safety or rights of the participant, or 
the integrity of the study, must be reported to the Sponsor by the PI as soon as the deviation is 
identified. In that event, the PI will notify the Emmes/Sponsor immediately by phone, notify UMB 
IRB, enter the deviation into the appropriate eCRF, and confirm notification to the Sponsor in 
writing within ten working days after the change is implemented. All deviations will be noted in the 
continuing review report to and UMB IRB, the annual report to the Sponsor, and in the final study 
report for and UMB IRB. 
Except where the PI's signature is specifically required, it is understood that the term "investigator" 
as used in this protocol and on the eCRFs refers to the PI or appropriate study personnel that the 
PI designates to perform a certain duty. The PI is ultimately responsible for the conduct of all 
aspects of the study. Sub-investigators or other appropriate study personnel are eligible to sign 
for the PI on designated eCRFs. 
The Emmes medical monitor will be responsible for reviewing all serious and unexpected AEs 
and providing an unbiased written report of the event. 
13. 
ETHICAL CONSIDERATIONS AND INFORMED CONSENT 
13.1. Informed Consent Process 
Before any study-related activities and in agreement with applicable regulatory requirements, the 
PI must ensure that the participant is fully informed about the aims, procedures, potential risks, 
and potential benefits of the study. The participant will be given the written, IRB approved ICF, 
allowed ample time to read the consent form, encouraged to ask questions about the study, have 
the questions answered and then be given time to decide if s/he would like to participate in the 
study. It will be emphasized that participation is voluntary, and that the participant has the right to 
withdraw from the study at any time without prejudice. 
The PI or designee must obtain the participant’s voluntary, personally signed and dated ICF 
before any study-related procedures. The original, signed ICF must be kept in the site study file.  
13.2. Risk/Benefit 
No benefits can be guaranteed to participants for their participation in this research study. 
Risks from Vaccine 
As with all injectable vaccines, appropriate medical treatment and supervision should always be 
readily available in case of a rare anaphylactic event following the administration of the vaccine. 
The mainstay in the treatment of severe anaphylaxis is the prompt use of adrenaline, which can 
be lifesaving.  

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Post vaccination, the participant should remain under the observation of not less than 60 minutes 
for occurrences of immediate or early allergic reactions. Corticosteroids and antihistaminics 
should also be available in addition to supportive measures such as oxygen inhalation and 
intravenous fluids (IV fluids).  
This being a Phase 1 trial there is no safety data available with the use of MCV-5 vaccine. This 
trial aims to generate the same.  
In clinical trials of Menactra®, most commonly reported injection site reactions following 
vaccination among adults were injection site pain (53.9%), induration (17.1%), redness (14.4%) 
and swelling (12.6%). In the same population, commonly reported systemic reactions were 
headache (41.4%), fatigue (34.7%), malaise (23.6%), arthralgia (19.8%), diarrhea (16.0%) and 
anorexia (11.8%), chills (9.7%) and vomiting (2.3%). All these are the frequencies reported within 
seven days of single vaccine dose. SAEs occurred in these individuals at a rate of 1.0% following 
Menactra® vaccine.23 
It is expected that the solicited reactions with adjuvanted and non-adjuvanted MCV-5 would be 
consistent with those reported in clinical trials of Menactra®. 
Risks from blood draw 
Drawing peripheral blood can cause discomfort; it might cause minor bleeding and/or bruising 
where the needle enters the skin, and very rarely might cause infection. This risk will be mitigated 
by ensuring that only study staff members who are adequately trained in safe drawing of blood 
conduct this portion of the study. It is not anticipated that the risks in any one of the vaccine groups 
would be higher than others. 
Risks from participating in a clinical trial 
In addition to the risks described above, all clinical trial participants are likely to experience 
increased inconvenience due to the visits as they may be of longer duration than standard 
treatment, which might cause more anxiety. They also incur additional risks to their privacy from 
participating in a clinical trial. This risk will be minimized by ensuring that participant confidentiality 
is maintained by enforcing appropriate data collection, storage, and analysis techniques and 
employing the use of unique identifiers with carefully stored linking files. There may be additional 
risks to study trial participation that we do not know about. 
13.3. Protocol Review Process 
Scientific review of this protocol will be conducted by PATH, the sponsor of the study. The protocol 
will be submitted under a new IND. Protocol ethical review and oversight will be performed by 
UMB IRB. Continuing review will be undertaken in accordance with existing regulations. The 
Sponsor will be responsible for trial registration at ClinicalTrials.gov. 
Copies of the approved continuing review and final study reports, along with the respective local 
IRB approval notifications, will be submitted to the Sponsor as soon as these documents become 
available. 

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13.4. Participant Confidentiality 
The PI must ensure that participant confidentiality is maintained. Personal identifiers will not be 
included in any study reports. All study records will be kept confidential to the extent provided by 
national and local laws.  
All study procedures will be conducted per GCP guidelines, and every effort will be made to 
protect participant privacy and confidentiality to the extent possible.  
All study-related information will be stored securely at the study site or at a designated, secure 
off-site location. When not in use and under immediate control of study staff, all participant 
information will be stored in locked areas with access limited to study staff. Data collection, 
process, and administrative forms, laboratory specimens, and other reports will be identified 
exclusively by a coded number to maintain participant confidentiality. All local databases will be 
secured with password-protected access systems. Participants’ study information will not be 
released without their written permission, except as necessary for monitoring or compliance with 
legal or regulatory requirements. 
Medical records containing identifying information may be made available for review when the 
study is monitored by the sponsor or an authorized regulatory agency. Direct access may include 
examining, analyzing, verifying, and reproducing any records and reports that are important to 
the evaluation of the study. 
13.5. Reimbursement 
Pending IRB approval, participants will be compensated for their time and effort in this study, and 
be reimbursed for travel to study visits. The study ICF will state the plan for reimbursement. Study 
participants will not be charged for study vaccinations, research clinic visits, research-related 
examinations, or research-related laboratory tests. 
13.6. Storage of Specimens 
Stored study research samples (including samples retained for elective analysis) will be labeled 
by a code that only the study site can link to the participant. All stored research samples will be 
logged into a secure database and any use documented. Samples may be stored at several 
different repositories and laboratories to complete the analyses required to meet study primary, 
secondary and exploratory analyses. As a part of the informed consent process, participants will 
be informed of and asked to agree to long-term storage of specimens for use in future, related 
research. 
 
 

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14. 
APPENDICES 
14.1. APPENDIX I: Schedule of Events 
Study visit 
Visit 1 / 
screening 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Final 
Study 
Contact 
Study Day 
D-28 to-1 
D1 
D8+3 
D29+14 
D85+14 
D180±21 
Informed Consent 
√ 
- 
- 
- 
- 
- 
Demographics 
√ 
 
 
 
 
 
Medical history 
√ 
√A 
√A 
√A 
√A 
√ 
(For SAEs) 
Prior and concomitant 
medications 
√ 
√ 
√ 
√ 
√ 
(For SAEs) 
√ 
(For SAEs) 
Physical examination 
√ 
√B 
√B 
√B 
√B 
- 
Pregnancy test F  
(female only) 
√ 
√ 
 
√ 
√ 
- 
Vital signs 
√ 
√ 
√ 
√ 
√ 
- 
Safety laboratory 
evaluationC 
10 mL 
- 
8 mL 
- 
- 
- 
Screening for HIV, 
hepatitis B and CD 
8 ml 
 
 
 
 
- 
Eligibility criteria 
√ 
√ 
- 
- 
- 
- 
Randomization of 
eligible participants 
- 
√ 
- 
- 
- 
- 
Vaccination 
- 
√ 
- 
- 
- 
- 
Visual inspection of 
injection site 
 
√ 
√ 
 
 
- 
Memory card review 
and collection 
- 
√ 
√ 
 
- 
- 
Observe for 60 minutes: 
Assess and record post 
vaccine reactions 
- 
√ 
- 
- 
- 
- 
Immunogenicity Blood 
collection 
- 
20 mLE 
 
30 mL 
- 
- 
Cumulative blood 
volume 
18 mL 
20 mL 
8 mL 
30 mL 
 
 
Adverse event 
reporting 
 
Solicited local and 
systemic reactions 
 
 
Adverse Events 
 
 
Serious Adverse Events 
A. Updated medical history only 
B. Targeted physical examination, as indicated 
C. Complete blood count (CBC): WBC, Hemoglobin, Platelets, Chemistry panel: ALT, Creatinine, Albumin, Total bilirubin 
D. HBsAg, anti-HCV (if positive, by PCR), HIV EIA 
E. Before vaccination 
F. Only in case of female participants with child bearing potential. At the time of screening a serum pregnancy test will be 
performed whereas on the day of vaccination, urine or serum pregnancy test will be performed  
 
 

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14.2. APPENDIX II: Toxicity Grading Scale 
 
 

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14.3. APPENDIX III: References 
 
Reference List 
 
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Drug Resist 2014;7:85-99. 
 3.  Harrison LH, Trotter CL, Ramsay ME. Global epidemiology of meningococcal disease. Vaccine 
2009;27 Suppl 2:B51-B63. 
 4.  Meningococcal vaccines: WHO position paper, November 2011. Wkly Epidemiol Rec 
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 5.  Molesworth AM, Thomson MC, Connor SJ et al. Where is the meningitis belt? Defining an area at 
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Meningococcal Serogroups A, C, W-135 and Y Tetanus Toxoid Conjugate Vaccine (MenACWY-TT) 
Administered to Adults Aged 56 Years and Older: Results of an Open-Label, Randomized, 
Controlled Trial. Drugs Aging 2013;30(5):309-319. 
 8.  Stephens DS. Conquering the meningococcus. FEMS Microbiol Rev 2007;31(1):3-14. 
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Philos Trans R Soc Lond B Biol Sci 2013;368(1623):20120147. 
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of serogroup A vaccination in the African meningitis belt. Vaccine 2013;31(11):1453-1457. 
 11.  Harrison LH. Prospects for vaccine prevention of meningococcal infection. Clin Microbiol Rev 
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 12.  Poolman J, Borrow R. Hyporesponsiveness and its clinical implications after vaccination with 
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 13.  Cohn AC, MacNeil JR, Clark TA et al. Prevention and control of meningococcal disease: 
recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm 
Rep 2013;62(RR-2):1-28. 
 14.  Balmer P, Borrow R, Miller E. Impact of meningococcal C conjugate vaccine in the UK. J Med 
Microbiol 2002;51(9):717-722. 
 15.  Sow SO, Okoko BJ, Diallo A et al. Immunogenicity and safety of a meningococcal A conjugate 
vaccine in Africans. N Engl J Med 2011;364(24):2293-2304. 
 16.  Borrow R, Tang Y, Yakubu A, Kulkarni PS, LaForce FM. MenAfriVac as an Antitetanus Vaccine. 
Clin Infect Dis 2015;61 Suppl 5:S570-S577. 

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 17.  Frasch C, Preziosi MP, LaForce FM. Development of a group A meningococcal conjugate vaccine, 
MenAfriVac (TM). Hum Vaccin Immunother 2012;8(6). 
 18.  Kshirsagar N, Mur N, Thatte U et al. Safety, immunogenicity, and antibody persistence of a new 
meningococcal group A conjugate vaccine in healthy Indian adults. Vaccine 2007;25(Supplement 
1):A101-A107. 
 19.  Hirve S, Bavdekar A, Pandit A et al. Immunogenicity and safety of a new meningococcal A 
conjugate vaccine in Indian children aged 2-10 years: a phase II/III double-blind randomized 
controlled trial. Vaccine 2012;30(45):6456-6460. 
 20.  Kristiansen PA, Diomande F, Ba AK et al. Impact of the serogroup A meningococcal conjugate 
vaccine, MenAfriVac, on carriage and herd immunity. Clin Infect Dis 2013;56(3):354-363. 
 21.  Kristiansen PA, Ba AK, Ouedraogo AS et al. Persistent low carriage of serogroup A Neisseria 
meningitidis two years after mass vaccination with the meningococcal conjugate vaccine, 
MenAfriVac. BMC Infect Dis 2014;14:663. 
 22.  LaForce FM, Okwo-Bele JM. Eliminating epidemic Group A meningococcal meningitis in Africa 
through a new vaccine. Health Aff (Millwood) 2011;30(6):1049-1057. 
 23.  Okwo-Bele JM, LaForce FM, Borrow R, Preziosi MP. Documenting the Results of a Successful 
Partnership: A New Meningococcal Vaccine for Africa. Clin Infect Dis 2015;61 Suppl 5:S389-S390. 
 24.  Novak RT, Kambou JL, Diomande FV et al. Serogroup A meningococcal conjugate vaccination in 
Burkina Faso: analysis of national surveillance data. Lancet Infect Dis 2012;12(10):757-764. 
 25.  Nimenrix Product Information. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002226/WC500127663.pdf. 9-2-2015. 4-4-2016.  
Ref Type: Online Source 
 26.  Menactra Package Insert. 
http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM131170.pdf. 
Food. 2016. 4-4-2016.  
Ref Type: Online Source 
 27.  Menveo Package Insert. 
http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM201349.pdf. 
2016. 4-4-2016.  
Ref Type: Online Source 
 28.  Ali A, Jafri RZ, Messonnier N et al. Global practices of meningococcal vaccine use and impact on 
invasive disease. Pathog Glob Health 2014;108(1):11-20. 
 29.  Nadel S. Prospects for eradication of meningococcal disease. Arch Dis Child 2012;97(11):993-998. 
 30.  Trumenba Package Insert. 
http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM421139.pdf. 
2016. 4-4-2016.  
Ref Type: Online Source 
 31.  Bexsero Package Insert. 
http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM431447.pdf. 
2016. 4-4-2016.  
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 32.  Folaranmi T, Rubin L, Martin SW, Patel M, MacNeil JR. Use of Serogroup B Meningococcal 
Vaccines in Persons Aged >/=10 Years at Increased Risk for Serogroup B Meningococcal Disease: 
Recommendations of the Advisory Committee on Immunization Practices, 2015. MMWR Morb 
Mortal Wkly Rep 2015;64(22):608-612. 
 33.  Jafri RZ, Ali A, Messonnier NE et al. Global epidemiology of invasive meningococcal disease. Popul 
Health Metr 2013;11(1):17. 
 34.  Sow SO, Okoko BJ, Diallo A et al. Supplementary Appendix to: Immunogenicity and safety of a 
meningococcal A conjugate vaccine in Africans. N Engl J Med 2011;364:2293-304. 2016. 4-4-2016.  
Ref Type: Online Source 
 35.  Meningococcal Vaccine Information Statements. http://www.cdc.gov/vaccines/hcp/vis/vis-
statements/mening.html. 2016. 4-4-2016.  
Ref Type: Online Source