A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study to Evaluate the Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium Hydroxide Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy Adults (18-45 Years of Age).
Phase: PHASE1
Conditions: Infections, Meningococcal
Sponsor: GlaxoSmithKline

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CLINICAL STUDY PROTOCOL V132_01EXP Version 1 
A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study to Evaluate the 
Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R Adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium Hydroxide  
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy Adults (18-45 
years of age) 
EUDRACT No. 2014-002430-31 
Property of Novartis Vaccines and Diagnostics (hereafter referred to as Novartis) 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of Novartis. 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................... 1 
PROTOCOL SYNOPSIS V132_01EXP ............................................................................. 7 
LIST OF ABBREVIATIONS ............................................................................................ 30 
1.0  BACKGROUND AND RATIONALE ....................................................................... 31 

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1.1  Background ............................................................................................................. 31 
1.2  Rationale ................................................................................................................. 35 
2.0  OBJECTIVES ............................................................................................................. 36 
2.1  Primary Objectives ................................................................................................. 36 
2.2  Secondary Objectives ............................................................................................. 36 
2.3  Exploratory Objectives ........................................................................................... 36 
3.0  STUDY DESIGN ....................................................................................................... 38 
3.1  Overview of Study Design...................................................................................... 38 
3.2  Study Period ........................................................................................................... 39 
3.3  Blinding Procedures................................................................................................ 39 
3.4  Data Collection ....................................................................................................... 40 
3.4.1  Data Collected from Subjects .......................................................................... 40 
3.4.2  Tools Used for Data Collection ....................................................................... 40 
3.5  Collection of Clinical Specimens ........................................................................... 42 
3.6  Stopping/Pausing Guidelines .................................................................................. 44 
3.7  Data Monitoring Committee ................................................................................... 45 
3.8  Premature Withdrawal from Study ......................................................................... 45 
3.9  End of Study ........................................................................................................... 48 
4.0  SELECTION OF STUDY POPULATION ................................................................ 49 
4.1  Inclusion Criteria .................................................................................................... 49 
4.2  Exclusion Criteria ................................................................................................... 49 
4.3  Criteria for Delay of Vaccination or Blood Draw .................................................. 51 
5.0  STUDY PROCEDURES ............................................................................................ 52 
5.1  Pre-vaccination Clinic Visit(s) ............................................................................... 52 
5.1.1  Informed Consent ............................................................................................. 52 
5.1.2  Screening .......................................................................................................... 53 
5.2  Vaccination Clinic Visit(s) ..................................................................................... 54 

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5.2.1  Pre-vaccination Procedures .............................................................................. 54 
5.2.2  Enrolment ......................................................................................................... 55 
5.2.3  Randomization ................................................................................................. 56 
5.2.4  Vaccination ...................................................................................................... 56 
5.2.5  Post-vaccination Procedures ............................................................................ 56 
5.3  Post-vaccination Visit(s) ......................................................................................... 57 
Draw Clinic Visits ...................................................................................................... 58 
5.3.2  Safety Follow-up Calls ..................................................................................... 61 
5.4  Unscheduled Visits ................................................................................................. 62 
5.5  Study Termination Visit ......................................................................................... 62 
5.5.1  Early Termination Visit ................................................................................... 63 
6.0  TREATMENT OF SUBJECTS .................................................................................. 64 
6.1  Study Vaccine(s) ..................................................................................................... 64 
6.2  Non-Study Vaccines ............................................................................................... 67 
6.3  Vaccine Preparation and Administration ................................................................ 67 
6.4  Misadministration of Vaccine ................................................................................ 68 
6.5  Prior and Concomitant Medications and Vaccines ................................................. 68 
6.6  Vaccine Supply, Labeling, Storage and Tracking .................................................. 69 
7.0  ASSESSMENTS ......................................................................................................... 71 
7.1  Safety Assessment .................................................................................................. 71 
7.1.1  Solicited Adverse Events ................................................................................. 71 
7.1.2  Unsolicited Adverse Events ............................................................................. 73 
7.1.3  Evaluation of Adverse Events .......................................................................... 73 
7.1.4  Serious Adverse Events ................................................................................... 75 
7.1.4.1  Adverse Events of Special Interest ........................................................... 76 
7.1.5  Methods for Recording Adverse Events and Serious Adverse Events ............ 77 
7.1.5.1  Post-Study Events ..................................................................................... 78 

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7.1.6  Pregnancies ...................................................................................................... 78 
7.1.7  Safety Laboratory Measurements .................................................................... 79 
7.2  Efficacy Assessment ............................................................................................... 79 
7.3  Immunogenicity Assessment .................................................................................. 79 
7.4  Exploratory Measurements ..................................................................................... 80 
8.0  STATISTICAL CONSIDERATIONS ....................................................................... 82 
8.1  Endpoints ................................................................................................................ 82 
8.1.1  Primary Endpoint(s) ......................................................................................... 82 
8.1.1.1  Primary Safety Endpoint(s) ...................................................................... 82 
8.1.1.2  Primary Efficacy Endpoint(s) ................................................................... 83 
8.1.1.3  Primary Immunogenicity Endpoint(s) ...................................................... 83 
8.1.2  Secondary Endpoint(s) ..................................................................................... 83 
8.1.2.1  Secondary Safety Endpoint(s) .................................................................. 83 
8.1.2.2  Secondary Efficacy Endpoint(s) ............................................................... 83 
8.1.2.3  Secondary Immunogenicity Endpoint(s) .................................................. 83 
8.1.3  Exploratory Endpoint(s) ................................................................................... 84 
8.2  Success Criteria ...................................................................................................... 84 
8.2.1  Success Criteria for Primary Objective(s) ......................................................... 5 
8.2.2  Success Criteria for Secondary Objective(s) ..................................................... 5 
8.3  Analysis Sets ............................................................................................................. 5 
8.3.1  All Enrolled Set .................................................................................................. 5 
8.3.2  All Exposed Set .................................................................................................. 5 
8.3.3  Safety Set ........................................................................................................... 5 
8.3.4  Full Analysis Set (FAS) Efficacy/Immunogenicity Set ..................................... 5 
8.3.5  Per Protocol (PP) Set Efficacy/Immunogenicity Set ......................................... 5 
8.3.6  Other Analysis Sets ............................................................................................ 5 
8.3.7  Subgroups ........................................................................................................... 5 

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8.3.8  Protocol Deviations ............................................................................................ 5 
8.4  Statistical Analysis Plan ........................................................................................... 5 
8.4.1  Analysis of Demographic and Baseline Characteristics .................................... 5 
8.4.2  Analysis of Primary Objective(s) ....................................................................... 5 
8.4.2.1  Analysis of Primary Safety Objective(s) .................................................... 5 
8.4.2.1.1  Analysis of Extent of Exposure ........................................................... 5 
8.4.2.1.2  Analysis of Solicited Local, Systemic and Other Adverse Events ...... 5 
8.4.2.1.3  Analysis of Unsolicited Adverse Events ............................................. 5 
8.4.2.1.4  Analysis of Safety Laboratory Values ................................................. 5 
8.4.2.2  Analysis of Primary Efficacy Objective(s) ................................................. 5 
8.4.2.3  Analysis of Primary Immunogenicity Objective(s) .................................... 5 
8.4.2.3.1  Statistical Hypotheses .......................................................................... 5 
8.4.2.3.2  Analysis Sets ........................................................................................ 5 
8.4.2.3.3  Statistical Methods .............................................................................. 5 
8.4.3  Analysis of Secondary Objective(s) ................................................................... 5 
8.4.3.1  Analysis of Secondary Safety Objective(s) ................................................ 5 
8.4.3.2  Analysis of Secondary Efficacy Objective(s) ............................................. 5 
8.4.3.3  Analysis of Secondary Immunogenicity Objective(s) ................................ 6 
8.4.3.3.1  Statistical Hypotheses .......................................................................... 6 
8.4.3.3.2  Analysis Sets ........................................................................................ 6 
8.4.3.3.3  Statistical Methods .............................................................................. 6 
8.4.4  Analysis of Exploratory Objectives ................................................................... 6 
8.5  Sample Size and Power Considerations of Primary Objectives ............................... 6 
8.6  Interim Analysis........................................................................................................ 6 
9.0  SOURCE DOCUMENTATION, STUDY MONITORING AND AUDITING .......... 6 
9.1  Source Documentation.............................................................................................. 6 
9.2  Study Monitoring, Auditing and Source Data Verification ...................................... 6 

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10.0  DATA MANAGEMENT ........................................................................................... 6 
10.1  Data Entry and Management .................................................................................. 6 
10.2  Data Clarification.................................................................................................... 6 
10.3  Data Protection ....................................................................................................... 6 
11.0  RECORD RETENTION ............................................................................................. 6 
12.0  USE OF INFORMATION AND PUBLICATION .................................................... 6 
13.0  ETHICS ...................................................................................................................... 6 
13.1  Regulatory and Ethical Compliance ....................................................................... 6 
13.2  Informed Consent Procedures................................................................................. 6 
13.3  Responsibilities of the Investigator and IRB/EC .................................................... 6 
13.4  Protocol Amendments ............................................................................................ 6 
14.0  REFERENCE LIST .................................................................................................... 6 
APPENDIX A:  GRADING SCALES FOR SOLICITED LOCAL ADVERSE EVENTS 6 
APPENDIX B:  GRADING SCALES FOR SOLICITED SYSTEMIC ADVERSE 
EVENTS .............................................................................................................................. 6 
APPENDIX C:  TOXICITY SCALES FOR LABORATORY ABNORMALITIES 
(SERUM CLINICAL CHEMISTRY) ................................................................................. 7 
APPENDIX D:  TOXICITY SCALES FOR LABORATORY ABNORMALITIES 
(HEMATOLOGY) .............................................................................................................. 7 
APPENDIX E:  TOXICITY SCALES FOR LABORATORY ABNORMALITIES 
(URINE) .............................................................................................................................. 7 
 
 
5.3.1  
Subject Diary Reminder, Safety Follow-up and/or Post-vaccination Blood  

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PROTOCOL SYNOPSIS V132_01EXP 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Title of Study: A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study to  
Evaluate the Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R 
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium  
Hydroxide Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy Adults 
(18-45 years of age) 
Study Period: Approximately 12 months for 
each subject 
Clinical Phase: Phase 1 

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Background and Rationale: 
Neisseria meningitidis (N. meningitides)serogroup C (MenC) is one of the major 
serogroups causing invasive meningocococcal disease. Case fatality in Germany has 
ranged between 6% and 8% between 1999 and 2006, and has remained generally 
consistent across the different European countries, varying between 6-11%, with the case 
fatality rate being notably higher for serogroup C disease than for serogroup B. The 
safety and immunogenicity of the Novartis Meningococcal C-CRM197 Conjugate 
Vaccine (Menjugate®) has been confirmed through years of commercial use. For children 
over the age of 12 months, for adolescents and for adults a single dose is recommended. 
For infants between 2 and 12 months of age, the recommended schedule for primary 
immunization with the Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) is 
two doses given with an interval of at least 2 months, followed by a booster. (Novartis 
Meningococcal C-CRM197 Conjugate Vaccine Investigator Brochure). 
A more potent Meningococcal C-CRM197 Conjugate Vaccine formulation might enable a 
reduction of the antigen dosage and/or a reduction in the number of doses needed in 
infants. One approach to achieve more potent well-characterized sub-unit vaccines - like 
the Novartis Meningococcal C-CRM197 Conjugate Vaccine - is the use of new adjuvants 
that activate Toll-like receptors (TLRs). 
Novartis is developing a small molecule immune potentiator (SMIP) LHD153 that targets 
TLR7. The objective driving the development of LHD153 is to achieve a vaccine 
adjuvant with strong immunopotentiating properties and minimal side effects. In line 
with this objective, it has been postulated that the ideal SMIP should remain local and 
target innate immune cells at the injection site. To this end, LHD153 contains a  
 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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functional phosphonate group to allow for adsorption to aluminum hydroxide. The 
arginine salt derivative of this compound is LHD153R. Preclinical results from animal 
models for bacterial and viral antigens, including MenC, MenB, rabies, HIV and 
respiratory syncytial virus (RSV) showed increased functional antibodies and 
antigenspecific T-cells with LHD153R adsorbed to aluminum hydroxide (aluminium 
hydroxide/LHD153R) when compared to aluminum hydroxide adjuvanted controls. In 
vitro toxicity screens confirmed that LHD153R is not phototoxic, genotoxic or 
mutagenic. Furthermore, toxicology studies in dog and rats showed that intramuscular 
(IM) injection of aluminum hydroxide/LHD153R was well tolerated. Importantly, in 
contrast to free LHD153R, toxicokinetic analysis in rats and dogs confirmed very 
limited exposure of LHD153R when adsorbed to aluminum hydroxide after IM 
injection. 
The aim of this Phase 1 clinical study is to assess the safety of aluminium 
hydroxide/LHD153R adjuvanted MenC-CRM197 conjugate vaccine 
(MenCCRM197/Aluminium Hydroxide/LHD153R) and to compare the antibody-
mediated immune response elicited by MenC-CRM197/Aluminium Hydroxide/LHD153R 
with the licensed aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate 
Vaccine (Menjugate®). Furthermore, a comprehensive set of exploratory objectives has 
been selected to assess the systemic exposure of LHD153 after intramuscular injection of 
MenC-CRM197/Aluminium Hydroxide/LHD153R, to evaluate the quality of the specific 
immune response against MenC-CRM197 in detail and to evaluate  biomarkers that may 
be predictive of safety and/or innate immune activation 
The licensed Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) has been 
selected as the primary vaccine candidate to assess the safety and immunopotentiating 
properties of aluminium hydroxide/LHD153R for several reasons. Firstly, the safety and 
immunogenicity profiles of the Meningococcal C-CRM197 Conjugate Vaccine  
(Menjugate®) have been well established through years of commercial use. Secondly, a 
more potent MenC-CRM197 conjugate vaccine might enable a reduction of the antigen 
dosage or the number of doses needed in infants. Finally, the MenC-CRM197 conjugate 
is a well-characterized, single antigen preparation which provides an ideal setting to 
compare the potential of this new aluminium hydroxide/LHD153R adjuvant. 
 

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Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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Study Objectives: 
Primary Safety Objective: 
To assess the safety of MenC-CRM197/Aluminium Hydroxide/LHD153R as compared to 
that of aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
Primary Immunogenicity Objective: 
To compare the antibody responses of MenC-CRM197/Aluminium Hydroxide/LHD153R 
and aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at 
Day 29, as measured by human complement serum bactericidal assay (hSBA) directed 
against N. meningitidis serogroup C. 
Secondary Immunogenicity Objectives: 
1. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine, at Day 8 and Day 181 after vaccination, as measured 
by hSBA directed against N. meningitidis serogroup C. Baseline antibody titers will 
also be measured by hSBA. 
2. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine at Day 8, Day 29 and Day 181 after vaccination, as 
measured by an enzyme-linked immunosorbent assay (ELISA) to N. meningitidis 
serogroup C. Baseline antibody concentrations will also be measured by ELISA. 
Exploratory Objectives: 
1. To evaluate the systemic exposure of LHD153 at several early time-points after IM 
injection of MenC-CRM197/Aluminium Hydroxide/LHD153R or aluminium 
hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
2. To explore the frequency of B cells specific for Men C polysaccharide and CRM197 
protein at baseline (Day 1) and at Day 8, Day 29 and Day 181 after vaccination with  
 

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Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
MenC-CRM197/Aluminium Hydroxide/LHD153R or the aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. Subsequently, the B cell 
repertoire of the antigen specific B cells and the specific antibody functionality will 
be analyzed in a selected subset of subjects. 
3. To explore the baseline T cell mediated immunity to CRM197 and to evaluate the 
frequency and quality of CRM197 specific T cells induced by MenC- 
CRM197/Aluminium Hydroxide/ LHD153R compared to aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at Day 8 and Day 29. 
4. To evaluate biomarkers that may be predictive for safety and/ or innate immune 
activation. 

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Study Design: 
This Phase 1, randomized, observer-blind, dosage-escalation study will be performed at 
a single center. In total, approximately 80 healthy male and healthy non-pregnant female 
adults (18-45 years of age) will be enrolled in the study. Subjects will be randomized to 
receive a single IM vaccination of either the licensed aluminium hydroxide adjuvanted 
Meningococcal C-CRM197 Conjugate Vaccine (i.e. 10 µg MenC conjugated to CRM197,  
adjuvanted with 1 mg aluminium hydroxide) or one of four dosages of the 
investigational vaccine, MenC-CRM197/Aluminium Hydroxide/LHD153R (i.e. 10 µg 
MenC conjugated to CRM197,  adjuvanted with 1 mg aluminium hydroxide and one of 
four dosages [12.5, 25, 50 or 100 µg] of LHD153R) 
For the dosage-escalation of LHD153R, the subjects will be enrolled into 1 of 4 cohorts, 
in a stepwise manner with 20 subjects per cohort. Subjects in all cohorts will be 
randomized in a 1:4 ratio, to receive either aluminium hydroxide adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine (control) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R with increasing doses of LHD153R.Cohort 1 will receive 12.5 μg 
of LHD153R; Cohort 2 will receive 25 μg of LHD153R; Cohort 3 will receive 50 μg of 
LHD 153; and Cohort 4 will receive 100 μg of LHD153R (Table 1). 
 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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Table 1. Subjects Randomized per Cohort and Treatment Dose Group 
Cohort 
Group 
Subjects/ 
Group 
MenC  
Dosage*  
(µg) 
Adjuvant Dosages  
Total 
Volume/Dose 
Total 
Subjects/Group 
Aluminium  
Hydroxide  
(mg) 
LHD153R  
(µg) 
1 
A 
4 
10 
1 
0 
0.5 mL 
20 
B 
16 
10 
1 
12.5 
0.5 mL 
2 
A 
4 
10 
1 
0 
0.5 mL 
20 
C 
16 
10 
1 
25 
0.5 mL 
3 
A 
4 
10 
1 
0 
0.5 mL 
20 
D 
16 
10 
1 
50 
0.5 mL 
4 
A 
4 
10 
1 
0 
0.5 mL 
20 
E 
16 
10 
1 
100 
0.5 mL 
*Conjugated to 12.5-25 µg CRM197 
After vaccination, all subjects will be confined to the clinical site for 24 hours for 
clinical observation and blood sampling for exploratory endpoint measurements. 
Importantly, all cohorts will have a staggered entry. 
▫ For each cohort, the first 5 subjects (i.e. the first 1:4 randomization block) to receive 
either aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate 
Vaccine (n=1) or MenC-CRM197/Aluminium Hydroxide/LHD153R (n=4) will be 
treated at a vaccination rate of 1 subject each day. 
▫ After entry of the first 5 subjects in each cohort, the enrollment will be paused. The 
remaining 15 subjects for each cohort will be enrolled only after DMC review of the 
safety results obtained through Day 15 has been finalized (Table 2). 
▫ Furthermore, after entry of all 20 subjects in each cohort, enrollment will be paused 
again.Enrollment of the first 5 subjects in the next cohort will only proceed after the 
Day 29 safety results of the previous cohort have been reviewed by the Data 
Monitoring Committee (DMC) (Table 2). 
 

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Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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Table 2. Overview of staggered entry of subjects for each cohort 
Cohort 
1st Stage of 
enrollment 
MenC- 
CRM197/ 
Aluminium 
Hydroxide 
MenC- 
CRM197/ 
Aluminium  
Hydroxide  
/LHD153R 
2nd Stage of 
enrollment 
MenC- 
CRM197/ 
Aluminium 
Hydroxide 
MenC- 
CRM197/ 
Aluminium  
Hydroxide  
/LHD153R 
1 
First 5 
subjects with  
vaccination 
rate of 1 
subject/day 
1 
4 
Remaining 15 
subjects, after  
DMC review of  
Day 15 safety 
results 
3 
12 
2 
1 
4 
3 
12 
3 
1 
4 
3 
12 
4 
1 
4 
3 
12 
The DMC review after the first 5 subjects of each cohort and in between the cohorts will 
be performed according to predefined stopping/pausing guidelines used to ensure the 
safety of study subjects. These stopping/pausing guidelines are based on FDA guidance 
and with grading scales from the CBER Guidance for Industry “Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials”. See protocol section 3.6 for further details. 
Safety Measurements 
Schedule of safety data collection: 
▫ Solicited local and systemic adverse events (AEs), body temperature and all 
unsolicited AEs will be collected until Day 15. 
▫ All serious adverse events (SAEs), medically attended AEs, AEs leading to study 
withdrawal, new onset of chronic disease (NOCDs), and adverse events of special 
interest (AESIs) will be collected from the date of signed informed consent to study 
completion at Day 366. 
▫ All concomitant medications administered in relation to the reported AEs will be 
collected from vaccination to study completion at Day 366. 
 

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Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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Solicited local AEs include injection site erythema, injection site induration, injection 
site pain and injection site swelling. Solicited systemic AEs include body temperature ≥ 
38.0°C (as measured orally), loss of appetite, nausea, fatigue, generalized myalgia, 
generalized arthralgia, headache, chills, vomiting, diarrhea, generalized rash and 
urticaria. 
All AESIs will be reported in the same manner as SAEs. All AEs will be monitored until 
resolution or, if the AE becomes chronic, a cause is identified. If an AE is unresolved at 
the conclusion of the study, a clinical assessment will be made by the investigator and 
the medical monitor to determine whether or not continued follow-up of the AE is 
warranted. 
The relationship of the study treatment to any AE will be determined by the investigator 
as probably related, possibly related, or not related; the relationship of the study 
treatment to any SAE will be determined by the investigator as probably 
related/suspected, or not related. 
Safety Laboratory Parameters 
To assess laboratory AEs, blood and urine samples will be collected from each subject as 
outlined in Table 3 to perform blood chemistry, hematology, and urine analyses. 
Safety laboratory samples will be drawn from all subjects at pre-vaccination screening 
(between Day -21 and Day -3) at Day 1 (pre-vaccination), at Day 8 and at Day 29. Safety 
laboratory assessments will include sodium, potassium, bicarbonate, blood urea nitrogen, 
creatinine, liver function tests (ALT, AST), a complete blood count and Creactive 
protein. A urine sample will be collected at the same time-points and will be assessed for 
the presence of protein, glucose and red blood cells. 
Primary and Secondary Immunogenicity Measurements 
Four blood samples per subject (i.e. at Day 1, Day 8, Day 29 and Day 181) will be 
collected for serum preparation and determination of antibody-mediated immune 
responses to MenC-CRM197 as outlined in Table 3 and Table 4. See section 7.3 for 
further details. 
 

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Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Exploratory Measurements 
In all subjects who agree by signing a separate Informed Consent, additional blood 
samples will be collected at Day 1, Day 4, Day 8, Day 29 and Day 181 for exploratory 
assays. The purpose of these assays is to assess the systemic exposure of LHD153, to 
determine the frequency and quality of B- and T-cells specific for MenC polysaccharide 
and/or CRM197 and to evaluate biomarkers that may be predictive of safety and/or innate 
immune activation. Subsequently, MenC-CRM197 specific B-cell repertoires as well as 
the MenC-CRM197 specific antibody functionalities will be analyzed in a selected subset 
of subjects, dependent on the results from primary and secondary immunogenicity 
measurements and the volume of whole blood (specific B cell repertoire) and serum 
(specific antibody functionality) remaining for additional testing. See section 7.4 for 
further details. All exploratory analyses may be performed after the Clinical Study 
Report (CSR) has been completed, in which case these data will be submitted as an 
addendum to the CSR. 
Number of Subjects planned: 
Approximately 80 adult subjects will be randomized, with anticipated dropout rates of 
5% by Day 181 (last serology time point), and 10%, by Day 366 (last safety time point). 
Sample size is not driven by statistical assumptions for formal hypothesis testing, but the 
proposed number of subjects will be sufficient to provide a descriptive summary of the 
safety and immunogenicity of the study vaccine. 
Study Population and Subject Characteristics: 
Healthy adult male and female volunteers between 18-45 years of age, inclusive. 
The list of inclusion and exclusion criteria is included in protocol section 4.0, Selection of 
Study Population. 

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Study Vaccines: 
The MenC-CRM197 conjugate  is a lyophilized powder consisting of 10 µg of Men C 
polysaccharide conjugated to 12.5-25 µg CRM197 carrier protein. The MenC-CRM197 
lyophilized powder will be reconstituted with adjuvant by the unblinded designated site  
 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
staff member who is to follow the procedure as described in the vaccine preparation 
instructions in the Investigator Site File (i.e. the vaccine will be prepared in the clinic 
prior to administration). 
The lyophilized Men-CRM197 powder will be reconstituted with either: 
(a) aluminium hydroxide adjuvant 
(b) aluminium hydroxide/LHD153R adjuvant with specified dosages of LHD153R 
(12.5, 25, 50 and 100 µg) 
The components for each formulation of MenC-CRM197 will be provided in a separate 
kit, together with detailed instructions for reconstitution and dilution steps. 
Aluminium hydroxide/LHD153R with specified dosages of LHD153R will be prepared  
by dilution of the highest aluminium hydroxide/LHD153R dosage (100 µg of 
LHD153R) with aluminium hydroxide. 
In each cohort, subjects will be randomized to receive one injection of MenC- 
CRM197/Aluminium Hydroxide/LHD153R adjuvant or aluminium hydroxide adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine. The 0.5 mL of vaccine will be injected 
IM in the deltoid muscle, with preference that the injection is administered in the 
nondominant arm. 

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Primary Endpoints: 
Safety Endpoint(s): 
Safety will be assessed by measuring the frequency of local and systemic solicited AEs, 
unsolicited AEs, SAEs, AESIs, NOCDs, and safety laboratory data for all subjects.  
Specifically, 
▫ The frequency and percentage of subjects with solicited local and systemic AEs 
through Day 15. Time intervals after vaccination that will be summarized are: 30 
min post-vaccination, Days 1-4 (without 30 min), Days 5-8, Days 8-15, Days 1-8 
(without 30 min) and Days 1-15 (without 30 min). 
▫ The frequency and percentage of subjects with any unsolicited AEs from the day of  
 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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vaccination (Day 1) to Day 15. 
▫ The frequency and percentage of subjects with SAEs, medically attended AEs,  AEs 
leading to study withdrawal, NOCDs, AESIs for the following time periods: day of 
signed informed consent until study completion (Day 366), day of vaccination (Day 
1) to Day 29 and Day 29 to study completion (Day 366). 
▫ The absolute values and changes in hematology, chemistry, and urinalysis parameters. 
▫ The frequency and percentage of subjects with abnormal laboratory parameter values 
as classified by investigator normal ranges (low, normal, high) and as classified by 
CBER toxicity grading scales, when available. 
Primary Immunogenicity Endpoints: 
Geometric mean titers (GMTs) measured by hSBA directed against N. meningitidis 
serogroup C from samples collected on Day 1 (baseline, before vaccination) and Day 29 
as well as the GMR of the titers (Day 29 / Day 1). 
Secondary Immunogenicity Endpoint(s): 
▫ GMTs and corresponding GMRs measured by hSBA directed against N. meningitidis 
serogroup C for samples collected at Day 8 and Day181. 
▫ Percentage of subjects with hSBA seroresponse at Day 8, Day 29, and Day 181. 
seroresponse is defined as a post vaccination hSBA ≥8 for subjects with a baseline 
hSBA <4 or have an increase of at least 4 times the baseline hSBA level for subjects 
with pre-vaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against N. meningitidis serogroup 
C measured by ELISA for samples collected on Day 1 (baseline, prior to 
vaccination), Day 8, Day 29 and Day 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations to 
N. meningitidis serogroup C measured by ELISA on Day 8, Day 29 and Day 181 
relative to baseline (Day 1). 
 

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Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Exploratory Endpoint(s): 
Testing and analyses of exploratory endpoints may be performed after the Clinical Study 
Report (CSR) has been completed, in which case these data will be submitted as an 
addendum to the CSR. 
1. Serum concentration of LHD153 at Day 1 baseline (prior to vaccination), Day 1 (1h , 
2h, 4h, 8h and 24h after vaccination) and Day 4 by LC-MS/MS. 
2. Frequency of meningococcal C polysaccharide-specific and CRM197-specific B cells 
at Day 1 (baseline), Day 8, Day 29 and Day 181 by ELISPOT. 
3. Diversity of the meningococcal C polysaccharide-specific B-cell repertoire at Day 1 
(baseline), Day 8, Day 29, and Day 181 by immunoglobulin cDNA sequencing. 
4. Functionality of antigen specific antibodies will be assessed at Day 1 (baseline), Day 
8, Day 29 and Day 181 by analysis of immunoglobulin isotype, glycosylation state 
and their ability to fix complement, promote antibody-dependent cell mediated 
cytoxicity, induce phagocytosis and activate FcR+ cells. If the quantity of serum 
available for this specific exploratory objective is limited, assessments of isotype, 
glycosylation state and complement fixing capacity will be prioritized over the other 
assessments. 
5. Frequency and quality of T cells specific for CRM197 at Day 1 (baseline), Day 8 and 
Day 29 by fluorescence activated cell sorting (FACS) analysis using intracellular 
staining with a wide panel of cytokines and surface markers to identify cell 
populations. 
6. Serum concentrations of a panel of 30 chemokines and cytokines at Day 1 (baseline), 
Day 1 (6h and 24h after vaccination), Day 4 and Day 8 by multiplex Electro-
chemoluminescence based assay. 
7. Gene expression profile in whole blood at Day 1 (baseline), Day 1 (6h and 24h after 
vaccination), Day 4 and Day 8 by RNA micro array analysis. 

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Statistical Analyses: 
The study is exploratory in nature, thus analyses will be descriptive and no formal 
hypothesis testing will be performed. 
 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Primary Safety Analyses 
The primary safety analyses will be based on the safety set for solicited and unsolicited 
adverse events. There is no statistical null hypothesis associated with the safety 
objective, which will be analyzed descriptively. 
Immunogenicity Analyses 
The primary immunogenicity analyses will be based on the per-protocol set (PPS) on 
Day 29. The primary analyses will also be performed using the Full Analysis Set (FAS) 
as a measure of the sensitivity/robustness of the results. All other immunogenicity 
assessments will be performed using the PPS or the appropriate subset of subjects. The 
antibody concentrations/titers will be summarized using GMC/GMTs and two-sided 
95% confidence intervals (CIs) constructed by exponentiation (base 10) of the least 
square means of the logarithmically transformed (base 10) antibody titer. The 95% CIs 
will be obtained from an analysis of covariance (ANCOVA) with baseline 
concentration/titer as a covariate. Additional details will be further described in the 
statistical analysis plan. 
The immunogenicity endpoints based on subjects meeting criteria for seroconversion or 
achieving a certain threshold value will be summarized using frequencies and 
percentages and associated two-sided 95% Clopper-Pearson CIs. For analyses of 
seroconversion, separate summaries may be provided based on seropositivity status at 
baseline. 

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Interim Analysis: 
An Interim Analysis will be performed on the immunogenicity and safety data collected 
from all subjects until Day 29 after all cohorts have been enrolled. Further details 
regarding the interim analysis are contained in section 8.6. 
Data Monitoring Committee: 
A Data Monitoring Committee (DMC) will be implemented to review safety data during 
scheduled periodic reviews. The DMC will review safety data collected until Day 15, as 
described in the DMC charter and in the statistical analysis plan, after enrollment of the  
 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
first 5 subjects in each cohort, before proceeding with enrollment of the remaining 
subjects in each cohort. In addition, the DMC will review safety data collected until Day 
29 after enrollment for each cohort. Enrollment of subjects in subsequent cohorts will 
only proceed after the DMC review is completed. The same enrollment sequence will be 
utilized for each cohort. Further information regarding the DMC is discussed in more 
detail in the protocol, section 3.7, Data Monitoring Committee. 

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Table 3: 
Time and Events Table – Treatment Period (until Day 29) 
 
Visit Type 
Clinic Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
 
Study Day 
-21 to -3 
1 
4 
8 
15 
22 
29 
 
Visit Window (Days) 
n/a 
n/a 
n/a 
-1/+1 
-1/+1 
n/a 
-2/+2 
 
Visit Number 
Screening  
1 
2 
3 
4 
5 
6 
Study Event 
References 
 
 
 
 
 
 
 
Study Treatment 
 
 
 
 
 
 
 
 
Vaccination 
Section 5.2 
 
X 
 
 
 
 
 
Screening and Safety 
 
 
 
 
 
 
 
 
Informed Consent  
Section 5.1.1 
X 
 
 
 
 
 
 
Demographic Data & Medical History 
Sections 5.1.2 
X 
 
 
 
 
 
 
Physical Exam 
Sections 5.1.2 and 5.2.1 
X 
Xa 
 
 
 
 
 
Safety Laboratory blood draw (10 ml) 
Section 7.1.7 
X 
Xa 
 
X 
 
 
X 
Urinalysis 
Sections 3.5 
X 
Xa 
 
X 
 
 
X 
Pregnancy Test 
Sections 5.1.2 and 5.2.1 
X 
Xa 
 
 
 
 
 
Exclusion/Inclusion Criteria 
Section 4.0 
X 
Xa 
 
 
 
 
 
Randomization 
Section 5.2.3 
 
Xa 
 
 
 
 
 
30 Minutes Post Injection Assessment 
Section 5.2.6 
 
X 
 
 
 
 
 
Subject Diary Dispensed with Training 
Section 5.2.6 
 
X 
 
 
 
 
 
Subject Diary Reminder 
Section 5.2.6 
 
 
X 
X 
 
 
 

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Subject Diary Reviewed and Collected 
Section 5.3.1 
 
 
 
 
X 
 
 
Assess all solicited AEs 
Section 7.1.1 and 7.1.3 
 
 
 
 
X 
 
 
Assess all unsolicited AEs 
Sections 7.1.2 and 7.1.3 
X 
X 
X 
X 
X 
 
 
PRO-01 TEMP 06 / Atlas No. 293620 
Visit Type 
Clinic Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Study Day 
-21 to -3 
1 
4 
8 
15 
22 
29 
Visit Window (Days) 
n/a 
n/a 
n/a 
-1/+1 
-1/+1 
n/a 
-2/+2 
Visit Number 
Screening  
1 
2 
3 
4 
5 
6 
Study Event 
References 
 
 
Assess SAEs 
Section 7.1.4 
X 
X 
X 
X 
X 
X 
X 
Assess AESIs 
Section 7.1.4.1 
X 
X 
X 
X 
X 
X 
X 
Assess NOCDs, medically attended 
AEs, AEs leading to withdrawal  
Sections 7.1.3 
X 
X 
X 
X 
X 
X 
X 
Assess relevant medications 
Sections 5.1.2 and 6.5 
X 
X 
X 
X 
X 
X 
X 
Blood draws for Immunogenicity and Exploratory Objectives 
 
Serum Blood Draw (Primary and 
Secondary Objectives; 10 mL)  
Section 3.5. 
 
Xa 
 
X 
 
 
X 
Serum Blood Draw (Exploratory 
Objectives; 5 mL)  
Section 3.5. 
 
Xb 
X 
X 
 
 
 
Whole Blood Draws (Exploratory 
Objectives; 2 mL) 
Section 3.5. 
 
Xc 
X 
 
 
 
 
Whole 
Blood 
Draw 
(Exploratory 
Objectives; 5 mL) 
Section 3.5. 
 
Xd 
X 
X 
 
 
 

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Whole 
Blood 
Draw 
(Exploratory 
Objectives; 50 mL) 
Section 3.5. 
 
Xa 
 
X 
 
 
X 
Notes: 
a. Procedure must be performed prior to vaccination 
b. Three Serum Blood Draws (3 x 5ml) must be taken at Study Day 1, i.e. at baseline (prior to vaccination), at 6h and at 24h after vaccination. 
c. Six whole Blood Draws (6 x 2 mL) must be taken at Study Day 1, i.e. at baseline (prior to vaccination) and at 1, 2, 4, 8 and 24h after 
vaccination. 
d. Three Whole Blood Draw (3 x 5 mL) must be taken at Study Day 1, i.e. at baseline (prior to vaccination), at 6h and at 24h after vaccination 
 
PRO-01 TEMP 06 / Atlas No. 293620 
Table 4: 
Time and Events Table – Follow-up Period (until Day 366) 
Visit Type 
Clinic Visit 
Clinic Visit 
Clinic Visit 
Phone Call 
Phone Call 
Clinic Visit 
Study Day 
85 
113 
181 
209 
271 
366 
Visit Window (Days) 
-7 to +7 
-7 to +7 
-7 to +7 
-14 to +14 
-14 to +14 
-14 to +14 
Visit Number 
7 
8 
9 
10 
11 
12 
Study Event 
References 
 
 
Safety 
 
Assess SAEs 
Section 7.1.4 
X 
X 
X 
X 
X 
X 
Assess AESI 
Section 7.1.4.1 
X 
X 
X 
X 
X 
X 
Assess NOCDs, medically attended 
AEs, AEs leading to withdrawal 
Sections 7.1.4.1 and 7.1.3 
X 
X 
X 
X 
X 
X 
Assess relevant medications 
Sections 5.1.2 and 6.5 
X 
X 
X 
X 
X 
X 
Blood draws for Immunogenicity and Exploratory Objectives 
 
Serum Blood Draw (Secondary 
Objective; 10 mL) 
Section 3.5 
 
 
X 
 
 
 

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Whole Blood Draw  
(Exploratory Objectives; 50 mL) 
Section 3.5 
 
 
X 
 
 
 
Study Completion Procedures 
 
Study Terminationa 
Section 5.5 
 
 
 
 
 
X 
Notes: 
a. Subjects who terminate the study early are recommended to complete certain study-related procedures. See section 5.5 for further details. 
 
PRO-01 TEMP 06 / Atlas No. 293620 

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LIST OF ABBREVIATIONS 
ADCC 
Antibody-dependent cell mediated cytotoxicity 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BZN 
Benzonaphthyridines 
CBER 
Center for Biologics Evaluation and Research 
cDNA 
Complementary deoxyribonucleic acid 
CI 
Confidence interval 
CRF 
Case report form 
CRM197 
Cross Reacting Material 197 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
EC 
Ethics committee 
EDC 
Electronic data capture 
ELISA 
Enzyme-linked immunosorbent assay 
ELISPOT 
Enzyme-Linked ImmunoSpot 
EMA 
European Medicines Agency 
FACS 
Fluorescence-activated cell sorting 
FAS 
Full analysis set 
FDA 
Federal Drug Agency 
GCP 
Good clinical practice 
GMC 
Geometric mean concentration 
GMP 
Good manufacturing practice 

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GMT 
Geometric mean titer 
GMR 
Geometric mean ratio 
HEENT  
Head, ears, eyes, nose and throat 
HIV 
Human immunodeficiency virus 
 
HPV 
Human papillomavirus 
hSBA 
Human complement serum bactericidal assay 
ICF 
Informed consent form 
ICH 
International Committee for Harmonization 
IM 
Intramuscular 
IRB 
Institutional review board 
IV 
Intravenous 
LLQ 
Lower limit of quantification 
MenC 
Meningococcal type C 
MPL 
Monophosphoryl lipid A 
NCR 
No carbon required 
NOCD 
New Onset of Chronic Disease 
PEG 
Polyethylene glycol 
PO 
Per oral 
PP 
Per protocol 
RNA 
Ribonucleic acid (RNA 
SAE 
Serious Adverse Event 
SMIP 
Small molecule immune potentiator 
TLR 
Toll-like receptor 
VSAE 
Vaccine serious adverse event 
1.0  
BACKGROUND AND RATIONALE 
1.1  
Background 
MenC-CRM197 Conjugate Vaccine 

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Meningococcal disease worldwide is predominantly a disease of infants and young 
children. N. meningitidis serogroup B and C remain the most prevalent strains in North 
America and Europe, (Rosenstein, N. et al., 2001) and together cause more than 95% of 
reported cases of meningococcal disease in Europe (Connolly, M, et al., 1999). In Europe, 
N. meningitidis serogroup C (MenC) is one of the major serogroups causing invasive 
disease. Case fatality in Germany has ranged between 6% and 8% between 1999 and 
2006, and has remained generally consistent across the different European countries, 
varying between 6-11%, with the case fatality rate being notably higher for serogroup C 
disease than for serogroup B (European Centre for Disease Prevention and Control, 
2011). Since Men C vaccination was added to Germany’s routine schedule for children in 
2006, there has been a reported decline in Men C incidence. However, the decline was not 
as rapid when compared to other European countries (Hellenbrand, W. et al., 2013)  
The Novartis Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) comprises 
MenC oligosaccharides conjugated to the protein carrier, CRM197, a nontoxic mutant of 
diphtheria toxin. The vaccine has been shown to be safe and immunogenic and able to 
prime infants, toddlers and young children for immunological memory (see Novartis 
Meningococcal C-CRM197 Conjugate Vaccine Investigator Brochure).  
In Germany, the Standing Committee on Vaccination (STIKO) of the Robert Koch  
Institute recommends a single dose of MenC conjugate vaccine in children over the age of  
12 months as part of the routine vaccination campaign (Robert Koch Institute 
Epidemiologisches Bulletin, August 2013). For specific indications, e.g. in case of 
postexposure prophylaxis, the recommended schedule for primary immunization of 
infants between 2 to 12 months of age with a MenC conjugate vaccine is two dosages 
given with an interval of at least 2 months. 
Although the Novartis Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) 
represents an example of how vaccination with a well characterized, purified 
polysaccharide antigen can yield pivotal public health triumphs, there remains a need for 
further improvement of the MenC vaccine. A more potent MenC vaccine formulation 
might yield an increase in the magnitude of the antigen-specific immune response 
enabling a reduction of the antigen dosage. Furthermore, induction of a more rapid 
antigen-specific immune response may enable a reduction in the number of doses needed 
for post-exposure prophylaxis in infants. 
Vaccine Adjuvants 
Immunization with purified protein or polysaccharide antigens typically results in the 
induction of a modest antibody response with little or no T cell response when compared 
to vaccines comprised of whole or killed bacteria or viruses that have inherent 

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immunepotentiating activity. The need to increase the immunogenic response of 
wellcharacterized and purified antigens that display suboptimal immunogenicity when 
used alone affirms the essential role for the use of adjuvants. Vaccine adjuvants may 
significantly reduce the amount of antigen needed (Del Giudice, G, et al., 2013) and may 
induce a more rapid immune response enabling a reduction in the number of doses in a 
regimen. 
Besides reducing the antigen dosage or number of doses in the vaccine regimen, there is 
now an increased appreciation of the capacity of adjuvants to increase not just overall 
antibody titer but also to increase the number of functional antibodies and/or antibodies 
with higher affinity for vaccine antigens. Many pathogens, such as influenza viruses, 
HIV, human papilloma virus (HPV) and the malaria parasite, display substantial antigenic 
drift, subtype and/or strain variations. Therefore, the ability of adjuvants to broaden an 
immune response profile could be crucial to the success of vaccines against such targets. 
Previous studies have shown that the broadening effect of adjuvants may be mediated via 
expansion of B cell diversity, not merely through increased titers (Khurana, et al., 2010, 
2011). Clinically, antibody response broadening by adjuvants such as AS04 or oil-inwater 
emulsions has been demonstrated in HPV vaccines and influenza, respectively (Bissett, 
SL et al., 2014; Del Giudice, G et al., 2013). 
One unmet need is the development of vaccines for effective T cell responses. Several 
vaccines in development are aimed at eliciting T cell responses, which historically have 
not been induced by the most commonly used adjuvants in vaccines for human use, such 
as aluminium hydroxide. Therefore, an objective of many adjuvant discovery and 
development programs is to elicit more effective engagement of T-helper cells for 
optimizing the quality, breadth and durability of antibody responses, or, to induce effector 
CD4+ or CD8+ T cells to kill intracellular pathogens. One approach for new generation 
vaccines is the use of agonists for Toll-like receptors (TLRs) that activate innate immune 
receptors, mainly on antigen presenting cells, and facilitate the generation of T helper cell 
responses. 
Adjuvants that are currently employed in human vaccines licensed for use in the USA 
and/or Europe include aluminium salts, oil-in-water emulsions (MF59, AS03 and AF03), 
virosomes, and AS04 (Alving, CR, et al., 2012). Among the most advanced adjuvants 
systems is AS04 which is used in the Cervarix® HPV vaccine and consist of the TLR4 
ligand monophosphoryl lipid A (MPL) combined with aluminium salt. MPL, along with 
QS21, is also part of the adjuvant system (AS01) in the RTS, S malaria vaccine from 
GlaxoSmithKline which has been evaluated in a Phase 3 clinical trial (Regules, JA, et al.,  

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2011). Another clinically advanced adjuvant is CpG oligodeoxynucleotide (ODN), a 
TLR9 ligand contained in the Heplisav® vaccine candidate for hepatitis B from Dynavax, 
that has completed a Phase 3 clinical trial (Reed, SG, et al., 2013). 
Small molecule immune potentiators as a new class of vaccine adjuvants 
A new class of adjuvants, small molecule immune potentiators (SMIPs), has been 
identified that activate immune cells by targeting TLR7 and TLR8. Imiquimod and 
Resiquimod (R848) are clinically advanced TLR7 and/or TLR8 SMIPs that are used as 
immunotherapeutics. Although Imiquimod and Resiquimod have been studied 
extensively as vaccine adjuvants in preclinical models (Vasilakos et al. 2013), they were 
never optimized for this use and, in general, compare poorly to other pre-clinical and 
clinical adjuvant candidates. Furthermore, when Imiquimod is applied topically (it is a 
licensed topical treatment for viral and malignant skin lesions) it induces strong local and 
systemic inflammatory reactions, and is poorly tolerated (Bauza, et al. 2009; Campanelli, 
et al. 2005; Meyer, et al. 2008). 
Unlike traditional drugs, TLR7 SMIPs activate innate immunity and initiate a cascade of 
immune responses that can have systemic impact and endure after the compound has been 
cleared from the organism. For SMIPs as vaccine adjuvants this difference is highlighted 
further by the fact that 2-3 local IM injections drive antigen-specific B and T cell 
responses at distal sites and these can provide protection in the form of immunologic 
memory (Tacken,  et al. 2011; Ilyinskii, et al., 2014). Therefore, limiting the systemic 
exposure of the SMIP adjuvants has been postulated as an approach to both increase 
vaccine efficacy and minimize side effects associated with systemic and generalized 
inflammation. Novartis is currently developing a novel adjuvant, containing a SMIP from 
the benzonaphthryridines (BZN) series, LHD153, which targets TLR7. The objective 
driving the discovery of this new TLR7 ligand was to develop a vaccine adjuvant with 
high efficacy in increasing the vaccine specific immune response and with minimal side 
effects. To obtain this objective it was postulated that the ideal compound would remain 
localized at the site of injection to help trigger the immune reaction to vaccine antigens, 
yet maintain a low systemic distribution. At the same time this compound had to be 
soluble to make industrial scale-up and manufacturing feasible. Soluble BZN were 
engineered so that they could be formulated with aluminium salts with the aim of limiting 
their systemic exposure and keeping them localized in the muscle for short time after 
immunization. The strongest adsorption to aluminium hydroxide particles is obtained 
through ligand exchange of hydroxyl and/or phosphate groups on the surface of 
aluminium hydroxide or phosphate with soft anionic moieties such as phosphates, 
phosphonates, phosphites, sulfates and carboxylates. To drive the adsorption to 
aluminium hydroxide through ligand exchange, LHD153 was functionalized with a 
polyethylene glycol (PEG) linker and a terminal phosphonate. Furthermore, LHD153 was 

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stabilized with arginine salt to allow scale up for GMP manufacturing, yielding 
LHD153R. As predicted, unformulated LHD153R exhibited high levels of systemic 
exposure when injected IM in mice, rats and dogs, whereas the serum concentrations of 
LHD153R adsorbed to aluminium hydroxide (aluminium hydroxide/LHD153R) was 
dramatically reduced. Moreover, aluminium hydroxide/LHD153R remained localized to 
the injection site. 
Preclinical studies using aluminium hydroxide/LHD153R to date confirm the activation 
of the TLR7 pathway and subsequent boost of both the humoral and cellular immune 
response. Moreover, aluminium hydroxide/LHD153R displays a unique pharmacokinetic 
profile as demonstrated by its minimal systemic exposure, potentially minimizing any 
systemic inflammatory response associated with tolerability issues. Aluminium 
hydroxide/LHD153R has achieved proof of concept in animal models using several 
vaccine antigens including MenC, MenB, rabies, HIV and respiratory syncytial virus 
(RSV). In vitro toxicity of LDH153R has been assessed, and in vivo nonclinical 
tolerability and safety of LHD153R and aluminium hydroxide/LHD153R have been 
evaluated in rats, dogs and non-human primates. LHD153R was not phototoxic, 
genotoxic or mutagenic (Ames and chromosomal aberration tests), and did not cause local 
or systemic toxicity in dogs or rats. Furthermore, aluminium hydroxide/LHD153R was 
well tolerated in rhesus monkeys. 
1.2  
Rationale 
The aim of this study is to assess the safety of aluminium hydroxide/LHD153R 
adjuvanted MenC-CRM197 conjugate vaccine (MenC-CRM197/Aluminium  
Hydroxide/LHD153R) and to compare the antibody-mediated immune response elicited 
by MenC-CRM197/Aluminium Hydroxide/LHD153R with the licensed aluminium 
hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®). 
Furthermore, a comprehensive set of exploratory objectives has been selected to assess 
the systemic exposure of LHD153 after intramuscular injection and to evaluate the quality 
of the specific immune response against MenC-CRM197 in detail and to evaluate  
biomarkers that may be predictive of safety and/or innate immune activation. 
The licensed Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) has been 
chosen as the primary vaccine candidate to assess the safety and immunopotentiating 
properties of aluminium hydroxide/LHD153R for several reasons. Firstly, the safety and 
immunogenicity profiles of the Meningococcal C-CRM197 Conjugate Vaccine have been 
well established through years of commercial use. Secondly, a more potent 
Meningococcal C-CRM197 Conjugate Vaccine might enable a reduction of the antigen 
dosage or the number of doses needed in infants between 2 and 12 months of age. Finally, 

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the Meningococcal C-CRM197 conjugate is a well-characterized, single antigen 
preparation which provides an ideal setting to explore the potential of this new aluminium 
hydroxide/LHD153R adjuvant. 
2.0  
OBJECTIVES 
2.1  
Primary Objectives 
Primary Safety Objective 
To assess the safety of MenC-CRM197/Aluminium Hydroxide/LHD153R as compared to 
that of aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
Primary Immunogenicity Objective 
To compare the antibody responses of MenC-CRM197/Aluminium Hydroxide/LHD153R 
and aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at 
Day 29, as measured by human complement serum bactericidal assay (hSBA) directed 
against N meningitidis serogroup C. 
2.2  
Secondary Objectives 
Secondary Immunogenicity Objective(s) 
1. To compare the antibody responses of MenC-CRM197/Aluminium 
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine at Day 8 and Day 181 after vaccination, as measured by 
hSBA directed against N. meningitidis serogroup C. Baseline antibody titers will also 
be measured by hSBA. 
2. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine, at Day 8, Day 29 and Day 181 after vaccination, as 
measured by an enzyme-linked immunosorbent assay (ELISA) to N. meningitidis 
serogroup C. Baseline antibody concentrations will also be measured by ELISA. 
2.3  
Exploratory Objectives 
1. To evaluate the systemic exposure of LHD153 at several early time-points after IM 
injection of MenC-CRM197/Aluminium Hydroxide/LHD153R or Meningococcal 
CCRM197 Conjugate Vaccine. 

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2. To explore the frequency of B cells specific for Men C polysaccharide and CRM197 
protein at baseline (Day 1) and at Day 8, Day 29 and Day 181 after vaccination with 
MenC-CRM197/Aluminium Hydroxide/LHD153R or the aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. Subsequently, the B cell 
repertoire of the antigen specific B cells and the specific antibody functionality will 
be analyzed in a selected subset of subjects. 
3. To explore the baseline T cell mediated immunity to CRM197 and to evaluate the 
frequency and quality of CRM197 specific T cells induced by 
MenCCRM197/Aluminium Hydroxide/ LHD153R compared to aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at Day 8 and Day 29. 
4. To evaluate biomarkers that may be predictive for safety and/ or innate immune 
activation. 
 

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3.0  
STUDY DESIGN 
3.1  
Overview of Study Design 
This is a Phase 1, randomized, observer blind, adjuvant dosage-escalation study. It will be 
performed at a single center. In total, approximately 80 healthy male and healthy 
nonpregnant female adults (18-45 years of age) will be enrolled in the study. 
Subjects will be randomized to receive a single IM vaccination of either the licensed 
aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine 
(Menjugate®) or the investigational vaccine, MenC-CRM197/Aluminium 
Hydroxide/LHD153R. 
The dosage of LHD153R will be escalated from 12.5 µg to 100 µg.  For the 
dosageescalation of LHD153R, the subjects will be enrolled into 1 of 4 cohorts, in a 
stepwise manner with 20 subjects per cohort. Subjects in all cohorts will be randomized 
in a 1:4 ratio, to receive either aluminium hydroxide adjuvanted Meningococcal C-
CRM197 Conjugate Vaccine (control) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R with increasing doses of LHD153R.Cohort 1 will receive 12.5 μg 
of LHD153R; Cohort 2 will receive 25 μg of LHD153R; Cohort 3 will receive 50 μg of 
LHD153R; and Cohort 4 will receive 100 μg of LHD153R (Table 3.1-1). 
Table 3.1-1: Subjects Randomized per Cohort and Treatment Dose Group 
Cohort 
Group 
Subjects/ 
Group 
MenC 
Dosage* 
(µg) 
Adjuvant Dosages 
Total 
Volume/Dose 
Total 
Subjects/Group 
Aluminium  
Hydroxide  
(mg) 
LHD153R  
(µg) 
1 
A 
4 
10 
1 
0 
0.5 mL 
20 
B 
16 
10 
1 
12.5 
0.5 mL 
2 
A 
4 
10 
1 
0 
0.5 mL 
20 
C 
16 
10 
1 
25 
0.5 mL 
3 
A 
4 
10 
1 
0 
0.5 mL 
20 
D 
16 
10 
1 
50 
0.5 mL 
4 
A 
4 
10 
1 
0 
0.5 mL 
20 
E 
16 
10 
1 
100 
0.5 mL 
*Conjugated to 12.5-25 µg CRM197 
All cohorts will have a staggered entry. For each cohort, the first 5 subjects (i.e. the first  
1:4 randomization block) to receive either aluminium hydroxide adjuvanted  

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Meningococcal C-CRM197 Conjugate Vaccine (n=1) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R (n=4) will be vaccinated at rate of 1 subject each day. 
After entry of the first 5 subjects in each cohort, the enrollment will be paused. The 
remaining 15 subjects for each cohort will be enrolled only after DMC review of the 
safety results obtained through Day 15 has been finalized (Table 3.1-2). Furthermore, 
after entry of all 20 subjects in each cohort, enrollment will be paused again. Enrollment 
of the first 5 subjects in the next cohort will only proceed after the Day 29 safety results 
of the previous cohort have been reviewed by the DMC. 
Table 3.1-2: Overview of staggered entry of subjects for each cohort 
Cohort 
1st Stage of 
enrollment 
MenC- 
CRM197/ 
Aluminium 
Hydroxide 
MenC- 
CRM197/ 
Aluminium  
Hydroxide 
/LHD153R 
2nd Stage of 
enrollment 
MenC- 
CRM197/ 
Aluminium 
Hydroxide 
MenC- 
CRM197/ 
Aluminium 
Hydroxide  
/LHD153R 
1 
First 5 subjects 
with  
vaccination rate 
of 1 subject/day 
1 
4 
Remaining 15 
subjects, after  
DMC review of  
Day 15 safety 
results 
3 
12 
2 
1 
4 
3 
12 
3 
1 
4 
3 
12 
4 
1 
4 
3 
12 
Post-vaccination procedures include collection of urine specimens at Day 8 and Day 29 
for safety analysis and blood specimens at Day 8, Day 29 and Day 181 for safety 
assessment and evaluation of the primary and secondary immunogenicity endpoints. 
Furthermore, additional blood specimens will be collected for assessment of exploratory 
endpoints at Day 1, Day 4, Day 8, Day 29 and Day 181 from those subjects that signed an 
additional informed consent concerning blood collection for exploratory assessment. 
3.2  
Study Period 
Each subject should expect to participate in the study for approximately 12 months, from 
the time of enrolment through the last study visit. 
3.3  
Blinding Procedures 
This study is designed as an observer-blind study. For each dosage cohort, subjects, 
investigators, laboratories and the sponsor will be blinded to vaccine assignments. 
To maintain the blindness within each cohort, designated nurse(s) or physician(s) will be 
responsible for administering the study vaccines to the subjects, and will be instructed not 
to reveal the identity of the study vaccines neither to the subject nor to the investigative 

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site personnel (investigator, study nurse, monitor) involved in the conduct or monitoring 
of the trial. This (these) designated individual(s) will have no contact with the subjects 
after the administration of the study vaccine. Furthermore, unblinded monitors are 
assigned to reconcile actual vaccine treatment. 
Study unblinding, at the group level, is planned for an Interim Analysis of the safety and 
immunogenicity data obtained up to Day 29 after all cohorts are enrolled and for full 
unblinding at the End of Study. 
Except in the case of medical necessity, a subject’s treatment should not be unblinded 
without the approval of the Sponsor. In such instance of medical emergency, every effort 
should be made to contact the Sponsor prior to unblinding. If unblinding should occur (by 
either accidental unblinding or emergency unblinding for a serious adverse event) prior to 
completion of the study, the investigator must promptly contact the Sponsor and 
document the circumstances on the appropriate forms. Instructions regarding emergency 
unblinding will be provided to the investigator. 
3.4  
Data Collection 
3.4.1  
Data Collected from Subjects 
The following data will be collected from each subject over the duration of their study 
participation: 
▫ Demographic Information 
▫ Adverse Events 
▫ Medical History 
▫ Concomitant Medications 
All data collected must only be identified using the Subject ID, as described in section 
5.2.3. 
3.4.2  
Tools Used for Data Collection 
Data will be recorded in the Subject Diary and collected on Case Report Forms (CRFs). 
Subject Diary 
Subject Diaries will be the only source document allowed for solicited local and systemic 
adverse events (including body temperature measurements), starting after the initial 24 

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hours post-vaccination observation period at the clinic. The following additional rules 
apply to documentation of safety information collected in the Subject Diary: 
1. No corrections or additions to the Subject Diary will be allowed after it is delivered to 
the site. 
2. Any blank or illegible fields on the Subject Diary must be described as missing in the 
CRF. 
3. Any corrections to the Subject Diary must be performed by the person completing the 
Subject Diary and should include a single strike through line through the incorrect 
value or text with a brief explanation for each change, the initials of that person, and 
date of correction. 
Case Report Forms 
This study utilizes Case Report Forms (CRFs) to collect study-related data from each 
subject. A qualified site staff member(s) is required to enter subject data in the CRFs in 
English based on the medical information available in each subject’s source record. The 
following additional rules apply to documentation of Subject Diary information collected 
in the CRFs: 
1. The site must enter all readable entries in the Subject Diary into the CRF, including 
those values that may be biologically implausible (e.g. body temperature: 400°C). 
2. Any illegible or implausible data should be reviewed with the subject. If an 
underlying solicited or unsolicited adverse event is described on review with the 
subject, this should be described in the source document and reported as an 
unsolicited adverse event in the Adverse Event CRF (e.g., if the subject above 
confirms body temperature of 40°C on the day in which body temperature: 400°C was 
written into his/her Subject Diary, this fever of 40°C should be recorded in the 
Adverse Event CRF). 
3. Any newly described safety information (including a solicited adverse event) must not 
be written into the Subject Diary and must be described in the study file as a verbally 
reported adverse event. Any adverse event reported in this fashion must be described 
as an unsolicited adverse event and therefore entered on the Adverse Event CRF. 
Data should be entered into the CRF in a timely fashion following each subject’s clinic 
visit, study procedure, or phone call. Each subject’s CRF casebook will be compared with 
the subject’s source records by a Novartis-approved study monitor (or designee) over the 
duration of the study in order to ensure data collection accuracy. 

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3.5  
Collection of Clinical Specimens 
The following clinical specimens are required to be collected from each subject in this 
study: 
▫ Blood 
▫ Urine 
Processing of each specimen should be completed by a qualified site member. Testing of 
clinical specimens will be performed by a Novartis or designated laboratory. 
Blood Specimens 
Before Vaccination 
▫ At the Pre-vaccination Screening Visit (between Day -21 to -3) one sample of 
approximately 10 ml blood will be drawn from all subjects. 
▫ At Visit 1 (Day 1) - prior to vaccination – two samples of approximately 10 ml blood 
will be drawn from all subjects. 
▫ At Visit 1 (Day 1) - prior to vaccination - the following blood samples will be drawn 
from subjects that gave additional informed consent for blood collection for 
exploratory assays: 
- 
One sample of  approximately 2 ml 
- 
Two samples of approximately 5 ml 
- 
One sample of approximately 50 ml 
After Vaccination 
▫ At Visit 1 (Day 1) - 1 hour after vaccination - one sample of approximately 2 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 2 hours after vaccination - one sample of approximately 2 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 4 hours after vaccination - one sample of approximately 2 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 

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▫ At Visit 1 (Day 1) - 6 hours after vaccination – two samples of approximately 5 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 8 hours after vaccination - one sample of approximately 2 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 24 hours after vaccination - the following blood samples will be 
drawn from subjects that gave additional informed consent for blood collection for 
exploratory assays: 
- 
One sample of approximately 2 ml 
- 
Two samples of  approximately 5 ml 
▫ At Visit 2 (Day 4) the following blood samples will be drawn from subjects that gave 
additional informed consent for blood collection for exploratory assays: 
- 
One sample of  approximately 2 ml 
- 
Two samples of  approximately 5 ml 
▫ At Visit 3 (Day 8) two samples of approximately 10 ml blood will be drawn from all 
subjects. 
▫ At Visit 3 (Day 8) the following blood samples will be drawn from subjects that gave 
additional informed consent for blood collection for exploratory assays 
- 
Two samples of approximately 5 ml 
- 
One sample of approximately 50 ml 
▫ At Visit 6 (Day 29) two samples of approximately 10 ml blood will be drawn from all 
subjects. 
▫ At Visit 6 (Day 29) one sample of approximately 50 ml blood will be drawn from 
subjects that gave additional informed consent for blood collection for exploratory 
assays. 
▫ At Visit 9 (Day 181) one sample of approximately 10 ml blood will be drawn from all 
subjects. 
▫ At Visit 9 (Day 181) one sample of approximately 50 ml blood will be drawn from 
subjects that gave additional informed consent for blood collection for exploratory 
assays. 

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The blood will be used for screening and safety laboratory assessments, immunological 
serology assays, pharmacokinetic analysis, cell mediated immunity assays and gene 
expression and protein production assays. See section 5.1.2, section 5.2.1 and section 7.0 
for additional details. 
Processing of each blood specimen should be completed in accordance with the study 
specific Clinical Specimen Laboratory Manual. 
The total amount of blood collected over the study period for all subjects will be 
approximately 80 ml. 
For subjects that signed an additional informed consent for blood collection for 
exploratory assays the total amount of blood collected over the study period will be 
approximately 344 ml. 
Urine Specimens 
Urine will be collected at the Pre-vaccination Screening Visit (between Day -21- to -3), at 
Visit 1 (Day 1; before vaccination), at Visit 3 (Day 8) and at Visit 6 (Day 29). Results 
will be recorded in the source document and CRF. 
Urine will be collected from all subjects for safety laboratory assessments and drugs-
ofabuse testing. Furthermore, urine will be collected for pregnancy testing in all females. 
3.6  
Stopping/Pausing Guidelines 
Stopping/pausing guidelines are predefined criteria that halt the conduct of a study (either 
a vaccine group or the entire study). These guidelines are used to ensure the safety of study 
subjects.  
The following criteria, with grading scales (see Appendix A to E), adapted from the  
CBER Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive vaccine Clinical Trials”, will be used for this study: 
Enrollment into the study will be paused for an unscheduled safety analysis if any of the 
following events occur across any subject groups:  
▫ One or more vaccine-related Grade 4 AE ▫ Six 
or more of the following, in any combination: 
- 
Vaccine-related Grade 3 AEs. 

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- 
Vaccine-related Grade 3 AEs leading to study withdrawal. 
After thorough analysis of the events (and possible unblinding), the DMC will decide if 
dosing should resume (see section 3.7). 
3.7  
Data Monitoring Committee 
A DMC will be formed to review safety data during scheduled periodic reviews. The 
DMC may also perform reviews on an ad hoc basis. DMC membership will consist of 3 
individuals who are external to the site and sponsor, and will include 1 statistician who is 
independent from the study team.  
Subjects will be enrolled in a stepwise manner in each of the four vaccine dosage cohorts  
(Cohort 1: 12.5 μg LHD153R, Cohort 2: 25 μg of LHD153R, Cohort 3: 50 μg of  
LHD153R and Cohort 4: 100 μg of LHD153R). The DMC will review all safety data, as 
described in the DMC charter and in the statistical analysis plan, after the first 5 subjects 
in each cohort have completed Visit 4 (Day 15) and their data are available for analysis, 
and before enrollment of the remaining subjects in each cohort. In addition, the DMC will 
review all safety data after enrollment in each cohort has been completed, after Visit 6 
(Day 29) data are available for analysis/review and before proceeding with enrollment of 
the subsequent cohort. 
The specific roles and responsibilities of the DMC members and other personnel involved 
will be documented in the DMC charter. The DMC charter will be finalized before the 
start of the study and will outline in detail all pausing and stopping rules according to the 
Clinical Study Protocol. 
3.8  
Premature Withdrawal from Study 
Subjects may withdraw at any time, or be dropped from the study at the discretion of the 
investigator should any untoward effects occur and/or for safety reasons. In addition, a 
subject may be withdrawn by the investigator or the Sponsor if he/she violates the study 
plan or for administrative reasons. The investigator or study coordinator must notify the 
Sponsor immediately when a subject has been withdrawn due to an adverse event. 
The circumstances above are referred to as premature withdrawal from the study, and the 
reason for premature withdrawal should be clearly documented and detailed in the source 
documentation. The investigator should make every attempt to evaluate the subject’s 
safety, including resolution of ongoing AEs, at the time of premature withdrawal. If a 
subject wants to withdraw from the study  prior to the last planned study visit, the subject 
will be asked to be followed for safety for the duration of the study. When a subject 

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withdraws, or is withdrawn, from the study, the procedures described in section 5.5.1 
should be completed if possible. 
The reasons for premature withdrawal from the study include: Adverse event, death, 
withdrawal of consent, lost to follow-up, administrative reason, and protocol deviation.  
These reasons are described in greater detail below. 
Adverse Event 
For any subject withdrawn from study participation prior to the planned Study  
Termination Visit, it is important to determine if an AE was associated with the reason for 
discontinuing the study. This AE must be identified on the AE CRF page by indicating 
“Withdrawn from study due to AE”. Any ongoing AEs at the time of study withdrawal 
must be followed until resolution or stabilization. 
Death 
For any subject withdrawn from study participation due to death, this should be noted on 
the Study Termination CRF page and the associated SAE that led to the death must be 
reported. 
Withdrawal of consent 
The subject can withdraw consent for participation in the study at any time without 
penalty or loss of benefit to which the subject is otherwise entitled. Reason for early 
termination should be deemed as “withdrawal of consent” if the subject withdraws from 
participation due to a non-medical reason (i.e., reason other than AE). If the subject 
intends to withdraw consent from the study, the investigator should clarify if the subject 
will withdraw completely from the study or if the subject will continue study participation 
for safety, or a subset of other study procedures. If the subject requests complete 
withdrawal from the study, no further study interventions will be performed with the 
subject. 
Lost to Follow-Up 
For subjects who fail to show up for study visits (clinic or telephone contacts), study staff 
is encouraged to make at least three documented attempts to contact the subject by 
telephone and at least one documented written attempt to contact the subject to encourage 
the completion of study termination procedures. These efforts to contact the subject must 
be recorded in the source document. The termination date for the subject to be captured 

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on the Study Termination CRF page is the date of the last contact (clinic visit or 
telephone) with the subject. 
Administrative Reason 
Examples for subjects withdrawn from the study due to administrative reason can include: 
Sponsor decision to terminate the study, subject meeting a pre-specified withdrawal 
criterion, subject discontinuation for insurance issues, moving, no time, etc. This reason 
should be noted in the Study Termination CRF page and any ongoing AEs at the time of 
study withdrawal must be followed until resolution/stabilization. 
If the clinical study is prematurely terminated by the Sponsor, the investigator is to 
promptly inform the study subjects and local EC/IRB and should assure appropriate 
therapy and follow up for the subjects. All procedures and requirements pertaining to the 
archiving of study documents should be followed. All other study materials (study 
medication/vaccines, etc.) must be returned to the Sponsor. 
For subjects who are withdrawn from the study due to receipt of an excluded 
medication/vaccination or due to significant protocol non-compliance, this reason should 
be noted in the Study Termination CRF page. 
Protocol Deviation 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. In general, subjects associated with protocol deviations 
may remain in the study unless continuation in the study jeopardizes the subject’s health, 
safety, or rights. 
Investigators will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring 
the study to request approval of a protocol deviation, as no authorized deviations are 
permitted. If the investigator feels a change to the protocol would improve the conduct of 
the study this must be considered a protocol amendment, and unless such an amendment 
is agreed upon by Novartis and approved by the IRB/EC and health authorities it cannot 
be implemented. 
Any subject who becomes pregnant during the study should be encouraged to continue 
participating in the study for safety follow-up. The site must complete a Pregnancy 
Report CRF (initial report) as soon as possible after learning of pregnancy occurrence 
(see section 7.1.6 for further details). If the subject withdraws from the study for any of 
the above categories except death, the site will obtain permission from the subject to 

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continue to remain in contact with her until the outcome of the pregnancy is known, even 
if the outcome is not known until after the subject reaches the end of the routine study 
period. 
3.9  
End of Study 
Most clinical trials intended to support the efficacy/immunogenicity and safety of an 
Investigational Product proceed to full completion of planned sample size accrual. 
A subject is considered to have completed this study when he/she has: (1) received the 
intended dose of study vaccine and (2) completed 365 days (Visit 12) of safety follow-up 
after receiving the study vaccine. 
Evaluation of the primary and/or secondary immunogenicity objectives requires the 
testing of biological samples from all study subjects, which can only be completed after 
all samples are collected. The last samples for the analysis of the primary and/or 
secondary objectives will be taken at Visit 9 (Day 181). For the purpose of this protocol, 
End of Study is defined as the completion of the testing of such biological samples, to be 
achieved no later than 8 months after collection of the last biological sample at Visit 9. 

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4.0  
SELECTION OF STUDY POPULATION 
4.1  
Inclusion Criteria 
In order to participate in this study, all subjects must meet all of the inclusion criteria 
described. 
1. Male or female individuals of 18 through 45 years of age on the day of informed 
consent. 
2. Healthy volunteers with good physical and mental health status, determined on the 
basis of the medical history, a physical examination and the results of the screening 
tests as judged by the investigator. 
3. Individuals who have voluntarily given written informed consent after the nature of 
the study has been explained according to local regulatory requirements, prior to 
study entry. 
4. Individuals who can comply with study procedures including follow-up1. 
5. Individuals that are able to understand, read and write German language. 
6. Females of childbearing potential who are using an effective birth control method2 
which they intend to use for at least 30 days after the study vaccination. 
4.2  
Exclusion Criteria 
Each subject must not have or must not be: 
1. Progressive, unstable or uncontrolled clinical conditions. 
2. Hypersensitivity, including allergy, to any component of vaccines, medicinal products 
or medical equipment whose use is foreseen in this study. 
                                                
1 A subject is considered to be compliant if the Investigator judges that the subject will complete the Subject 
Diary, return for all the follow-up visits and be available for telephone calls as scheduled in the study. 
2 The following birth control methods are considered effective: 
- 
Abstinence 
- 
Hormonal contraceptive (such as oral, injection, transdermal patch, implant) if used for at least 30 
days prior to informed consent 
- 
Diaphragm with spermicide, tubal occlusion device 
- 
Intrauterine device (IUD) 

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- 
Tubal ligation 
- 
Male partner using condom with spermicide 
- 
Male partner having been vasectomized at least six months prior to informed consent 
3. Clinical conditions representing a contraindication to intramuscular vaccination and 
blood draws. 
4. Abnormal function of the immune system resulting from: 
a. Clinical conditions. 
b. Systemic administration of corticosteroids (PO/IV/IM) for more than 14 
consecutive days within 90 days prior to informed consent. 
c. Administration of antineoplastic and prescription immunomodulating agents or 
radiotherapy within 90 days prior to informed consent. 
5. Received immunoglobulins or any blood products within 180 days prior to informed 
consent. 
6. Received an investigational or non-registered medicinal product within 30 days prior 
to informed consent or intend to participate in another clinical study at any time 
during the conduct of this study. 
7. Vulnerable subjects (e.g. persons kept in detention), study personnel or an immediate 
family or household member of study personnel, subjects with legal incapacity or 
limited legal capacity 
8. Any relevant deviation from the laboratory parameters at screening as judged by the 
investigator. 
9. Previously received any vaccine that included a meningococcal C antigen. 
10. Previously suspected or confirmed disease caused by N. meningitides. 
11. Had household contact with and/or intimate exposure to an individual with culture 
proven N. meningitides serogroup C. 
12. A positive serum or urine pregnancy test prior to the study vaccine administration or 
are currently lactating. 
13. A positive drugs-of-abuse test prior to the study vaccine administration 
14. Received any other vaccines within 30 days prior to enrolment in this study or who 
are planning to receive any vaccine within 30 days from the administration of study 
vaccines. 

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15. Any other condition that, in the opinion of the investigator, might interfere with the 
results of the study or pose additional risk to the subject due to participation in the 
study. 
4.3  
Criteria for Delay of Vaccination or Blood Draw 
There may be instances when individuals meet all eligibility criteria for vaccination or 
blood draw yet have a transient clinical circumstance which may warrant delay of 
vaccination or blood draw. Under such circumstances, a subject may be considered 
eligible for study enrolment after the appropriate window for delay has passed and 
inclusion/exclusion criteria have been rechecked, and if the subject is confirmed to be 
eligible. 
Reasons for delay of vaccination include: 
▫ Body temperature elevation ≥38.0°C (measured orally) within 3 days prior to intended 
study vaccination. 
▫ Use of antipyretics and/or analgesic medications within 24 hours prior to vaccination. 
Reasons for delay of blood draw include: 
▫ Subject has received a dose of systemic antibiotics less than 6 days before blood 
collection for the hSBA directed against N meningitidis serogroup C. 
 

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5.0  
STUDY PROCEDURES 
The sections that follow provide an overview of the procedures that are to be followed in 
enrolling, evaluating, and following subjects who participate in this clinical study. Visits 
can be either clinic visits or safety follow-up telephone calls, as specified in the Table 
below and in the Time and Events Tables 3 and 4 of the Study Synopsis. 
Table 5.0-1: Study procedures 
Visit Category 
Procedures 
Pre-vaccination Clinic Visit 
Section 5.1 describes procedures to be followed 
prior to subject enrollment, including: informed 
consent and screening procedures. 
Vaccination Clinic Visit 
Section 5.2 describes procedures to be followed 
during the vaccination clinic visit, including: 
prevaccination procedures, enrolment, 
randomization, vaccination and post-vaccination 
procedures. 
Post-vaccination Visits 
Section 5.3 describes follow-up clinic visits and 
safety follow-up calls. 
Unscheduled Visits 
Section 5.4 describes possible procedures to be 
followed at unscheduled clinic visit. 
Study Termination Visit 
Section 5.5 describes procedures to be followed at 
the last study visit for a subject (may include early 
termination visit). 
5.1 
Pre-vaccination Clinic Visit(s) 
The Pre-vaccination Clinic Visit must be performed in the period between Day -21 and 
Day -3. 
This section describes the procedures that must be performed for each potential subject 
prior to enrollment, including obtaining informed consent and screening. 
5.1.1  
Informed Consent 
"Informed consent" is the voluntary agreement of an individual or his/her legal 
guardian(s) to participate in research. Consent must be given with free will of choice, and 
without undue inducement. The individual must have sufficient knowledge and 
understanding of the nature of the proposed research, the anticipated risks and potential 
benefits, and the requirements of the research to be able to make an informed decision. 

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Informed consent following local IRB/EC guidance must be obtained before conducting 
any study-specific procedure (i.e., all of the procedures described in the protocol). Prior to 
any additional blood sample collection for exploratory objectives, a secondary informed 
consent must be signed by subjects. The process of obtaining informed consent should be 
documented in the subject source document in addition to maintaining a copy of the 
signed and dated informed consent. 
5.1.2  
Screening 
After an individual has consented to participate in the study and informed consent is 
signed, that individual will be given a unique Screening Number. The subject’s unique 
Screening Number will be documented in the Screening and Enrolment log. The 
eligibility of the subject will be determined based on the inclusion and exclusion criteria 
listed in section 4.0 and evaluated during this screening procedure. 
Screening procedures at the Pre-vaccination Clinical Visit (between Day -21 and Day -3) 
will include the following: 
▫ Review of demographic data, including age, gender, race, body weight and height. 
▫ Review of medical history, including but not limited to any medical history, ongoing 
illnesses or injuries that may be relevant to subject eligibility for study participation. 
Relevant medical history can also include any medical history that contributes to the 
understanding of an adverse event that occurs during study participation, if it 
represents an exacerbation of an underlying disease/pre-existing problem. 
▫ Perform physical examination, including but not limited to: 
- 
Assessment of general appearance 
- 
Collection of vital signs, including body temperature, blood pressure and 
respiratory rate 
- 
Examination of head, ears, eyes, nose and throat (HEENT) 
- 
Examination of skin 
- 
Auscultation of heart and lungs 
▫ Collection and review of prior and concomitant medications or vaccinations taken 
prior to start of study (refer to section 6.5 for further details). 
▫ Collection of any unsolicited AEs occurring prior to administration of the study 
vaccine. 

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▫ Blood draw (approximately 10 ml) for Safety Laboratory assessments, measurement of 
Hepatitis B surface antigen, anti-Hepatitis C virus antibodies, anti-HIV 1 and 2 
antibodies and serum pregnancy test (all women). 
▫ Urine sample for Safety Laboratory assessments and drugs-of-abuse testing. 
NOTE: A general physical examination is to be performed by a qualified health care 
practitioner. “Qualified health care practitioner” refers to any licensed health care 
professional who is permitted by institutional policy to perform physical examinations 
and who is identified within the Study Staff Signature Log 
Data collected during the Pre-vaccination Screening Clinic Visit must be written in the 
source document (see section 9.1) and will be captured in the Screening CRF Forms .In 
the event that the individual is determined ineligible for study participation, he/she is 
considered a screen failure. The reason for screen failure must be documented in the 
Screening and Enrolment log. 
5.2  
Vaccination Clinic Visit(s) 
This section describes the procedures to be performed at the Vaccination Clinic Visit 
(Visit 1, Day 1), including: pre-vaccination procedures, enrolment, randomization, 
prevaccination blood draw, vaccination and post-vaccination procedures. 
5.2.1  
Pre-vaccination Procedures 
During pre-vaccination procedures at Visit 1 (Day 1), the eligibility of the subject will be 
confirmed based on the inclusion and exclusion criteria listed in section 4.0. 
Pre-vaccination procedures at Visit 1 (Day 1) will include the following: 
▫ Review of systems by means of a structured interview that queries the subject as to any 
complaints the subject has experienced across each organ system. 
▫ Perform physical examination, including but not limited to: 
- 
Assessment of general appearance 
- 
Assessment of body weight and collection of vital signs, including body 
temperature, blood pressure and respiratory rate 
- 
Examination of head, ears, eyes, nose and throat (HEENT) 
- 
Examination of skin 

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- 
Auscultation of heart and lungs 
▫ Urine sample for Safety Laboratory assessments, pregnancy testing (all women) and 
drugs-of-abuse testing. 
▫ Collection of any unsolicited AEs occurring prior to administration of the study 
vaccine. 
▫ Collection and review of prior and concomitant medications or vaccinations taken, or 
recalled, since the last visit (refer to section 6.5 for further details). 
▫ One blood sample (approximately 10 ml) will be drawn from all subjects for serology 
testing. 
▫ One blood sample (approximately 10 ml) will be drawn from all subjects for baseline 
safety laboratory assessment. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of blood draws are provided in section 3.5. 
NOTE: A general physical examination is to be performed by a qualified health care 
practitioner. “Qualified health care practitioner” refers to any licensed health care 
professional who is permitted by institutional policy to perform physical examinations 
and who is identified within the Study Staff Signature Log. 
Data collected during pre-vaccination procedures at Visit 1 must be written in the source 
document (see section 9.1). In the event that the individual is determined ineligible for 
study participation, he/she is considered a screen failure. The reason for screen failure 
must be documented in the Screening and Enrolment log. If the individual is determined 
to be eligible for the study, he/she can be enrolled into the study. 
5.2.2 
Enrolment 
After an individual is determined to be eligible for study participation, the investigator 
will enroll the subject into the Electronic Data Capture (EDC) system where the 
randomization to the treatment group will occur. The Screening Number ceases to be used 
and remains in the Screening and Enrolment Log only. 
If for any reason, after signing the informed consent form (ICF), the subject who is 
eligible and enrolled fails to be randomized, this is called a randomization failure. In this 
case the early termination study procedures must be applied. The reason for all 
randomization failures should be recorded in the Screening and Enrolment Log and in the 

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source document as specified in the Source Data Agreement. The information on subjects 
who are randomization failures should be kept distinct from subjects who are screen 
failures, as described in section 5.1.2 and section 5.2.1 
5.2.3 
Randomization 
Enrolled subjects will be randomized and automatically assigned a unique Subject ID. 
The Subject ID will be the subject’s unique identification number for all CRFs and 
associated study documentation that will be used for the duration of the study. 
If for any reason, after signing the informed consent form (ICF), the eligible subject is 
enrolled and randomized but fails to undergo treatment, this is an Early Termination and 
the reason should be recorded in source document as specified in the Source Data 
Agreement. The information on these Early Termination subjects should be kept distinct 
in the source documentation from randomization failures, which are described in section 
5.2.2. 
5.2.4 
Vaccination 
After completing the pre-vaccination procedures at Visit 1 (Day 1), administer the 
vaccine to the subject according to the procedures described in section 6.3. Observe the 
blinding procedures described in section 3.3. 
5.2.5 
Post-vaccination Procedures 
The following post-vaccination procedures will be performed at Visit 1 (Day 1): 
▫ After vaccination, the subject will be observed for at least 30 minutes for any 
immediate solicited adverse events, body temperature measurement and unsolicited 
adverse events. All safety data collected during this time are to be recorded in the 
subject’s source document. 
▫ After vaccination, the subject will be observed for at least 24 hours at the clinic 
including observation for solicited AEs, body temperature measurement and 
unsolicited AEs. All safety data collected during this time are to be recorded in the 
subject’s source document. 
▫ From those subjects that signed an additional Informed Consent for exploratory assays, 
additional blood samples will be drawn in the first 24 hours after vaccination. Details 
regarding the number and volume of post-vaccination blood draws are provided in 
section 3.5. 

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After the initial 24 hours inpatient observation period, a Subject Diary will be used in this 
study to document solicited and unsolicited AEs until Day 15. The Subject Diary is the 
only source for collection of solicited AEs after the initial 24 hours inpatient observation 
period. Therefore, it is critical that the subject completes the Subject Diary correctly. 
The following training regarding completion of the Subject Diary must be provided: 
▫ The subject should be trained on how and when to complete each field of the Subject 
Diary. 
▫ The subject should be trained on how to self-measure local solicited adverse events 
and body temperature. The measurement of solicited local adverse events is to be 
performed using the ruler provided by the site. 
▫ The subject should be instructed how to perform body temperature measurement using 
the thermometer provided by the site. If the subject feels unusually hot or cold during 
the day, the subject should check body temperature. If the subject has fever, the 
highest body temperature observed that day should be recorded in the Subject Diary. 
Subject Diary training should be directed at the individual(s) who will perform the 
measurements of adverse events and who will enter the information into the Subject 
Diary. This individual may not be the subject, but if a person other than the subject enters 
information into the Subject Diary, this person’s identity must be documented in the 
Third Party Delegation section of the Subject Diary. Any individual that writes in the 
Subject Diary must receive training on completion of the Diary Card at the time of the 
visit. This training must be documented in the subject’s source record. 
The site should schedule the next study activity (clinic visit) with the subject. 
The subject will receive a written reminder of the next planned study activity. The subject 
will be reminded to complete the Subject Diary and to contact the site if there are any 
questions, and to contact the site immediately (or as soon as the subject is medically 
stable) if the subject has a medical condition that leads to a hospitalization or an 
emergency room visit. 
5.3  
Post-vaccination Visit(s) 
5.3.1 Subject Diary Reminder, Safety Follow-up and/or Post-vaccination  

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Blood Draw Clinic Visits 
Subject Diary reminder, Safety follow-up and/or post-vaccination blood draw clinic visits 
will be performed on Day 4 (Visit 2), Day 8 (Visit 3), Day 15 (Visit 4), Day 29 (Visit 6), 
Day 85 (Visit 7), Day 113 (Visit 8) and Day 181 (Visit 9) 
At Day 4 (Visit 2) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. All unsolicited AEs, SAEs, AESIs, 
medically attended AEs, AEs leading to study withdrawal and NOCD must be 
recorded on source documents. Any concomitant medications or vaccinations 
associated with those events must also be recorded on the source documents. 
▫ All subjects will be reminded to complete the Subject Diary and to contact the site if 
there are any questions, and to contact the site immediately (or as soon as the subject 
is medically stable) if the subject has a medical condition that leads to a 
hospitalization or an emergency room visit. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of blood draws are provided in section 3.5. 
▫ The site should schedule the next study activity (clinic visit) with the subject and the 
subject will receive a written reminder of the next planned study activity. 
At Day 8 (Visit 3) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. All unsolicited AEs, SAEs, AESIs, 
medically attended AEs, AEs leading to study withdrawal and NOCD must be 
recorded on source documents. Any concomitant medications or vaccinations 
associated with those events must also be recorded on the source documents. 
▫ The subject will be reminded to complete the Subject Diary and to contact the site if 
there are any questions, and to contact the site immediately (or as soon as the subject 

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is medically stable) if the subject has a medical condition that leads to hospitalization 
or an emergency room visit. The site should schedule the next study activity (clinic 
visit) with the subject and the subject will receive a written reminder of the next 
planned study activity. 
▫ Blood draw (approximately 10 ml) from all subjects for Safety Laboratory 
assessments. 
▫ Urine sample from all subjects for Safety Laboratory assessments. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of blood draws are provided in section 3.5. 
At Day 15 (Visit 4) the following procedures will be performed: 
▫ The Subject Diary will be collected and reviewed. No changes to the Subject Diary 
should be done at the clinic visit. For details on the Subject Diary see sections 3.4.2, 
and 5.2.5. The healthcare professional reviewing these data will discuss the symptoms 
(if any) reported by the subject and will determine if any additional diagnoses and/or 
adverse events are present. All unsolicited AEs until Day 15, solicited local and 
systemic AEs continuing beyond Day 15, SAEs, AESIs, medically attended AEs, AEs 
leading to study withdrawal and NOCD must be recorded on source documents. All 
concomitant medications or vaccinations associated with those events must also be 
recorded on the source documents. 
▫ The site should schedule the next study activity (safety phone call) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 29 (Visit 6) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. Any solicited local and systemic AEs 
continuing beyond Day 15, SAEs, AESIs, medically attended AEs, AEs leading to 
study withdrawal and NOCD must be recorded on source documents. All concomitant 

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medications or vaccinations associated with those events must also be recorded on the 
source documents. 
▫ Blood draw (approximately 10 ml) from all subjects for Safety Laboratory 
assessments. 
▫ Urine sample from all subjects for Safety Laboratory assessments. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of post-vaccination blood draws are provided in section 3.5. 
▫ The site should schedule the next study activity (clinic visit) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 85 and Day 113 (Visit 7 and Visit 8), the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. Any solicited local and systemic AEs 
continuing beyond Day 15, SAEs, AESIs, medically attended AEs, AEs leading to 
study withdrawal and NOCD must be recorded on source documents. All concomitant 
medications or vaccinations associated with those events must also be recorded on the 
source documents. 
▫ The site should schedule the next study activity (clinic visit) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 181 (Visit 9), the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 

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the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. Any solicited local and systemic AEs 
continuing beyond Day 15, SAEs, AESIs, medically attended AEs, AEs leading to 
study withdrawal and NOCD must be recorded on source documents. All concomitant 
medications or vaccinations associated with those events must also be recorded on the 
source documents. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of post-vaccination blood draws are provided in section 3.5. 
▫ The site should schedule the next study activity (safety phone call) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
5.3.2  
Safety Follow-up Calls 
Safety follow-up calls will be performed on Day 22 (Visit 5), Day 209 (Visit 10) and Day 
271 (Visit 11) and include the following procedures: 
▫ Safety follow-up calls are calls made to the subject by a healthcare professional 
designated on the site log. These calls will follow a script which will facilitate the 
collection of relevant safety information. The subject will be interviewed according to 
the script, and information relating to solicited local and systemic AEs persisting 
beyond Day 15 and unsolicited adverse events including SAEs, AESIs, medically 
attended AEs, AEs leading to study withdrawal, and/or NOCD and concomitant 
medications or vaccinations associated with those events. All safety information 
described by the subject must be written down in a designated location within the 
source document and not written on the script used for the telephone call. 
▫ The site should schedule the next study activity (clinic visit or study termination visit) 
with the subject. 
▫ The subject will be reminded to contact the site if there are any questions and to 
contact the site immediately (or as soon as the subject is medically stable) if the 
subject has a medical condition that leads to a hospitalization or an emergency room 
visit. 

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5.4  
Unscheduled Visits  
An unscheduled visit describes a non-routine study visit triggered by a specific event. 
These could include anticipated or unanticipated adverse events or interventions. 
The following procedures should be carried out for all unscheduled visits: 
1. Evaluate the subject’s vital signs body temperature, heart rate, and blood pressure and 
perform a symptom-directed physical examination. 
2. Record any observed AEs in the source documents. 
3. Record any concomitant medications or vaccinations associated with AEs in the 
source documents. 
5.5  
Study Termination Visit 
The study termination visit is scheduled on Day 366 (Visit 12). The termination visit is a 
clinic visit. The date of termination is the date of the last contact  in which the subject’s 
health status was assessed or, in cases where the subject does not agree to any further 
safety follow-up, it is the date consent is withdrawn. This date should be recorded on the 
termination CRF page. For visit procedures to be performed for a subject whose planned 
study participation ends prematurely, please see section 5.5.1. 
At the Study Termination clinic visit the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. 
▫ The healthcare professional reviewing these data will discuss the symptoms (if any) 
reported by the subject and will determine if any additional diagnoses and/or adverse 
events are present. 
▫ Medically attended AEs, SAEs, NOCDs, or AESIs will be recorded on source 
documents. 
▫ All medications taken or vaccines received will also be recorded on the source 
documents. 
▫ The site will review with the subject the plan of when information relating to the 
subject’s participation in the study may be available (e.g., study results, treatment 
assignments). It will also be discussed how information relating to the subject’s 

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participation in the study will be shared with the subject’s healthcare provider, if the 
subject chooses to share this information. 
▫ The site will complete the termination CRF page and this will mark the completion of 
the subject’s participation in the study. 
5.5.1  
Early Termination Visit 
When a subject is withdrawn from treatment or withdraws from the study, the investigator 
will notify the Sponsor and, when possible, will perform the procedures listed below. 
The reason(s) for the early termination must be included in the subject’s source 
documentation. If the Early Termination Visit is a telephone call, collect as much 
information as possible. Early Termination Visits include subjects who were randomized 
but not treated. 
At the clinic visit or during the telephone call, the following procedures should be 
performed, when possible: 
▫ Collection and review of Subject Diary (if not already collected). 
▫ Interview of subject to collect unsolicited adverse events, medically attended AEs, 
AEs leading to withdrawal, SAEs, AESIs, and NOCD. 
▫ Interview of subject to collect concomitant medications and/or vaccinations. 
▫ Symptom-directed physical assessment, at least including measurement of vital signs 
(body temperature [via oral route], respiratory rate, blood pressure, heart rate) and a 
check of general appearance (in case of clinic early termination visit). 
▫ Draw a blood sample (approximately 10 ml) and an urine sample for Safety 
Laboratory assessment (in case of clinic early termination visit). 
▫ The site will review with the subject the plan of when information relating to the 
subject’s participation in the study may be available (e.g., study results, treatment 
assignments). It will also be discussed how information relating to the subject’s 
participation in the study will be shared with the subject’s healthcare provider, if the 
subject chooses to share this information. 
▫ The site will complete the termination CRF page and this will mark the completion of 
the subject’s participation in the study. 
 

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6.0  
TREATMENT OF SUBJECTS 
All vaccines associated with this study are to be stored separately from other vaccines and 
medications in a secure location under appropriate storage conditions with temperature 
monitoring. All vaccines associated with this study must be checked for expiration 
date prior to use. Expired vaccines must not be administered to subjects. 
6.1  
Study Vaccine(s) 
The term ‘study vaccine’ refers to those vaccines provided by the Sponsor, which will be 
evaluated as part of the study objectives. The study vaccines specific to this study are 
described in Table 6.1-1. 
Table 6.1-1: Study Vaccine Composition 
Group A (Control) Meningococcal C-CRM197 Conjugate Vaccine 
 
Vaccine Component 
Quantity per 0.5 ml dose 
 
 
Vial Containing Vaccine Conjugate 
 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
 
Aluminum Hydroxide Solvent Components (for 0.5 mL dose) 
 
Aluminum hydroxide 
1.0 mg 
Sodium Chloride 
3.5 mg 
Sterile water for injection, up to 
0.5 ml 
 
 
Group B (12.5µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
 

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Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
12.5 µg 
Sodium Chloride 
3.4 mg 
Histidine  
0.1 mg 
Tris 
30 µg 
Sterile water for injection, up to 
0.5 ml 
 
 
Group C (25 µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
25 µg 
Sodium Chloride 
3.4 mg  
Histidine 
0.2 mg 
Tris 
61 µg 
Sterile water for injection, up to 
0.5 ml 

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Group D (50µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
50 µg 
Sodium Chloride 
3.2 mg 
Histidine 
0.4 mg 
Tris 
121 µg 
Sterile water for injection, up to 
0.5 ml 
 
Group E (100µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 

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Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
100 µg 
Sodium Chloride 
2.9 mg 
Histidine 
0.8 mg 
Tris 
243 µg 
Sterile water for injection, up to 
0.5 ml 
6.2  
Non-Study Vaccines 
The term ‘non-study vaccine’ refers to those vaccines which will be intentionally given to 
study subjects but not formally included in the analysis of study objectives. 
No non-study vaccines are planned for this study. Any non-study vaccines administered 
during the study conduct will be captured in the eCRF as concomitant medications and/or 
vaccinations. 
6.3  
Vaccine Preparation and Administration 
The investigator or designee will be responsible for oversight of the administration of 
vaccine to subjects enrolled in the study according to the procedures stipulated in this 
study protocol. All vaccines will be administered only by unblinded personnel who are 
qualified to perform that function under applicable local laws and regulations for the 
specific study site. 
The vaccine components will be provided in 5 separate kits (i.e. onefor the control and 
one for each of the 4 dosage groups). The vaccine components must be mixed prior to 
vaccination taking into account the appropriate aseptic procedures. Detailed vaccine 
preparation and administration instructions, including the maximal administration period, 
will be provided to investigators prior to study start and must be filed in the Investigator 
Site File. 
PRECAUTIONS TO BE OBSERVED IN ADMINISTERING STUDY VACCINE: 
- 
Prior to vaccination, subjects must be determined to be eligible for study vaccination 
and it must be clinically appropriate in the judgment of the investigator to vaccinate. 
Eligibility for vaccination prior to first study vaccine administration is determined by 
evaluating the entry criteria outlined in protocol sections 4.0. 

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- 
Study vaccines must not be administered to individuals with known hypersensitivity 
to any component of the vaccines. 
- 
Standard immunization practices are to be observed and care should be taken to 
administer the injection intramuscularly. Before administering vaccine, the 
vaccination site is to be disinfected with a skin disinfectant (e.g., 70% alcohol). Allow 
the skin to dry. DO NOT inject intravascularly. 
- 
As with all injectable vaccines, trained medical personnel and appropriate medical 
treatment must be readily available in case of anaphylactic reactions following 
vaccine administration. For example, epinephrine 1:1000, diphenhydramine, and/or 
other medications for treating anaphylaxis should be available. 
6.4  
Misadministration of Vaccine 
Misadministration is defined as receiving a dose of study vaccine that was not 
reconstituted as instructed or administered by a different route from the intended route of 
administration. An overdose of study vaccine (whether accidental or intentional) is 
defined as receiving more than the dosing quantities referred to in Table 6.1-1 
Any misadministration or overdose of study vaccine detailed in this protocol must be 
treated as a serious adverse event (whether or not associated with an adverse experience) 
and reported as such within 24 hours to the Sponsor. 
6.5  
Prior and Concomitant Medications and Vaccines 
All medications, vaccines and blood products taken or received by the subject within 180 
days prior to the start of the study are to be recorded in the Prior and Concomitant 
Medications eCRF. 
Medications taken for prophylaxis are those intended to prevent the onset of symptoms. 
Medications taken for treatment are intended to reduce or eliminate the presence of 
symptoms that are present. 
The use of antipyretics and/or analgesic medications within 24 hours prior to vaccination 
must be identified and the reason for their use (prophylaxis versus treatment) must be 
described in the source document and/or Subject Diary and must be recorded in the eCRF 
as concomitant medications. NOTE: Use of antipyretics/analgesics within 24 hours prior 
to vaccine administration is a reason to delay study vaccination (see section 4.3) 

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Concomitant medications include all medications (including vaccines) taken 
by/administered to the subject at and after enrolment and must be documented in the Prior 
and Concomitant Medications eCRF. 
When recording concomitant medications/vaccines, they should be checked against the 
study entry criteria in section 4.0, to ensure that the subject should be enrolled in the 
study. 
6.6  
Vaccine Supply, Labeling, Storage and Tracking 
The Sponsor will ensure the following: 
▫ Supply the study vaccines. 
▫ Appropriate labeling of all study vaccines provided that complies with the legal 
requirements of each country where the study is to be performed. 
The investigator must ensure the following: 
▫ Acknowledge receipt of the study vaccines by a designated staff member at the site, 
including: 
- 
Confirmation that the vaccines were received in good condition 
- 
Confirmation to the Sponsor of the temperature range during shipment from the  
Sponsor to the investigator’s designated storage location 
- 
Confirmation by the Sponsor that the vaccines are authorized for use. 
▫ Proper storage of the study vaccines, including: 
- 
Storage in a secure, locked, temperature-controlled location. 
- 
Proper storage according to the instructions specified on the labels. 
- 
Appropriate record keeping and inventory of the study vaccines, including regular 
documentation of adequate storage temperature. 
▫ Appropriate use of the study vaccines, including: 
- 
No use of vaccines prior to receipt of authorization for use from the Sponsor. 
- 
Use only in accordance with the approved protocol. 
- 
Proper handling, including confirmation that the vaccine has not expired prior to 
administration. 

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- 
Appropriate documentation of administration of vaccines to study subjects 
including: 
▪ 
Date, dosage, batch/lot numbers, expiration dates, unique identifying 
numbers assigned to subjects and study vaccines, and time of vaccine 
administration. This information will be maintained in an accountability log 
that will be reviewed by the site monitor. 
▪ 
Reconciliation of all vaccines received from the Sponsor. Reconciliation is 
defined as maintaining records of which and how many vaccines were 
received, which vaccines were administered to subjects, which vaccines 
were destroyed at the site, and which vaccines were returned to the Sponsor, 
as applicable. 
▫ Proper adherence to the local institutional policy with respect to destruction of study 
vaccines. 
▫ Complete record keeping of vaccine use, wastage, return or destruction, including 
documentation of: 
- 
Copy of the site’s procedure for destruction of hazardous material. 
- 
Number of doses destroyed, date of destruction, destruction code (if available), 
method of destruction, and name of individual performing destruction. 
Vaccines that have been stored differently from the manufacturer’s indications must not 
be used unless the Sponsor provides written authorization for use. In the event that the use 
cannot be authorized, the Sponsor will make every effort to replace the vaccine supply. 
All vaccines used in conjunction with this protocol must be stored separately from normal 
hospital/practice stocks to prevent unintentional use of study vaccines outside of the 
clinical study setting. 
Monitoring of vaccine accountability will be performed by the study monitor during site 
visits and at the completion of the study. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator must ensure that all unused study vaccines, packaging and supplementary 
labels are destroyed locally (upon approval from Sponsor) or returned to the Sponsor. 

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7.0  
ASSESSMENTS 
7.1  
Safety Assessment 
The measures of safety used in this study are based on previous study data and based on 
comparable routine clinical/laboratory procedures. They include a close vigilance for, and 
stringent reporting of selected local and systemic adverse events routinely monitored in 
vaccine studies as indicators of reactogenicity. 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product at any dose that does 
not necessarily have to have a causal relationship with this treatment. Therefore, an AE 
can be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the investigational product. 
This definition includes intercurrent illnesses or injuries and exacerbation of pre-existing 
conditions. 
The period of observation for AEs extends from the time the subject signs informed 
consent until he or she completes the specified safety follow-up period (Day 366) or 
terminates the study early (whichever comes first). AEs occurring after the informed 
consent form is signed but prior to receiving study vaccine/product will be documented as 
an adverse event and recorded within the source documents. However, any AEs occurring 
prior to receipt of any study vaccine will be analyzed separately from “treatment 
emergent” AEs (AEs occurring after administration of the first study vaccine). 
Adverse events are collected as either solicited or unsolicited adverse events. Solicited 
events are derived from organized data collection systems, such as Subject Diaries or 
interview. 
7.1.1 
Solicited Adverse Events 
The term “reactogenicity” refers to solicited signs and symptoms (“solicited adverse 
events”) occurring in the hours and days following a vaccination, to be collected by the 
subject after the first 24 hours inpatient observation period at Day 1until Day 15, using a 
pre-defined Subject Diary. 
The following solicited adverse events are included in the Subject Diary. Each adverse 
event is to be assessed using the scoring system shown in Appendix A (Solicited Local 
AEs) and Appendix B (Solicited Systemic AE): 

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Solicited Local Adverse Events 
Solicited local AEs include: 
- 
injection site erythema 
- 
injection site induration 
- 
injection site pain 
- 
injection site swelling Solicited Systemic Adverse Events 
Solicited systemic AEs include: 
- 
body temperature ≥38.0°C (as measured orally) 
- 
loss of appetite 
- 
nausea 
- 
fatigue 
- 
generalized myalgia 
- 
generalized arthralgia 
- 
headache 
- 
chills 
- 
vomiting 
- 
diarrhea 
- 
generalized rash 
- 
urticaria 
Other Solicited Data 
Other solicited data collected per Subject Diary include: 
▫ Use of analgesics/antipyretics recorded as “absent” or “present” and summarized by 
“for treatment” or “for prophylaxis” 
▫ Body temperature as recorded daily, ideally at same time, by the oral route 
The study staff must review the data entered into the Subject Diary as described in 
sections 3.4.2 and 5.3.1. 

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NOTE: Any solicited adverse event that meets any of the following criteria must be 
entered into the subjects’ source documents (see section 9.1) and also as an adverse event 
in the eCRF: 
▫ Solicited local or systemic adverse event that continues beyond Day 15 after 
vaccination. 
▫ Solicited local or systemic adverse event that leads to a visit to a healthcare provider 
(medically attended adverse event, see section 7.1.3). 
▫ Solicited local or systemic adverse event leading to the subject withdrawing from the 
study or the subject being withdrawn from the study by the investigator (adverse event 
leading to withdrawal, see section 7.1.3). 
▫ Solicited local or systemic adverse event that otherwise meets the definition of a 
serious adverse event (see section 7.1.4). 
7.1.2  
Unsolicited Adverse Events 
An unsolicited adverse event is an adverse event that was not solicited using a Subject 
Diary and that was spontaneously communicated by a subject who has signed the 
informed consent. 
7.1.3  
Evaluation of Adverse Events 
Every effort should be made by the investigator to evaluate safety information reported by 
a subject for an underlying diagnosis and to capture this diagnosis as the event in the AE 
page. In other words, the practice of reporting only symptoms (e.g., “cough” or “ear 
pain”) are better reported according to the underlying cause (e.g., “asthma exacerbation” 
or “otitis media”). 
The severity of events reported on the Adverse Events CRF will be determined by the 
investigator as: 
Mild: 
transient with no limitation in normal daily activity. 
Moderate: 
some limitation in normal daily activity. 
Severe: unable to perform normal daily activity. 
The relationship of the study treatment to an AE will be determined by the investigator 
based on the following definitions: 

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1. Not Related 
The AE is not related to an investigational vaccine if there is evidence that clearly 
indicates an alternative explanation. If the subject has not received the vaccine, the timing 
of the exposure to the vaccine and the onset of the AE are not reasonably related in time, 
or other facts, evidence or arguments exist that reasonably suggest an alternative 
explanation, then the AE is not related. 
2. Possibly Related 
The administration of the investigational vaccine and AE are considered reasonably 
related in time and the AE could be explained by exposure to the investigational vaccine 
or by other causes. 
3. Probably Related 
Exposure to the investigational vaccine and AE are reasonably related in time and no 
alternative explanation has been identified. 
The relationship of the study treatment to an unsolicited AE will be determined by the 
investigator.  
Note: solicited AEs will not be evaluated for relationship to study treatment. Grading for 
severity of solicited local and systemic AEs is described in section 7.1.1. 
Adverse events will also be evaluated by the investigator for the co-existence of any of 
the other following conditions: 
▫ “Medically attended adverse event”: an adverse event that leads to a visit to a 
healthcare provider. 
▫ “New onset of chronic disease” (NOCD): an adverse event that represents a new 
diagnosis of a chronic medical condition that was not present or suspected in a subject 
prior to study enrolment. 
▫ AEs leading to withdrawal: adverse events leading to study or vaccine withdrawal. 
All AEs, regardless of severity, will be monitored until resolution or until the investigator 
assesses them as chronic or stable. All subjects experiencing AEs - whether considered 
associated with the use of the study vaccine or not - must be monitored until symptoms 
subside and any abnormal laboratory values have returned to baseline, or until there is a 
satisfactory explanation for the changes observed, or until death, in which case a full 
pathologist’s report should be supplied, if possible. 

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7.1.4  
Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose results in one or more of the following: 
▫ Death. 
▫ Is life-threatening (i.e., the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred); it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
▫ Required or prolonged hospitalization. 
▫ Persistent or significant disability/incapacity (i.e., the event causes a substantial 
disruption of a person’s ability to conduct normal life functions). 
▫ Congenital anomaly/or birth defect. 
▫ An important and significant medical event that may not be immediately life 
threatening or resulting in death or hospitalization but, based upon appropriate 
medical judgment, may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed above. 
Adverse events which do not fall into these categories are defined as non-serious. 
It should be noted that a severe adverse event need not be serious in nature and that a 
serious adverse event need not, by definition, be severe. 
Serious adverse events will be captured both on the Vaccines Serious Adverse Event 
(VSAE) form as well as on the AE CRF. All SAEs will be evaluated by the investigator 
for relationship of the event to study vaccine. SAEs that are judged to be possibly or 
probably related to the study vaccine should be reported to the Sponsor as 
related/suspected events. 
The relationship of the study treatment to an SAE will be determined by the investigator 
based on the following definitions: 
1. Related/suspected 
The SAE is judged by the investigator to be possibly or probably related to the study 
vaccine on the AE CRF page (see section 7.1.3). 

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2. Not Related 
The SAE is not related if exposure to the study vaccine has not occurred, or the 
occurrence of the SAE is not reasonably related in time, or the SAE is considered 
unlikely to be related to use of the study vaccine, i.e., there are no facts (evidence) or 
arguments to suggest a causal relationship. 
The relationship of the study vaccine to an SAE will be determined by the investigator. 
In addition, SAEs will be evaluated by the Sponsor or designee for “expectedness.” An 
unexpected AE is one that is not listed in the current Summary of Product Characteristics 
or the Investigator’s Brochure or an event that is by nature more specific or more severe 
than a listed event. 
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded on the Medical History CRF. If the onset of an event occurred before the subject 
entered the study (e.g., any pre-planned hospitalization for conditions like cosmetic 
treatments or for non-emergency routine visits for a pre-existing condition), the 
hospitalization would not lead to an AE being classified as serious unless, in the view of 
the investigator, hospitalization was prolonged as a result of participation in the clinical 
study or was necessary due to a worsening of the pre-existing condition. 
7.1.4.1  
Adverse Events of Special Interest 
Certain adverse events of special interest (AESIs) are monitored for after the 
administration of immunostimulatory agents. All subjects enrolled in the study will be 
monitored for AESIs for the entire follow-up period. The AESIs will be defined 
according to MedDRA preferred terms. The investigator will be provided with a list of 
AESIs prior to study start. Receipt of this list will be documented and stored, along with 
the list of AESIs, in the Investigator Site File. During the course of the trial the list of 
AESIs may change. If this occurs, the investigators will be advised of the change and 
confirmation of receipt will be documented. The updated list of AESIs and 
documentation of receipt are also stored in the Investigator Site File. The occurrence of 
any of these adverse events will be treated as a serious adverse event (SAE), meeting the 
criterion of a “medically important event.” 
Subjects will be assessed for diagnosis of an AESI at the following visits: 
- 
Pre-vaccination clinic visit (Day -21 to Day -3)  
- 
Visit 1 (Day 1, pre-vaccination) 

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- 
Visit 2 (Day 4) - 
Visit 3 (Day 8) 
- 
Visit 4 (Day 15) 
- 
Visit 5 (Day 22; Safety Follow-Up Call) 
- 
Visit 6 (Day 29) - 
Visit 7 (Day 85) 
- 
Visit 8 (Day 113) 
- 
Visit 9 (Day 181) 
- 
Visit 10 (Day 209; Safety Follow-Up Call) 
- 
Visit 11 (Day 271; Safety Follow-Up Call) 
- 
Visit 12 (Day 366; Study Termination Visit) 
At these visits a qualified health care practitioner listed on the site’s responsibilities and 
delegation logs will conduct a review of organ systems and a targeted physical exam and 
will evaluate subjects for any new signs or symptoms that could indicate one of the 
AESIs as specified in the list of AESIs stored in the Investigator Site File. They will also 
interview the subject about recent medical history and any new diagnosis that could 
indicate an AESI. Medical records related to any new medical event or diagnosis will be 
requested, reviewed by the site staff, and recorded in the subject’s source documents. 
A diagnosis of an AESI will be reported in the same manner and time frame as an SAE 
using the VSAE form. The investigator must notify Novartis within 24 hours. The AESI 
diagnosis, as well as any medications taken to treat the condition, will be recorded in the 
subject’s source documents and on the Adverse Events eCRF. 
7.1.5  
Methods for Recording Adverse Events and Serious Adverse Events 
All findings regarding Adverse Events must be reported on an Adverse Events CRF and 
on the VSAE form, if applicable, which is part of the Investigator Site File. All findings 
in subjects experiencing AEs must be reported also in the subject's source document. 
All SAEs which occur during the course of the study, whether considered to be associated 
with the study vaccination or not, must be reported within 24 hours of the site becoming 
aware of the event to Novartis or its designee. Specific instructions and contact details 
for collecting and reporting SAEs to Novartis will be provided to the investigator. 
All SAEs are also to be documented on the Adverse Events CRF. Any medication or 
other therapeutic measures used to treat the AE will be recorded on the appropriate 
CRF(s) in addition to the outcome of the AE. 

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After receipt of the initial report, representatives of Novartis or its designee will contact 
the investigator if it is necessary to obtain further information for assessment of the event. 
All SAEs must be reported by the investigator to his/her corresponding EC and applicable 
regulatory authorities in accordance with institutional policy/regulatory requirements and 
adequate documentation of this notification must be provided to the Sponsor. 
Novartis or its designee must also comply with the applicable regulatory requirement(s) 
related to the reporting of suspected unexpected serious adverse vaccine reactions (also 
known as SUSARs) to the regulatory authority(ies) and the IRB/EC. If a SUSAR or other 
safety signal relating to use of one of the study vaccines is reported to Novartis or its 
designee, the Sponsor will communicate the information to the investigator and the 
investigator will be responsible for submitting this information to the EC and other 
relevant authorities. 
7.1.5.1 
Post-Study Events 
Any suspected SAE that occurs outside of the protocol-specified follow-up period or after 
the end of the study but considered to be caused by the study vaccine must be reported to 
Novartis or its designee. These SAEs will be processed by Novartis or its designee as 
during the course of the study, until 3 months after the last scheduled study visit. 
Instructions and contact details for collecting and reporting these suspected SAEs will be 
provided to the investigator. 
7.1.6  
Pregnancies 
To ensure subjects’ safety, each pregnancy in a subject after study vaccination must be 
reported to Novartis within 72 hours of the site learning of its occurrence. If the subject 
agrees to submit this information, the pregnancy must be followed to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. This follow-up should occur even if intended duration of safety follow-up 
for the study has ended. 
Pregnancy data must be recorded on a Pregnancy Report CRF (initial report) and 
Pregnancy Follow-Up CRF (outcome report) and reported to Novartis. Instructions and 
contact details for submitting the Pregnancy CRFs will be provided to the investigator. 
Any pregnancy outcome meeting the definition of a SAE (see section 7.1.4) must also be 
reported on the VSAE Report Form. 

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7.1.7  
Safety Laboratory Measurements 
Blood and urine samples will be collected from all subjects at the Pre-vaccination 
Screening, at Visit 1, at Visit 3 and at Visit 6 as outlined in Time and Events Table 3. The 
blood safety laboratory assessments will include sodium, potassium, bicarbonate, blood 
urea nitrogen, creatinine, liver function tests (ALT, AST), a complete blood count and 
Creactive protein. The urine safety laboratory assessments will include protein, glucose 
and red blood cells. An additional blood and urine sample will be collected in case of a 
clinic Early Termination Visit as outlined in section 5.5.1. 
All testing will be conducted by qualified and certified laboratories. Abnormal laboratory 
values will be defined following the FDA CBER Guidance for Industry “Toxicity  
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials” dated September 2007, or the institution’s normal ranges if they 
differ from CBER guidance. Please see Appendix C, D and E for further details on the 
Toxicity Grading Scales according to CBER. 
Retesting may be performed in case of abnormal values per guidance of the investigator.  
Retest results will not be captured in the eCRF. 
7.2  
Efficacy Assessment 
Efficacy measurement will not be performed as part of this study. 
7.3  
Immunogenicity Assessment 
The measures to assess the primary and secondary immunogenicity endpoints for this 
study are standard, i.e., widely used and generally recognized as reliable, accurate, and 
relevant (able to describe the quality and extent of the immune response). 
The assay’s used in this study to assess the primary and immunogenicity endpoints are 
human serum bactericidal assay (hSBA) and ELISA specific for meningococcal 
serogroup C 
The hSBA is a functional measure of the ability of specific antibodies, in conjunction 
with human complement, to kill meningococcal serogroup C indicator strains, and is 
widely used and generally recognized as the serological correlate of protection. The 
specific ELISA will be used to measure the induction of antibodies directed against 
meningococcal serogroup C following vaccination with the study vaccines. 

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Blood samples (approximately 10 ml) to obtain serum for hSBA and ELISA assays will 
be collected at Day 1, Day 8, Day 29 and Day 181 (refer to section 3.5 for detailed 
specimen collection procedures). 
Testing will be conducted by a Novartis or designated laboratory in a blinded manner 
towards the treatment group. Laboratory contact details are listed in the Protocol 
Ancillary Document. 
All data will be captured at the laboratory and transferred via Electronic Data Transfer  
(EDT) 
Details on all blood sample handling steps are described in the Clinical Specimen Lab 
Manual provided to the study site. 
7.4 
Exploratory Measurements 
In those subjects who agree to a separate Informed Consent, additional blood samples will 
be collected at Day 1, Day 4, Day 8, Day 29 and Day 181 for exploratory measurements. 
The purpose of these exploratory measurements is to assess the systemic exposure of 
LHD153, to further delineate vaccine induced antigen specific immune responses and to 
evaluate  biomarkers that may be predictive for safety and/or innate immune activation. 
All exploratory measurements will be conducted by a Novartis or a designated laboratory. 
Laboratory contact details are listed in the Protocol Ancillary Document. 
Exploratory measurements may be performed after the Clinical Study Report (CSR) has 
been completed, in which case these data will be submitted as an addendum to the CSR. 
Systemic exposure of LHD153R 
Systemic exposure of LHD153 will be assessed by analyzing LHD153 blood plasma 
levels at Day 1 (baseline, 1, 2, 4, 8 and 24h after vaccination) and Day 4 using 
LC/MS/MS. Time-points for assessment of clinical exposure of LHD153 have been 
selected based on non-clinical data in dogs and rats. 
Vaccine-induced antigen-specific immune responses 
The frequency of B cells specific for MenC polysaccharide and CRM197 will be 
determined by enzyme-linked immunosorbent spot (ELISPOT) at Day 1, Day 8, Day 29 
and Day 181 in order to evaluate the baseline specific B-cell frequency (Day 1), the peak 
of plasmablast responses (Day 8), the peak of B cell memory responses (Day 29), and the 
persistence of memory B cell responses (Day 181). 

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Subsequently, the diversity of the antigen specific B-cell repertoire as well as the specific 
antibody functionality will be analyzed in a selected subset of subjects. The selection of 
the subset will be based on the most pronounced response to the study vaccines when 
compared to baseline as determined by the primary and secondary immunogenicity 
assessment. 
The diversity of the elicited B-cell receptors will be assessed through sequence analysis of 
complementary DNA (cDNA) generated from immunoglobulin (Ig) messenger RNA 
(mRNA). The Ig cDNAs will be analyzed from antigen-specific B cells obtained at Day 
1, Day 29 and/or Day 181 and plasmablasts isolated at Day 8. The analysis of the B-cell 
receptor diversity does not have the intent nor the capability to identify or rule out any 
genetic modifications in the RNA or DNA that are presumably linked to disease or 
predisposition to disease. 
To evaluate the functionality specific antibodies induced by the study vaccines, 
biochemical and cell-based assays will be performed on a selected subset of serology 
samples collected for the assessment of the primary and secondary immunogenicity 
endpoints at Day 1, Day 8, Day 29 and Day 181. The evaluation of antigen specific 
antibody functionality includes determination of the antibody isotype and the antibody 
glycosylation state. Furthermore, the ability of the MenC-specific antibodies to fix 
complement, to promote antibody-dependent cell mediated cytoxicity (ADCC), to induce 
phagocytosis and to activate FcR+ cells in vitro will be assessed. If the quantity of serum 
available for this specific exploratory objective is limited, assessments of isotype, 
glycosylation state and complement fixing capacity will be prioritized over the other 
assessments. 
The frequency of T cells specific for the CRM197 protein at baseline (Day 1), at Day 8 and 
at Day 29 after vaccination with the study vaccines will be determined by FACS analysis 
using intracellular staining with a wide panel of cytokines and surface markers to identify 
cell populations. 
Early Markers for Safety and Innate immune activation 
The evaluation of potential biomarkers of safety and innate immune activation will be 
performed on blood specimens collected at Day 1 (baseline, 6h and 24h after vaccination) 
and Day 4. 
The vaccine-induced production of inflammatory cytokines and chemokines will be 
monitored on serum samples using a commercially available multiplex ELISA assay for a 
panel of pro-inflammatory cytokines and chemokines, including Eotaxin, Eotaxin-3, 
GMCSF, IFN-g, IL-1a, IL-1b, IL-10, IL-12 p70, IL-12/IL-23p40, IL-13, IL-15, IL-16, 

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IL17A, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IP-10, MCP-1, MCP-4, MDC, 
MIP1a, MIP-1b, TARC, TNF-a, TNF-b, VEGF. 
The vaccine-induced expression of genes and gene families will be monitored on whole 
blood samples using of RNA microarrays by existing technologies The RNA micro array 
analysis does not have the intent nor the capability to identify or rule out any genetic 
modifications in the RNA or DNA that are presumably linked to disease or predisposition 
to disease. 
8.0  
STATISTICAL CONSIDERATIONS 
8.1  
Endpoints 
8.1.1 
Primary Endpoint(s) 
8.1.1.1  
Primary Safety Endpoint(s) 
The measures for assessing safety and tolerability (by vaccine group within each cohort 
and by LHD153R adjuvant dosage group overall) are as follows: 
▫ The frequency and percentage of subjects with solicited local and systemic  AEs 
through Day 15. Time intervals after vaccination that will be summarized are:30 
minutes post-vaccination, Days 1-4 (without 30 minutes), Days 5-8, Days 8-15, Days 
1-8 (without 30 minutes) and Days 1-15 (without 30 minutes). 
▫ The frequency and percentage of subjects with any unsolicited AEs from the day of 
vaccination (Day 1) to Day 15. 
▫ The frequency and percentage of subjects with SAEs, medically attended AEs,  AEs 
leading to study withdrawal, NOCDs, AESIs for the following time periods: day of 
signed informed consent until study completion (Day 366), day of vaccination (Day 1) 
to Day 29 and Day 29 to study completion (Day 366). 
▫ The absolute values and changes in hematology, chemistry, and urinalysis parameters 
(see section 7.1.7). 
▫ The frequency and percentage of subjects with abnormal laboratory parameter values 
as classified by investigator normal ranges (low, normal, high) and as classified by 
CBER toxicity grading scales, when available. 

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8.1.1.2  
Primary Efficacy Endpoint(s) 
Not applicable. 
8.1.1.3  
Primary Immunogenicity Endpoint(s) 
The primary immunogenicity endpoints are the GMTs measured by hSBA directed 
against N. meningitidis serogroup C from samples collected on Day 1 (baseline, before 
vaccination) and Day 29 as well as the GMR of the titers (Day 29 / Day 1). 
8.1.2 
Secondary Endpoint(s) 
8.1.2.1  
Secondary Safety Endpoint(s) 
Not applicable. 
8.1.2.2  
Secondary Efficacy Endpoint(s) 
Not applicable. 
8.1.2.3  
Secondary Immunogenicity Endpoint(s) 
The secondary immunogenicity endpoints are: 
▫ the GMTs and corresponding GMRs measured by hSBA directed against N. 
meningitidis serogroup C for samples collected at Day 8 and Day181. 
▫ the percentage of subjects with hSBA seroresponse at Days 8, 29, and 181.  
seroresponse is defined as a post vaccination hSBA ≥8 for subjects with a baseline 
hSBA <4 or have an increase of at least 4 times the baseline hSBA level for subjects 
with pre-vaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against N. meningitidis serogroup C 
measured by ELISA for samples collected on Days 1 (baseline, prior to vaccination), 
8, 29 and 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations to 
N. meningitidis serogroup C as measured by ELISA on Day 8, 29 and 181 relative to 
baseline (Day 1) 

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8.1.3  
Exploratory Endpoint(s) 
The exploratory  endpoints are based on results of testing which may not be performed 
until after the study report has been finalized and will be further refined prior to testing. 
They include the following: 
▫ Serum concentration of LHD153 at Day 1 baseline (prior to vaccination), Day 1 (1h , 
2h, 4h, 8h and 24h after vaccination), Day 4 by LC-MS/MS. 
▫ Frequency of meningococcal C polysaccharide-specific and CRM197-specific B cells at 
Day 1 (baseline), Day 8, Day 29 and Day 181 by ELISPOT. 
▫ Diversity of the meningococcal C polysaccharide-specific B-cell repertoire at Day 1 
(baseline), Day 8, Day 29, and Day 181 by immunoglobulin cDNA sequencing. 
▫ Functionality of antigen specific antibodies will be assessed at Day 1 (baseline), Day 
8, Day 29 and Day 181 by analysis of immunoglobulin isotype, glycosylation state 
and their ability to fix complement, promote antibody-dependent cell mediated 
cytoxicity, induce phagocytosis and activate FcR+ cells. If the quantity of serum 
available for this specific exploratory objective is limited, assessments of isotype, 
glycosylation state and complement fixing capacity will be prioritized over the other 
assessments. 
▫ Frequency and quality of T cells specific for CRM197 at Day 1 (baseline), Day 8 and 
Day 29 by fluorescence activated cell sorting (FACS) analysis using intracellular 
staining with a wide panel of cytokines and surface markers to identify cell 
populations. 
▫ Serum concentrations of a panel of 30 chemokines and cytokines at Day 1 (baseline), 
Day 1 (6h and 24h after vaccination), Day 4 and Day 8 by multiplex Electro-
chemoluminescence based assay. 
▫ Gene expression profile in whole blood at Day 1 (baseline), Day 1 (6h and 24h after 
vaccination), Day 4 and Day 8 by RNA micro array analysis 
8.2  
Success Criteria 
The study has no formal statistical hypotheses and will not be declared positive or 
negative according to given rules. The selection of an appropriate LHD153R adjuvant  
dosage for future studies will be determined by the joint evaluation of the 
immunogenicity and safety profiles of each dosage group. 8.2.1 
 Success Criteria for Primary Objective(s) Not applicable. 

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8.2.2  
Success Criteria for Secondary Objective(s) 
Not applicable. 
8.3  
Analysis Sets 
8.3.1  
All Enrolled Set 
All screened subjects who provide informed consent and provide demographic and/or 
baseline screening assessments, regardless of the subject’s randomization and treatment 
status in the study and received a Subject ID. 
8.3.2  
All Exposed Set 
All subjects in the enrolled set who receive a study vaccination. 
8.3.3  
Safety Set 
Safety Set (solicited adverse events and other solicited reactions) 
All subjects in the Exposed Set who: 
▫ Provide post vaccination reactogenicity data. 
Safety Set (unsolicited adverse events) 
All subjects in the Exposed Set who: 
▫ Have post-vaccination unsolicited adverse event records. 
Safety Set (overall) 
All subjects in the Exposed Set who: 
▫ Have either post-vaccination adverse event or reactogenicity records. 
Subjects will be analyzed as “treated” (i.e., according to the vaccine a subject received, 
rather than the vaccine to which the subject may have been randomized). 
8.3.4  
Full Analysis Set (FAS) Efficacy/Immunogenicity Set 
All subjects in the Enrolled Set who: 

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▫ Receive a study vaccination AND provide efficacy/immunogenicity data at relevant 
time points. 
FAS sets will be analyzed “as randomized” (i.e., according to the vaccine a subject was 
designated to receive, which may be different from the vaccine the subject actually 
received). 
8.3.5  
Per Protocol (PP) Set Efficacy/Immunogenicity Set 
All subjects in the FAS efficacy/immunogenicity set who: 
▫ Are not excluded due to reasons (see section 8.3.8) defined prior to unblinding or 
analysis. 
PPS are subsets of FAS and should always be defined even if the objectives do not 
require it. 
Examples for subjects excluded due to other reasons than protocol deviations are: 
- 
Subjects who withdrew informed consent. 
- 
Premature withdrawal due to an adverse event. 
Exclusions need to be considered by objective/time point, i.e., sometimes not all data of a 
subject but only part of the subject's data will be removed from the PPS analysis. 
8.3.6  
Other Analysis Sets  
All subjects in the Enrolled Set who consent to additional blood draws, receive a study 
vaccination AND provide exploratory assay data at relevant time points will be included 
in an exploratory assay subset. 
8.3.7  
Subgroups 
Selected immunogenicity analyses may be provided based on seropositivity status at 
baseline. 
8.3.8  
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. A protocol deviation may be a reason to remove data from 
an analysis set at the time of analysis. Reportable protocol deviations will be defined as 
exclusionary from the analysis according to protocol objectives and endpoints, which will 

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be specified in the statistical analysis plan. In some cases exclusion of data may be due to 
a reason other than a protocol deviation, e.g. early termination. 
8.4  
Statistical Analysis Plan 
This section provides a summary of the statistical methodology to be used. A more 
detailed description of analysis methods will be provided in a separate statistical analysis 
plan which may also include additional exploratory analyses not explicitly mentioned in 
the following sections. 
8.4.1  
Analysis of Demographic and Baseline Characteristics 
Descriptive statistics (number of non-missing observations, mean, standard deviation, 
median, minimum and maximum) for age, height and weight at enrolment will be 
calculated overall and by vaccine group and LHD153R adjuvant dosage. 
Distributions of subjects by sex and ethnic origin will be summarized overall and by 
vaccine group and LHD153R adjuvant dosage. 
8.4.2  
Analysis of Primary Objective(s) 
8.4.2.1  
Analysis of Primary Safety Objective(s) 
Safety of the study vaccines will be assessed in all subjects in terms of the frequency and 
percentage of reported AEs as well as by changes in clinical laboratory values.  
8.4.2.1.1  
Analysis of Extent of Exposure 
The frequency and percentage of subjects with vaccinations will be summarized by 
vaccine group and LHD153R adjuvant dosage, by cohort and overall, for the Enrolled 
Set. 
8.4.2.1.2  
Analysis of Solicited Local, Systemic and Other Adverse Events 
All solicited adverse events will be summarized according to defined severity grading 
scales. Use of medication to prevent/treat fever will be summarized according to 
frequencies and percentages reporting “Yes” and “No”. 
Frequencies and percentages of subjects experiencing each adverse event will be 
presented for each symptom severity. Summary tables showing the occurrence of any 
local or systemic adverse event overall and at each time point will also be presented. 

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Post-vaccination solicited adverse events reported from Day 1 to Day 15 will be 
summarized for the intervals Day 1-4 (without 30 minutes), Day 5-8, Day 1-8 (without 30 
minutes), Day 8-15 and Day 1-15 (without 30 minutes) by maximal severity and by 
vaccine group and LHD153R adjuvant. The severity of solicited local adverse events, 
including injection-site erythema, swelling and induration will be summarized according 
to categories based on linear measurement: 25 to 50 mm, 51-100 mm, > 100 mm. 
Injection site pain and systemic reactions (except fever) occurring up to Day 15 will be 
summarized according to “mild”, “moderate” or “severe”. 
Each solicited local and systemic adverse event will also be further summarized as “none” 
versus “any”. 
Implausible measurements (for further definition see statistical analysis plan) will be left 
out of the analysis. 
Use of antipyretics and analgesics will be summarized by frequency by type of use 
(prophylactic versus treatment) and percentage of subjects reporting use. The influence of 
antipyretics and analgesics use on the occurrence of specific adverse events (e.g., fever, 
pain) will be assessed. 
Body temperature will be summarized by 0.5 °C and 1.0 °C increments from 36.0 °C up 
to ≥40 °C. 
8.4.2.1.3  
Analysis of Unsolicited Adverse Events 
This analysis applies to all adverse events occurring during the study, judged either as 
probably related, possibly related, or not related to vaccination by the investigator, 
recorded in AE CRF, with a start date on or after the date of first vaccination. AE starting 
prior to the first vaccination will only be listed. The original verbatim terms used by 
investigators to identify adverse events in the CRFs will be mapped to preferred terms 
using the MedDRA dictionary. The adverse events will then be grouped by MedDRA 
preferred terms into frequency tables according to system organ class. 
All reported adverse events, as well as adverse events judged by the investigator as at 
least possibly related to study vaccine, will be summarized according to system organ 
class and preferred term within system organ class. These summaries will be presented by 
vaccination group and LHD153R adjuvant dosage for each cohort and by interval of 
study observation. When an adverse event occurs more than once for a subject, the 
maximal severity and strongest relationship to the vaccine group will be counted. 

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Separate summaries will be produced for the following categories: 
▫ Serious adverse events. 
▫ Adverse events that are possibly or probably related to vaccine. 
▫ Adverse events of special interest. 
▫ New onset of chronic disease. 
▫ Adverse event leading to withdrawal. 
▫ Adverse events leading to a medically attended visit. 
▫ Adverse event by data source. 
Data listings of all adverse events will be provided by subject. In addition, adverse events 
in the categories above will be provided as listed data. 
8.4.2.1.4  
Analysis of Safety Laboratory Values 
The investigator must review all safety laboratory results (see Section 7.1.7). Abnormal 
laboratory values and clinically significant changes in values from pre-vaccination 
(Screening Visit) will be assessed, using medical judgment, based on the FDA CBER  
Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent  
Volunteers Enrolled in Preventive Vaccine Clinical Trials” dated September 2007, or the 
institution’s normal ranges if they differ from CBER guidance. Please see Appendix C, D 
and E for further details. 
The following information will be provided: 
▫ Change in absolute laboratory value from pre-vaccination (Screening Visit) to Day 8 
(Visit 3) and Day 29 (Visit 6) after vaccination 
▫ The classification of laboratory values and/or their changes from pre-vaccination 
according to the CBER toxicity grading scale 
▫ 3 x 3 shift tables by visit using the categorization of laboratory values according to 
institutional normal reference ranges (below, within, above) 8.4.2.2  
Analysis 
of Primary Efficacy Objective(s) 
Not applicable. 
8.4.2.3  
Analysis of Primary Immunogenicity Objective(s) 

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8.4.2.3.1  
Statistical Hypotheses 
There are no statistical hypotheses associated with the secondary immunogenicity 
objectives. All analyses are descriptive. 
8.4.2.3.2  
Analysis Sets 
The primary immunogenicity analyses will be based on the per-protocol set (PPS) at Day 
29. The primary analyses will be repeated using the Full Analysis Set (FAS) as a measure 
of the sensitivity/robustness of the results (further details are given in section 8.3). 
8.4.2.3.3  
Statistical Methods 
Before any statistical analysis that assumes normally distributed observations, antibody 
titers will be log10-transformed. Individual titers below the limit of quantitation (LLQ) 
will be set to half that limit. 
Geometric Mean Titers 
The logarithmically (base 10) transformed antibody titers will be modeled using an 
analysis of covariance (ANCOVA) model with a qualitative factor for LHD153R 
adjuvant dosage (0 [for unadjuvanted MenC], 12.5, 25, 50 or 100 µg) and log (base 10) 
pre-vaccination titer as a covariate. The adjusted GMT and the two-sided, 95%, 
confidence intervals (CIs) of the GMT will be calculated based on this model as will the 
ratio of GMTs and corresponding CIs. The adjusted GMT and two-sided 95% CIs will be 
constructed by exponentiation (base 10) of the least square means of the logarithmically 
transformed (base 10) antibody titer. The ratio of GMTs (LHD153R adjuvant dosage 
minus Men C), and corresponding two-sided 95% CIs, will be constructed by 
exponentiation (base 10) of the least square differences obtained from this model. The 
model can be written as:  
log10 (yik) = µ + αi + βxik + εik 
where µ represents a common overall mean, αi represents the adjuvant dose group i effect, 
β represents the common slope for the log10 pre-vaccination titer, xik for subject k in 
adjuvant dose group I, and εik represents random error for subject k in adjuvant dose 
group i. 
Geometric Mean Ratios 
The logarithmically (base 10) transformed within subject ratio of antibody titers (Day 29 / 
pre-vaccination) will be modeled using an analysis of variance model with a qualitative 

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factor for LHD153R adjuvant dosage (0 [for non-LHD153R adjuvanted MenC], 12.5, 25, 
50 or 100 µg). The adjusted GMR and the two-sided, 95% CIs of the GMR will be 
calculated based on this model. The model can be written as: 
log10 (yik) = µ + αi + εik 
where µ represents a common overall mean, αi represents the adjuvant dose group i effect 
and εik represents random error for subject k in adjuvant dose group i. 
Handling of missing values 
For immunogenicity data, it may be reasonable to consider missing immunogenicity 
values as missing completely at random (MCAR), i.e., not informative. Therefore, the 
primary analysis will comprise a complete case analysis only, without introducing any 
bias. Imputation methods will not be used. 
8.4.3  Analysis of Secondary Objective(s) 8.4.3.1 
 Analysis of Secondary Safety Objective(s) Not 
applicable. 
8.4.3.2  
Analysis of Secondary Efficacy Objective(s) 
Not applicable. 
8.4.3.3  
Analysis of Secondary Immunogenicity Objective(s) 
8.4.3.3.1  
Statistical Hypotheses 
There are no statistical hypotheses associated with the secondary immunogenicity 
objectives. All analyses are descriptive. 
8.4.3.3.2  
Analysis Sets 
The secondary immunogenicity analyses will be based on the PPS (further details are 
given in section 8.3) or the appropriate subset of subjects. 
8.4.3.3.3  
Statistical Methods 
The secondary immunogenicity endpoints are: 

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▫ the GMTs and corresponding GMRs measured by hSBA directed against N. 
meningitidis serogroup C for samples collected at Day 8 and Day181. 
▫ the percentage of subjects with hSBA seroresponse at Days 8, 29, and 181.  
seroresponse is defined as a post vaccination hSBA ≥8 for subjects with a baseline 
hSBA <4 or have an increase of at least 4 times the baseline hSBA level for subjects 
with pre-vaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against N. meningitidis serogroup C 
measured by ELISA for samples collected on Days 1 (baseline, prior to vaccination), 
8, 29 and 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations to 
N. meningitidis serogroup C as measured by ELISA on Day 8, 29 and 181 relative to 
baseline (Day 1) 
The GMTs for samples collected at Day 8 and Day 181 as well as the GMCs for samples 
collected at Day 1, Day 8, Day 29 and Day 181 will be analyzed using the same approach 
as for the primary immunogenicity endpoint. 
The remaining immunogenicity endpoints are based on subjects meeting criteria for 
seroconversion or achieving a certain threshold value. These endpoints will be 
summarized using frequencies and percentages by LHD153R adjuvant dosage (0 [for 
non-LHD153R adjuvanted MenC], 12.5, 25, 50 or 100 µg). Two-sided 95% 
ClopperPearson CIs will also be provided for percentages. For analyses of 
seroconversion, separate summaries may be provided based on seropositivity status at 
baseline. 
8.4.4  
Analysis of Exploratory Objectives 
Testing and analyses of exploratory endpoints may be performed after the Clinical Study 
Report (CSR) has been completed, in which case these data will be submitted as an 
addendum to the CSR. 
In general, concentration and titer results will be summarized for each LHD153R 
adjuvant dosage group using geometric means and associated 2-sided 95% confidence 
intervals; and, categorical data will be summarized using frequencies and percentages, 
with corresponding two-sided, 95% confidence intervals. Full details of the analysis will 
be described in an amendment/addendum to the SAP. 
8.5  
Sample Size and Power Considerations of Primary Objectives 

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Sample size is not driven by statistical assumptions for formal hypothesis testing, but was 
based on the safety objective for the study. The table below provides the probability for 
various combinations of sample size (N) and presumed true frequency of a given event 
within an individual vaccine group  
Frequency 
of Event 
Probability to Observe at Least 1 Subject with a Given Event For  
Various Choices of N 
4 
8 
12 
16 
0.05 
0.1855 
0.3366 
0.4596 
0.5599 
0.10 
0.3439 
0.5695 
0.7176 
0.8147 
0.15 
0.4780 
0.7275 
0.8577 
0.9257 
0.20 
0.5904 
0.8322 
0.9313 
0.9718 
0.30 
0.8250 
0.9423 
0.9862 
0.9967 
0.40 
0.8704 
0.9832 
0.9978 
0.9997 
The proposed combinations of sample sizes within each cohort are 4 aluminium 
hydroxide adjuvanted MenC-CRM197 and 16 MenC-CRM197 plus an assigned-level of 
LHD153R adsorbed to aluminium hydroxide. If all four cohorts are fully enrolled, there 
will be 16 subjects receiving aluminium hydroxide adjuvanted MenC-CRM197. 
With 16 subjects, events which occur at a frequency of 15% or more will be detected with 
at least 90% probability; and, events which occur at a frequency of 10% or more will be 
detected with 81% probability. With 4 subjects, events which occur at a frequency of 30% 
or more will be detected with at least 80% probability. Intermediate values of 8 and 12 
are provided to correspond to sample sizes in the MenC- CRM197 after cohort 2 and 
cohort 3 are fully enrolled. 
8.6  
Interim Analysis 
The DMC will be reviewing the accumulating safety data from the study in order to 
continue enrollment of subjects within a cohort and whether to enroll subjects into the 
next cohort. 
In addition to these periodic reviews, there will be a safety and immunogenicity interim 
analysis for the selection of an LHD153R adjuvant dosage based on the data collected 
through Day 29 from subjects enrolled in all cohorts. This analysis will be performed by 
personnel not involved in study decisions. The results will be unblinded at the group level 

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thereby preserving the blind for individual subjects. No adjustment to the overall alpha 
will be performed as the data collected subsequent to this analysis involve secondary and 
exploratory endpoints. 
 

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9.0  
SOURCE DOCUMENTATION, STUDY MONITORING AND 
AUDITING 
Study monitoring and auditing will be standardized and performed in accordance with the 
Sponsor’s or delegated contract research organization’s (CRO) standard operating 
procedures and applicable regulatory requirements (e.g., FDA, EMA, and ICH 
guidelines). 
Prior to enrolment of the first study subject, Novartis or delegate will train investigators 
and/or their study staff on the study protocol, all applicable study procedures, 
documentation practices and all electronic systems. CRFs supplied by the Sponsor must 
be completed for each enrolled subject (see section 8.3.1 for definition of enrolled 
subject). Documentation of screened but not enrolled subjects must be maintained at the 
site and made available for review by the site monitor. Data and documents will be 
checked by the Sponsor and/or monitor. 
9.1  
Source Documentation 
Prior to the start of the study, the site staff participating in the study conduct will be 
instructed on what documents will be required for review as source documents. The kinds 
of documents that will serve as source documents will be agreed between Sponsor or 
delegate and investigator and designees and specified in the SDA prior to subject 
enrolment. 
In addition, source documentation must include all of the following: subject identification 
(on each page), eligibility and participation, proper informed consent procedures, dates of 
visits, adherence to protocol procedures, adequate reporting and follow-up of adverse 
events, documentation of prior/concomitant medication/vaccines, study vaccine 
receipt/dispensing/return records, study vaccine administration information, any data 
collected by a telephone conversation with the subject and date of completion and reason. 
The subject must also allow access to the subject’s medical records. Each subject must be 
informed of this prior to the start of the study and consent for access to medical records 
may be required in accordance with local regulations. 
All safety data reported by subjects must be written down in source documents prior to 
entry of the data into CRFs. If there are multiple sources of information (e.g., Subject 
Diary, verbal report of the subject, telephone contact details, medical chart) supporting 
the diagnosis of an adverse event, these sources must be identified in the source 
documents, discrepancies between sources clarified, the ultimate diagnosis must be 

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justified and written in the source documents, and this diagnosis must be captured in the 
Adverse Event CRF (AE CRF). The AE CRF must also capture which source(s) of 
information were used to determine the adverse event (e.g., subject recall, medical chart, 
Subject Diary). 
9.2  
Study Monitoring, Auditing and Source Data Verification 
Prior to enrolment of the first study subject, Novartis or its designee (e.g., a CRO) will 
develop a Monitoring Plan to specify how centralized and/or on-site monitoring, 
including clinical specimens reconciliation, will be performed for the study. Study 
progress will be monitored by Novartis or its designee as frequently as necessary to 
ensure: 
▫ that the rights and well-being of human subjects are protected, 
▫ the reported study data are accurate, complete, and verifiable from the source 
documents and 
▫ the conduct of the study is in compliance with the current approved 
protocol/amendment(s), GCP and applicable regulatory requirements. 
Contact details for the Novartis team or its designee involved in study monitoring will be 
provided to the investigator. Study data recorded on CRFs will be verified by checking 
the CRF entries against source documents in order to ensure data completeness and 
accuracy as required by study protocol. 
Additional documents such as the investigator site file, pharmacy records, and informed 
consent documentation must also be available for review if requested. Arrangements for 
monitoring visits will be made in advance in accordance with the monitoring plan, except 
in case of emergency. 
The investigator and/or site staff must make source documents of subjects enrolled in this 
study available for inspection by Novartis or its representative at the time of each 
monitoring visit and Sponsor audits, when applicable. These documents must also be 
available for inspection, verification and copying, as required by regulations, by officials 
of the regulatory health authorities (e.g., FDA, EMA and others) and/or ECs/IRBs. The 
investigator and study site staff must comply with applicable privacy, data protection and 
medical confidentiality laws for use and disclosure of information related to the study and 
enrolled subjects. 
10.0  
DATA MANAGEMENT 

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10.1 
Data Entry and Management 
In this study, all clinical data (including, but not limited to, AE/SAEs, concomitant 
medications, medical history, and physical assessments), safety data, and immunogenicity 
data will be entered into an EDC system, which is compliant with Title 21 Part 11 
policies of the Code of Federal Regulations (FDA, 1997). The data system includes 
password protection and internal quality checks. The EDC system will be designed and 
validated by the Sponsor prior to activation for data entry by sites. The investigator or 
designated delegate must review data entered and electronically sign the CRFs to verify 
their accuracy. 
Access to the EDC system for data entry or review will require training and distinct 
individual access code assignments to those site staff members who will be entering study 
data and those involved in study oversight who may review study data. Data are collected 
within the EDC system, to which the Sponsor and site monitors have exclusively “read 
only” access. 
Three-part “no carbon required” (NCR) paper CRFs will be provided for each pregnant 
subject by the Sponsor. All appropriate pregnant subject data collected will be recorded 
on this form. One copy must be retained by the investigator, and all other copies 
(including the original copy) will be returned as directed by the Sponsor. Instructions on 
how to complete this form will be provided to the investigator. 
10.2  
Data Clarification 
As part of the conduct of the trial, the Sponsor may have questions about the data entered 
by the site, referred to as queries. The monitors and the Sponsor are the only parties that 
can generate a query. All corrections and clarifications will be entered into the EDC 
system and will be identified by the person entering the information, the reason for the 
change, as well as the time of the changes made. If changes are made to a previously and 
electronically signed CRF, the investigator must confirm and endorse the changes 
10.3  
Data Protection 
Novartis respects the subjects’ rights to privacy and will ensure the confidentiality of their 
medical information in accordance with all applicable laws and regulations. 
The Sponsor as Data Controller according to the European Directive on the protection of 
individuals with regard to the processing of personal data and on the free movement of 
such data (95/46/EC) confirms herewith compliance to Directive 95/46/EC in all stages of 
Data Management. 
 

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11.0  
RECORD RETENTION 
Investigators must retain all study records required by Novartis and by the applicable 
regulations in a secure and safe facility. The investigator must consult a Novartis 
representative before disposal of any study records, and must notify the Sponsor of any 
change in the location, disposition, or custody of the study files. Essential documents 
must be retained for 15 years. “Essential documents” are defined as documents that 
individually and collectively permit evaluation of the conduct of a study and the quality 
of the data produced. These documents should be retained for a longer period, however, if 
required by the applicable national regulatory or institutional requirements.  
These principles of record retention will also be applied to the storage of laboratory 
samples, provided that the integrity of the stored sample permits testing. 
 

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12.0  
USE OF INFORMATION AND PUBLICATION 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov, and in compliance with current regulations. 
Novartis also assures that key results of this clinical study will be posted in a publicly 
accessible database within the required time-frame from the End of Study as defined in 
section 3.9. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. Any formal publication 
of the study in which contribution of Novartis personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Novartis personnel. 
Novartis must be notified of any intent to publish data collected from the study and prior 
approval from Novartis must be obtained prior to submission for publication. 

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13.0  
ETHICS 
13.1  
Regulatory and Ethical Compliance 
The study will be conducted in compliance with the protocol, GCP and applicable 
regulatory requirement(s). 
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, European 
Directive 2001/20/EC, Novartis codes on protection of human rights, and with the ethical 
principles laid down in the Declaration of Helsinki (European Council 2001, US Code of 
Federal Regulations, ICH 1997). 
13.2  
Informed Consent Procedures 
Eligible subjects may only be included in the study after providing written informed 
consent or assent, as described in section 5.1.1. Before the start of the study, the 
investigator will have the informed consent and any other materials that will be provided 
to the subjects reviewed and approved by the IRB/EC. This review and approval will be 
documented and stored with other study documents. The investigator or designee must 
fully inform the subject or legal guardian of all pertinent aspects of the study. A copy of 
the written informed consent will be given to the subject or the designee. The 
subject/designee must be allowed ample time to ask about the details of the study and to 
make a decision as to whether or not to participate in the study. The subject and/or legal 
guardian(s) must sign the consent form indicating their agreement to participate in the 
study before any study-related procedures are conducted. The informed consent process 
may be conducted up to 23 days prior to vaccination on Day 1. If the subject is unable to 
read and write, a witness must be present during the informed consent discussion and at 
the time of informed consent signature. 
Prior to the start of the study, Novartis will provide to investigators a proposed informed 
consent form that complies with the ICH GCP guideline and regulatory requirements and 
is considered appropriate for this study. Any changes to the proposed consent form 
suggested by the investigator must be agreed to by Novartis before submission to the 
IRB/EC and a copy of the approved version must be provided to the Novartis monitor 
after IRB/EC approval. 
Women of childbearing potential should be informed that taking the study medication 
may involve unknown risks to the fetus if pregnancy were to occur during the study and 
agree that in order to participate in the study they must adhere to the contraception 

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requirements indicated in the protocol for the duration of the study. In case of doubt on 
the ability of a subject to adhere to these requirements, that subject should not be allowed 
in the study 
13.3  
Responsibilities of the Investigator and IRB/EC 
The protocol and the proposed informed consent form must be reviewed and approved by 
a properly constituted IRB/EC before study start. Properly constituted IRB/EC is defined 
in ICH Guideline for Good Clinical Practice E6 (R1), Section 3 (ICH, 1997). A signed 
and dated statement that the protocol and informed consent have been approved by the 
IRB/EC must be given to Novartis before study initiation. Prior to study start and at any 
time the protocol is amended during study conduct, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance 
with these documents and all of the instructions and procedures found in this protocol and 
to give access to all relevant data and records to Novartis monitors, auditors, Novartis 
Clinical Quality Assurance representatives, designated agents of Novartis, IRBs/ECs, and 
regulatory authorities as required. If an inspection of the clinical site is requested by a 
regulatory authority, the investigator must inform Novartis immediately that this request 
has been made. 
The investigator also responsible for the following: 
▫ Maintaining a list of appropriately qualified persons to whom the investigator has 
delegated significant study-related duties. 
▫ Demonstrating the capability of recruiting the required number of suitable subjects 
within the recruitment period. 
▫ Demonstrating sufficient time and staffing to properly conduct and complete the study 
within the agreed study period. 
▫ Ensuring that all persons assisting with the study are adequately informed about the 
protocol, the investigational product(s), and their study-related duties and functions 
▫ Ensuring that appropriately trained health care professionals are responsible for all 
study-related medical decisions and for ensuring appropriate medical care of subjects 
experiencing any adverse event related to the study. 
▫ If permission to do so is given by the subject, ensuring that the subject’s primary 
healthcare provider is informed of the subject’s participation in the study. 
The investigator should not implement any deviation from, or changes of the protocol 
without agreement by the Sponsor and prior review and documented approval/favourable 

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opinion from the IRB/IEC of an amendment, except where necessary to eliminate an 
immediate hazard(s) to study subjects, or when the change(s) involves only logistical or 
administrative aspects of the study (e.g., change in monitor(s), change of telephone 
number(s)). In addition, the investigator, or person designated by the investigator, should 
document and explain any deviation from the approved protocol. 
The investigator may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior IRB/IEC 
approval/favourable opinion. As soon as possible, the implemented deviation or change, 
the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be 
submitted: 
(a) to the IRB/IEC for review and approval/favourable opinion, 
(b) to the Sponsor for agreement and, if required, 
(c) to the regulatory authority(ies). 
13.4  
Protocol Amendments 
An amendment is a written description of change(s) to or formal clarification of a study 
protocol which may impact on the conduct of the clinical study, potential benefit of the 
clinical study, or may affect subject safety, including changes of study objectives, study 
design, subject population, sample sizes, study procedures, or significant administrative 
aspects. An administrative change of a study protocol is a minor correction or 
clarification that has no significant impact on the way the clinical study is to be conducted 
and no effect on subject safety (e.g., change of telephone number(s), logistical changes). 
Protocol amendments must be approved by Novartis, health authorities where required, 
and the IRB/EC. In cases when the amendment is required in order to protect the subject 
safety, the amendment can be implemented prior to IRB/EC approval. Notwithstanding, 
the need for formal approval of a protocol amendment, the investigator is expected to take 
any immediate action required for the safety of any subject included in this study, even if 
this action represents a deviation from the protocol. In such cases, Novartis should be 
notified of this action, the IRB/EC at the study site, and, if required by local regulations, 
the relevant health authority should be informed within 10 working days. 
14.0  
REFERENCE LIST 
Alving CR, Peachman KK, Rao M, Reed SG. Adjuvants for human vaccines. Curr Opin 
Immunol. 2012 Jun; 24(3):310-5 

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Bauza, A et al., Pemphigus-like lesions induced by imiquimod. Clin Exp Dermatol 2009, 
34, e60-62 
Bissett SL, Draper E, Myers RE, Godi A, Beddows S. Cross-neutralizing antibodies 
elicited by the Cervarix(®) human papillomavirus vaccine display a range of Alpha-9 
inter-type specificities. Vaccine. 2014 Feb 26; 32(10):1139-46 
Campanelli, A et al., Topical application of imiquimod and associated fever in children. J 
Am Acad Dermatol 2005,52, E1. 
Code of Federal Regulations (1997): Food and Drug Administration, U.S. Department of 
Health and Human Services: Title 21, Part 11: Electronic Records Electronic Signatures. 
Federal Register 62: 13464 
Connolly M and Noah N, Is group C meningococcal disease increasing in Europe? A 
report of surveillance of meningococcal infection in Europe 1993-6. Epidemiol. Infect. 
1999; 122: 41-49. 
Del Giudice G, Fragapane E, Della Cioppa G, et al. Aflunov®: a vaccine tailored for 
prepandemic and pandemic approaches against influenza. Expert Opin Biol Ther. 2013; 
13: 121-35. 
European Centre for Disease Prevention and Control. Surveillance of invasive bacterial 
diseases in Europe 2008/2009. Stockholm: ECDC 2011 
European Parliament (1995): Directive 95/46/EC of the European Parliament and of the 
Council of 4 April 2001. Official Journal of the European Communities. L 281/31-39 
European Parliament (2001): Directive 2001/20/EC of the European Parliament and of the 
Council of 4 April 2001. Official Journal of the European Communities. L 121/34-44 
Hellenbrand W, Elias J, Wichmann O et al. Epidemiology of invasive meningococcal 
disease in Germany, 2002-2010, and impact of vaccination with meningococcal C 
conjugate vaccine. Journal of Infection 2013; 66: 48-56. 
ICH (1997) ICH Harmonised Tripartite ICH Guideline for Good Clinical Practices E6  
(R1). Federal Register, 62 (90): 25691-25709 
ICH (1998) ICH Harmonised Tripartite ICH Guideline for Statistical Principles for 
Clinical Trials E9. Federal Register, 63 (179): 49583 

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Ilyinskii, PO, et al., Adjuvant-carrying synthetic vaccine particles augment the immune 
response to encapsulated antigen and exhibit strong local immune activation without 
inducing systemic cytokine release. Vaccine, available online 1 March 2014. 
Khurana, S., W. Chearwae, F. Castellino, J. Manischewitz, L.R. King, A. Honorkiewicz, 
M.T. Rock, K.M. Edwards, G. Del Giudice, R. Rappuoli, and H. Golding. 2010. 
MF59adjuvanted vaccines expand antibody repertoires targeting protective sites of 
pandemic H5N1 influenza virus. Science Transl. Med. 2: 15ra5: 1-8. 
Khurana, S., N. Verma, J.W. Yewdell, A.K. Hilbert, F. Castellino, M. Lattanzi, G. Del 
Giudice, R. Rappuoli, and H. Golding. 2011. MF59 adjuvant affects human epitope 
repertoire, augments affinity maturation, and neutralization titers to pandemic influenza in 
all age groups. Science Transl. Med. 3: 85ra48. 
Levine RJ. (1988) Ethics and Regulations of Clinical Research. New Haven: Yale 
University Press. 
Meyer, T et al., Clinical investigations of Toll-like receptor agonists. Expert Opin Investig 
Drugs 2008, 17:1051-1065. 
Recommendations of the Standing Committee on Vaccination (STIKO) at the Robert 
Koch Institute / Effective: August 2013; Robert Koch Institut Epidemiologisches Bulletin 
34, 26 August 2013 
Reed SG, Orr MT, Fox CB. Key roles of adjuvants in modern vaccines. Nat Med. 
2013;19 :1597-608. 
Regules JA, Cummings, JF and Ockenhouse CF. The RTS, S vaccine candidate for 
malaria. Expert Rev Vaccines 2011; 10:589-599. 
Rosenstein N, Perkins B, Stephens DS, et al. N. Engl. J. Med. 2001; 344: 1378-1388. 
Tacken, PJ et al., Targeted delivery of TLR ligands to human and mouse dendritic cells 
strongly enhances adjuvanticity. Blood 2011, 118:6836-6844. 
Takeda K, Kaisho T, Akira S Toll-like receptors. Annu.Rev.Immunol. 2003; 21: 335-76. 
U.S. Department of Health and Human Services, Food and Drug Administration, CBER  
(2009): Guidance for Industry Patient-Reported Outcome Measures: Use in Medical  
Product Development to Support Labeling Claims 

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Vasilakos JP, and Tomai MA. The use of Toll-like receptor 7/8 agonists as vaccine 
adjuvants." Expert Rev Vaccines 2013; 12: 809-819. 
64th World Medical Association General Assembly (October 2013) Declaration of  
Helsinki - Ethical Principles for Medical Research Involving Human Subjects. Fortaleza, 
Brazil 
 

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APPENDIX A: GRADING SCALES FOR SOLICITED LOCAL ADVERSE 
EVENTS 
Adverse event Following  
Administration of  
Injectable Product  
Mild (Grade 
1)  
Moderate 
(Grade 2)  
Severe 
(Grade 3)  
Pain 
present but does not 
interfere with activity 
interferes with activity 
prevents daily activity 
Induration / Swelling /  
Erythema 
25 – 50 mm 
51 – 100 mm  
> 100 mm  
 
 

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APPENDIX B: GRADING SCALES FOR SOLICITED SYSTEMIC ADVERSE 
EVENTS 
Systemic  
Adverse event 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Fever 
°C 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 - 102 
39.0 – 40 
102.1 - 104 
°F 
Chills 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Loss of Appetite 
Loss of appetite without 
decreased oral intake  
decreased oral intake  
without weight loss 
decreased oral intake with 
weight loss 
Nausea 
Nausea present but not 
interfering with oral intake 
Nausea leading to decreased 
oral intake 
Nausea leading to minimal to 
no oral intake 
Vomiting 
1-2 episodes/24 hours 
>2 episodes/24 hours 
requires outpatient 
hydratation 
Diarrhea 
2-3 loose stools /24 hours 
4-5 loose stools /24 hours 
6 or more watery stools /24 
hours or requires outpatient 
IV hydration 
Generalized 
Myalgia 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Generalized  
Arthralgia 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Headache 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Fatigue 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Generalized  
Rash 
localized area of the skin (1 
extremity only) 
moderate area of the skin 
(2 or more body regions 
without whole body 
involvement) 
most of the skin 
Urticaria 
localized area of the skin (1 
extremity only) 
moderate area of the skin 
(2 or more body regions 
without whole body 
involvement) 
most of the skin 

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APPENDIX C:  
(SERUM CLINICAL CHEMISTRY)  
Serum*,** 
Mild (Grade 1)  
Moderate 
(Grade 2)  
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)*** 
Sodium – Hyponatremia 
mEq/L  
132 – 134  
130 – 131  
125 – 129  
< 125  
Sodium – Hypernatremia 
mEq/L  
144 – 145  
146 – 147  
148 – 150  
> 150  
Potassium – Hyperkalemia 
mEq/L  
5.1 – 5.2  
5.3 – 5.4  
5.5 – 5.6  
> 5.6  
Potassium – Hypokalemia 
mEq/L  
3.5 – 3.6  
3.3 – 3.4  
3.1 – 3.2  
< 3.1  
Blood Urea Nitrogen  
BUN mg/dL  
23 – 26  
27 – 31  
> 31  
Requires dialysis  
Creatinine – mg/dL  
1.5 – 1.7  
1.8 – 2.0  
2.1 – 2.5  
> 2.5 or requires 
dialysis  
Liver Function Tests –ALT,  
AST  
increase by factor  
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN  
5.1 – 10 x ULN  
> 10 x ULN  
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 

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** Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” *** The 
clinical signs or symptoms associated with laboratory abnormalities might result in characterization of 
the laboratory abnormalities as Potentially Life Threatening (Grade 4). For example. a low sodium value 
that falls within a grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia event 
if the subject had a new seizure associated with the low sodium value. “ULN” is the upper limit of the 
normal range. 
APPENDIX D:  
(HEMATOLOGY) 
Hematology*,** 
Mild (Grade 
1)  
Moderate  
(Grade 2)  
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)  
Hemoglobin (Female) 
gm/dL  
11.0 – 12.0  
9.5 – 10.9  
8.0 – 9.4  
< 8.0  
Hemoglobin (Female) 
change from baseline 
value - gm/dL  
Any decrease – 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
Hemoglobin (Male) 
gm/dL  
12.5 – 13.5  
10.5 – 12.4  
8.5 – 10.4  
< 8.5  
Hemoglobin (Male) 
change from baseline 
value – gm/dL  
Any decrease – 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
WBC Increase - cell/mm3 
10,800 – 15,000  
15,001 – 20,000  
20,001 – 25, 000  
> 25,000  
WBC Decrease cell/mm3 
2,500 – 3,500  
1,500 – 2,499  
1,000 – 1,499  
< 1,000  

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Platelets Decreased 
cell/mm3 
125,000 – 140,000 
100,000 – 124,000 
25,000 – 99,000  
< 25,000  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate.  
**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 
APPENDIX E:  
(URINE) 
Urine*,** 
Mild (Grade 
1)  
Moderate  
(Grade 2)  
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)  
Protein  
Trace  
1+  
2+  
Hospitalization or 
dialysis  
Glucose  
Trace  
1+  
2+  
Hospitalization for 
hyperglycemia  
Blood (microscopic) – 
red blood cells per high 
power field (rbc/hpf)  
1 - 10  
11 – 50  
> 50 and/or gross 
blood  
Hospitalization or 
packed red blood 
cells (PRBC) 
transfusion  
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 
** Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 

 
 
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Novartis Vaccines  
Clinical Study Protocol V132_01EXP Amendment 1 
10 SEP 14 
Confidential 
Page 1 of 2 
 
CLINICAL STUDY PROTOCOL AMENDMENT 
Study Number: V132_01EXP 
Protocol Title:  A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study 
to Evaluate the Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R 
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium  
Hydroxide Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy  
Adults (18-45 years of age) 
Amendment Number 1 
Revised Protocol version 2.0 issued on 10 SEP 2014 
The present amendment reflects changes to the Protocol version 1.0 issued on 
30JUN14   
Property of Novartis Vaccines  
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of Novartis Vaccines 

  
Confidential 
 
PRO-01 TEMP 08 / Atlas No. 293623 
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Novartis Vaccines 
Clinical Study Protocol V132_01EXP Amendment 1 
10 SEP 14 
Page 2 of 2 
 
DESCRIPTION OF CHANGE(S) AND RATIONALE: 
CHANGE 
LOCATION(S) OF  
CHANGE 
RATIONALE FOR  
CHANGE 
Interval for collection of 
solicited AE changed from 
collection until Day 15 to 
collection until Day 14 
Allowed visit window for 
Visit 4 (Day 15) changed 
from -1/+1 to +1. 
Synopsis, Times and Events  
Table 3, Section 3, Section  
5, Section 7, Section 8 
Diary Cards will be 
collected at Day 15. This 
change ensures that no 
incomplete Diary Cards will 
be presented at the Day 15 
visit. 
Chloride has been added to 
the 
Safety 
Laboratory 
Measurements. 
Synopsis, Section 7  
Correction of omission in 
Protocol version 1.0. 
Maximum interval between 
Screening Visit and Day 1 
changed from Day -21 to 
Day -28. 
Times and Events Table 3, 
Section 3, Section 5  
Allow more flexibility 
between Screening and  
Visit 1 (triggered by  
Christmas holiday period). 
Time-points for frequent 
temperature assessments in 
the first 24h inpatient 
observation period have 
been specified. 
Times and Events Table 3,  
Section 5 
Ensure a potential transient 
temperature rise shortly 
after vaccination is 
captured. 
Description of the stopping 
rules. 
Section 3.6, Appendix A-E 
Change is made to better 
reflect FDA standards. 
Heart rate has been added to 
the vital sign measurements 
at Screening Visit and Visit 
1. 
Section 5 
Correction of omission in 
Protocol version 1.0. 
Description of medication 
errors or overdose. 
Section 6.4 
Change made to add new 
template text. 
Corrections of typo’s. 
Throughout the document 
Corrections of omissions in 
Protocol version 1.0. 

 
 
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PRO-01 TEMP 06 / Atlas No. 293620 
Version No. 2 / Version Date: December 2, 2013 
CLINICAL STUDY PROTOCOL V132_01EXP Version 2 
A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study to Evaluate the 
Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R Adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium Hydroxide  
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy Adults (18-45 
years of age) 
EUDRACT No. 2014-002430-31 
Property of Novartis Vaccines and Diagnostics (hereafter referred to as Novartis) 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of Novartis. 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................ 2 
PROTOCOL SYNOPSIS V132_01EXP.......................................................................... 7 
LIST OF ABBREVIATIONS........................................................................................ 23 
1.0  
BACKGROUND AND RATIONALE............................................................... 25 

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1.1  
Background.................................................................................................... 25 
 
1.2  
Rationale........................................................................................................ 28 
2.0  
OBJECTIVES.................................................................................................... 29 
 
2.1  
Primary Objectives......................................................................................... 29 
 
2.2  
Secondary Objectives..................................................................................... 29 
 
2.3  
Exploratory Objectives................................................................................... 29 
3.0  
STUDY DESIGN .............................................................................................. 31 
 
3.1  
Overview of Study Design............................................................................. 31 
 
3.2  
Study Period .................................................................................................. 32 
 
3.3  
Blinding Procedures....................................................................................... 32 
 
3.4  
Data Collection.............................................................................................. 33 
 
3.4.1  
Data Collected from Subjects ................................................................. 33 
 
3.4.2  
Tools Used for Data Collection .............................................................. 33 
 
3.5  
Collection of Clinical Specimens ................................................................... 34 
 
3.6  
Stopping/Pausing Guidelines.......................................................................... 37 
 
3.7  
Data Monitoring Committee........................................................................... 38 
 
3.8  
Premature Withdrawal from Study................................................................. 38 
 
3.9  
End of Study.................................................................................................. 40 
4.0  
SELECTION OF STUDY POPULATION......................................................... 42 
 
4.1  
Inclusion Criteria ........................................................................................... 42 
 
4.2  
Exclusion Criteria .......................................................................................... 42 
 
4.3  
Criteria for Delay of Vaccination or Blood Draw........................................... 44 
5.0  
STUDY PROCEDURES ................................................................................... 45 
 
5.1  
Pre-vaccination Clinic Visit(s) ....................................................................... 45 
 
5.1.1  
Informed Consent................................................................................... 45 
 
5.1.2  
Screening ............................................................................................... 46 
 
5.2  
Vaccination Clinic Visit(s)............................................................................. 47 

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5.2.1  
Pre-vaccination Procedures..................................................................... 47 
 
5.2.2  
Enrolment .............................................................................................. 48 
 
5.2.3  
Randomization ....................................................................................... 48 
 
5.2.4  
Vaccination............................................................................................ 49 
 
5.2.5  
Post-vaccination Procedures................................................................... 49 
 
5.3  
Post-vaccination Visit(s) ................................................................................ 50 
 
5.3.1  
Subject Diary Reminder, Safety Follow-up and/or Post-vaccination Blood  
Draw Clinic Visits .................................................................................. 50 
 
5.3.2  
Safety Follow-up Calls........................................................................... 54 
 
5.4  
Unscheduled Visits ........................................................................................ 54 
 
5.5  
Study Termination Visit................................................................................. 54 
 
5.5.1  
Early Termination Visit.......................................................................... 55 
6.0  
TREATMENT OF SUBJECTS.......................................................................... 57 
 
6.1  
Study Vaccine(s)............................................................................................ 57 
 
6.2  
Non-Study Vaccines ...................................................................................... 60 
 
6.3  
Vaccine Preparation and Administration ........................................................ 60 
 
6.4  
Vaccine Administration Error or Overdose of Vaccine................................... 61 
 
6.5  
Prior and Concomitant Medications and Vaccines.......................................... 61 
 
6.6  
Vaccine Supply, Labeling, Storage and Tracking ........................................... 61 
7.0  
ASSESSMENTS................................................................................................ 64 
 
7.1  
Safety Assessment ......................................................................................... 64 
 
7.1.1  
Solicited Adverse Events........................................................................ 64 
 
7.1.2  
Unsolicited Adverse Events.................................................................... 66 
 
7.1.3  
Evaluation of Adverse Events................................................................. 66 
 
7.1.4  
Serious Adverse Events.......................................................................... 67 
 
7.1.4.1  
Adverse Events of Special Interest...................................................... 69 
 
7.1.5  
Methods for Recording Adverse Events and Serious Adverse Events ..... 70 

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7.1.5.1  
Post-Study Events .............................................................................. 71 
 
7.1.6  
Pregnancies............................................................................................ 71 
 
7.1.7  
Safety Laboratory Measurements ........................................................... 71 
 
7.2  
Efficacy Assessment ...................................................................................... 72 
 
7.3  
Immunogenicity Assessment.......................................................................... 72 
 
7.4  
Exploratory Measurements............................................................................. 73 
8.0  
STATISTICAL CONSIDERATIONS................................................................ 75 
 
8.1  
Endpoints....................................................................................................... 75 
 
8.1.1  
Primary Endpoint(s)............................................................................... 75 
 
8.1.1.1  
Primary Safety Endpoint(s) ................................................................ 75 
 
8.1.1.2  
Primary Efficacy Endpoint(s) ............................................................. 75 
 
8.1.1.3  
Primary Immunogenicity Endpoint(s)................................................. 75 
 
8.1.2  
Secondary Endpoint(s) ........................................................................... 75 
 
8.1.2.1  
Secondary Safety Endpoint(s)............................................................. 75 
 
8.1.2.2  
Secondary Efficacy Endpoint(s) ......................................................... 76 
 
8.1.2.3  
Secondary Immunogenicity Endpoint(s)............................................. 76 
 
8.1.3  
Exploratory Endpoint(s)......................................................................... 76 
 
8.2  
Success Criteria ............................................................................................. 77 

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8.2.1  
Success Criteria for Primary Objective(s)............................................... 77 
 
8.2.2  
Success Criteria for Secondary Objective(s) ........................................... 77 
 
8.3  
Analysis Sets ................................................................................................. 77 
 
8.3.1  
All Enrolled Set...................................................................................... 77 
 
8.3.2  
All Exposed Set...................................................................................... 77 
 
8.3.3  
Safety Set............................................................................................... 77 
 
8.3.4  
Full Analysis Set (FAS) Efficacy/Immunogenicity Set ........................... 78 
 
8.3.5  
Per Protocol (PP) Set Efficacy/Immunogenicity Set................................ 78 
 
8.3.6  
Other Analysis Sets................................................................................ 79 
 
8.3.7  
Subgroups.............................................................................................. 79 
 
8.3.8  
Protocol Deviations................................................................................ 79 
 
8.4  
Statistical Analysis Plan................................................................................. 79 
 
8.4.1  
Analysis of Demographic and Baseline Characteristics........................... 79 
 
8.4.2  
Analysis of Primary Objective(s)............................................................ 79 
 
8.4.2.1  
Analysis of Primary Safety Objective(s)............................................. 79 
 
8.4.2.1.1  
Analysis of Extent of Exposure.................................................... 80 
 
8.4.2.1.2  Analysis of Solicited Local, Systemic and Other Adverse Events. 80 
 
8.4.2.1.3  
Analysis of Unsolicited Adverse Events....................................... 81 
 
8.4.2.1.4  
Analysis of Safety Laboratory Values .......................................... 81 
 
8.4.2.2  
Analysis of Primary Efficacy Objective(s).......................................... 82 
 
8.4.2.3  
Analysis of Primary Immunogenicity Objective(s) ............................. 82 
 
8.4.2.3.1  
Statistical Hypotheses .................................................................. 82 
 
8.4.2.3.2  
Analysis Sets................................................................................ 82 
 
8.4.2.3.3  
Statistical Methods....................................................................... 82 
 
8.4.3  
Analysis of Secondary Objective(s)........................................................ 83 
 
8.4.3.1  
Analysis of Secondary Safety Objective(s) ......................................... 83 
 
8.4.3.2  
Analysis of Secondary Efficacy Objective(s)...................................... 83 

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8.4.3.3  
Analysis of Secondary Immunogenicity Objective(s).......................... 84 
 
8.4.3.3.1  
Statistical Hypotheses .................................................................. 84 
 
8.4.3.3.2  
Analysis Sets................................................................................ 84 
 
8.4.3.3.3  
Statistical Methods....................................................................... 84 
 
8.4.4  
Analysis of Exploratory Objectives ........................................................ 85 
 
8.5  
Sample Size and Power Considerations of Primary Objectives....................... 85 
 
8.6  
Interim Analysis............................................................................................. 86 
9.0  
SOURCE DOCUMENTATION, STUDY MONITORING AND AUDITING... 87 
 
9.1  
Source Documentation................................................................................... 87 
 
9.2  
Study Monitoring, Auditing and Source Data Verification ............................. 88 
10.0  
DATA MANAGEMENT................................................................................... 89 
 
10.1  
Data Entry and Management.......................................................................... 89 
 
10.2  
Data Clarification........................................................................................... 89 
 
10.3  
Data Protection .............................................................................................. 89 
11.0  
RECORD RETENTION.................................................................................... 91 
12.0  
USE OF INFORMATION AND PUBLICATION ............................................. 92 
13.0  
ETHICS............................................................................................................. 93 
 
13.1  
Regulatory and Ethical Compliance ............................................................... 93 
 
13.2  
Informed Consent Procedures ........................................................................ 93 
 
13.3  
Responsibilities of the Investigator and IRB/EC............................................. 94 
 
13.4  
Protocol Amendments.................................................................................... 95 
14.0  
REFERENCE LIST........................................................................................... 96 
APPENDIX A:  
GRADING SCALES FOR SOLICITED LOCAL ADVERSE  
EVENTS*........................................................................................ 99 
APPENDIX B:  
GRADING SCALES FOR SOLICITED SYSTEMIC ADVERSE  
EVENTS*...................................................................................... 100 

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APPENDIX C:  
TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(SERUM CLINICAL CHEMISTRY) ............................................ 101 
APPENDIX D:  
TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(HEMATOLOGY)......................................................................... 102 
APPENDIX E:  
TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(URINE)........................................................................................ 103 
PROTOCOL SYNOPSIS V132_01EXP 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Title of Study: A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study to  
Evaluate the Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R 
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium  
Hydroxide Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy Adults 
(18-45 years of age) 
Study Period: Approximately 12 months for 
each subject 
Clinical Phase: Phase 1 

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Page 8 of 103 
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Background and Rationale: 
Neisseria meningitidis (N. meningitides)serogroup C (MenC) is one of the major 
serogroups causing invasive meningocococcal disease. Case fatality in Germany has 
ranged between 6% and 8% between 1999 and 2006, and has remained generally 
consistent across the different European countries, varying between 6-11%, with the case 
fatality rate being notably higher for serogroup C disease than for serogroup B. The 
safety and immunogenicity of the Novartis Meningococcal C-CRM197 Conjugate 
Vaccine (Menjugate®) has been confirmed through years of commercial use. For children 
over the age of 12 months, for adolescents and for adults a single dose is recommended. 
For infants between 2 and 12 months of age, the recommended schedule for primary 
immunization with the Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) is 
two doses given with an interval of at least 2 months (Novartis Meningococcal C-
CRM197 Conjugate Vaccine Investigator Brochure). 
A more potent Meningococcal C-CRM197 Conjugate Vaccine formulation might enable a 
reduction of the antigen dosage and/or a reduction in the number of doses needed in 
infants. One approach to achieve more potent well-characterized sub-unit vaccines - like 
the Novartis Meningococcal C-CRM197 Conjugate Vaccine - is the use of new adjuvants 
that activate the Toll-like receptor (TLR) pathway. 
Novartis is developing a small molecule immune potentiator (SMIP) LHD153 that is an 
agonist for  TLR7. The objective driving the development of LHD153 is to achieve a 
vaccine adjuvant with strong immunopotentiating properties and minimal side effects. In 
line with this objective, it has been postulated that the ideal SMIP should remain local 
and target innate immune cells at the injection site. To this end, LHD153 contains a  
 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

Novartis Vaccines and Diagnostics  Protocol V132_01EXP 10 SEP  14 Version 2 
Confidential
 
Page 9 of 103 
PRO-01 TEMP 06 / Atlas No. 293620 
Version No. 2 / Version Date: December 2, 2013 
functional phosphonate group to allow for adsorption to aluminium hydroxide. The 
arginine salt derivative of this compound is LHD153R. Preclinical results from animal 
models for bacterial and viral antigens, including MenC, MenB, rabies, HIV and 
respiratory syncytial virus (RSV) showed increased functional antibodies and 
antigenspecific T-cells with LHD153R adsorbed to aluminium hydroxide (Aluminium  
Hydroxide/LHD153R) when compared to aluminium hydroxide adjuvanted controls. In 
vitro toxicity screens confirmed that LHD153R is not phototoxic, genotoxic or 
mutagenic. Furthermore, toxicology studies in dog and rats showed that intramuscular 
(IM) injection of Aluminium Hydroxide/LHD153R was well tolerated. Importantly, in 
contrast to free LHD153R, toxicokinetic analysis in rats and dogs confirmed very 
limited exposure of LHD153 when LHD153R was adsorbed to aluminium hydroxide 
after IM injection. 
The aim of this Phase 1 clinical study is to assess the safety of Aluminium  
Hydroxide/LHD153R adjuvanted MenC-CRM197 conjugate vaccine 
(MenCCRM197/Aluminium Hydroxide/LHD153R) and to compare the antibody-
mediated immune response elicited by MenC-CRM197/Aluminium Hydroxide/LHD153R 
with the licensed aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate 
Vaccine (Menjugate®). Furthermore, a comprehensive set of exploratory objectives has 
been selected to assess the systemic exposure of LHD153 after intramuscular injection of 
MenC-CRM197/Aluminium Hydroxide/LHD153R, to evaluate the quality of the specific 
immune response against MenC-CRM197 in detail and to evaluate  biomarkers that may 
be predictive of safety and/or innate immune activation. 
The licensed Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) has been 
selected as the primary vaccine candidate to assess the safety and immunopotentiating 
properties of Aluminium Hydroxide/LHD153R for several reasons. Firstly, the safety 
and immunogenicity profiles of the Meningococcal C-CRM197 Conjugate Vaccine 
(Menjugate®) have been well established through years of commercial use. Secondly, a 
more potent MenC-CRM197 conjugate vaccine might enable a reduction of the antigen 
dosage or the number of doses needed in infants. Finally, the MenC-CRM197 conjugate 
is a well-characterized, single antigen preparation which provides an ideal setting to 
evaluate the potential of this new Aluminium Hydroxide/LHD153R adjuvant. 
 

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PRO-01 TEMP 06 / Atlas No. 293620 
Version No. 2 / Version Date: December 2, 2013 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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Study Objectives: 
Primary Safety Objective: 
To assess the safety of MenC-CRM197/Aluminium Hydroxide/LHD153R as compared to 
that of aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
Primary Immunogenicity Objective: 
To compare the antibody responses of MenC-CRM197/Aluminium Hydroxide/LHD153R 
and aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at 
Day 29, as measured by human complement serum bactericidal assay (hSBA) directed 
against MenC. 
Secondary Immunogenicity Objectives: 
1. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine, at Day 8 and Day 181 after vaccination, as measured 
by hSBA directed against MenC. Baseline antibody titers will also be measured by 
hSBA. 
2. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine at Day 8, Day 29 and Day 181 after vaccination, as 
measured by an enzyme-linked immunosorbent assay (ELISA) to MenC. Baseline 
antibody concentrations will also be measured by ELISA. 
Exploratory Objectives: 
1. To evaluate the systemic exposure of LHD153 at several early time-points after IM 
injection of MenC-CRM197/Aluminium Hydroxide/LHD153R or aluminium 
hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
2. To explore the frequency of B cells specific for MenC polysaccharide and CRM197 
protein at baseline (Day 1) and at Day 8, Day 29 and Day 181 after vaccination with  
 

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Version No. 2 / Version Date: December 2, 2013 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
MenC-CRM197/Aluminium Hydroxide/LHD153R or the aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. Subsequently, the B cell 
repertoire of the antigen specific B cells and the specific antibody functionality will 
be analyzed in a selected subset of subjects. 
3. To explore the baseline T cell mediated immunity to CRM197 and to evaluate the 
frequency and quality of CRM197 specific T cells induced by MenC- 
CRM197/Aluminium Hydroxide/ LHD153R compared to aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at Day 8 and Day 29. 
4. To evaluate biomarkers that may be predictive for safety and/or innate immune 
activation. 

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Study Design: 
This Phase 1, randomized, observer-blind, dosage-escalation study will be performed at 
a single center. In total, approximately 80 healthy male and healthy non-pregnant female 
adults (18-45 years of age) will be enrolled in the study. Subjects will be randomized to 
receive a single IM vaccination of either the licensed aluminium hydroxide adjuvanted 
Meningococcal C-CRM197 Conjugate Vaccine (i.e. 10 µg MenC conjugated to CRM197,  
adjuvanted with 1 mg aluminium hydroxide) or one of four dosages of the 
investigational vaccine, MenC-CRM197/Aluminium Hydroxide/LHD153R (i.e. 10 µg 
MenC conjugated to CRM197,  adjuvanted with 1 mg aluminium hydroxide and one of 
four dosages [12.5, 25, 50 or 100 µg] of LHD153R). 
For the dosage-escalation of LHD153R, the subjects will be enrolled into 1 of 4 cohorts, 
in a stepwise manner with 20 subjects per cohort. Subjects in all cohorts will be 
randomized in a 1:4 ratio, to receive either aluminium hydroxide adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine (control) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R with increasing doses of LHD153R.Cohort 1 will receive 12.5 μg 
of LHD153R; Cohort 2 will receive 25 μg of LHD153R; Cohort 3 will receive 50 μg of 
LHD 153; and Cohort 4 will receive 100 μg of LHD153R (Table 1). 
 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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Table 1. Subjects Randomized per Cohort and Treatment Dose Group 
Cohort 
Group 
Subjects/ 
Group 
MenC  
Dosage*  
(µg) 
Adjuvant Dosages  
Total 
Volume/Dose 
Total 
Subjects/Group 
Aluminium  
Hydroxide  
(mg) 
LHD153R  
(µg) 
1 
A 
4 
10 
1 
0 
0.5 mL 
20 
B 
16 
10 
1 
12.5 
0.5 mL 
2 
A 
4 
10 
1 
0 
0.5 mL 
20 
C 
16 
10 
1 
25 
0.5 mL 
3 
A 
4 
10 
1 
0 
0.5 mL 
20 
D 
16 
10 
1 
50 
0.5 mL 
4 
A 
4 
10 
1 
0 
0.5 mL 
20 
E 
16 
10 
1 
100 
0.5 mL 
*Conjugated to 12.5-25 µg CRM197 
After vaccination, all subjects will be confined to the clinical site for 24 hours for 
clinical observation, including but not limited to observations for solicited and 
unsolicited adverse events, body temperature measurements and blood sampling for 
exploratory endpoint measurements. 
Importantly, all cohorts will have a staggered entry. 
▫ For each cohort, the first 5 subjects (i.e. the first 1:4 randomization block) to receive 
either aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate 
Vaccine (n=1) or MenC-CRM197/Aluminium Hydroxide/LHD153R (n=4) will be 
treated at a vaccination rate of 1 subject each day. 
▫ After entry of the first 5 subjects in each cohort, the enrollment will be paused. The 
remaining 15 subjects for each cohort will be enrolled only after DMC review of the 
safety results obtained through Day 14 has been finalized (Table 2). 
▫ Furthermore, after entry of all 20 subjects in each cohort, enrollment will be paused 
again. Enrollment of the first 5 subjects in the next cohort will only proceed after the 
Day 29 safety results of the previous cohort have been reviewed by the Data 
Monitoring Committee (DMC) (Table 2). 
 

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Version No. 2 / Version Date: December 2, 2013 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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Version No. 2 / Version Date: December 2, 2013 
Table 2. Overview of staggered entry of subjects for each cohort 
Cohort 
1st Stage of 
enrollment 
MenC- 
CRM197/ 
Aluminium 
Hydroxide 
MenC- 
CRM197/ 
Aluminium  
Hydroxide  
/LHD153R 
2nd Stage of 
enrollment 
MenC- 
CRM197/ 
Aluminium 
Hydroxide 
MenC- 
CRM197/ 
Aluminium  
Hydroxide  
/LHD153R 
1 
First 5 
subjects with  
vaccination 
rate of 1 
subject/day 
1 
4 
Remaining 15 
subjects, after  
DMC review of  
Day 14 safety 
results 
3 
12 
2 
1 
4 
3 
12 
3 
1 
4 
3 
12 
4 
1 
4 
3 
12 
The DMC review after the first 5 subjects of each cohort and in between the cohorts will 
be performed according to predefined stopping/pausing guidelines used to ensure the 
safety of study subjects. These stopping/pausing guidelines are based on FDA guidance 
and with grading scales from the CBER Guidance for Industry “Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials”. See protocol section 3.6 for further details. 
Safety Measurements 
Schedule of safety data collection: 
▫ Solicited local and systemic adverse events (AEs), body temperature and all 
unsolicited AEs will be collected until Day 14. 
▫ All serious adverse events (SAEs), medically attended AEs, AEs leading to study 
withdrawal, new onset of chronic disease (NOCDs), and adverse events of special 
interest (AESIs) will be collected from the date of signed informed consent to study 
completion at Day 366. 
▫ All concomitant medications administered in relation to the reported AEs will be 
collected from vaccination to study completion at Day 366. 
 

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Version No. 2 / Version Date: December 2, 2013 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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Version No. 2 / Version Date: December 2, 2013 
Solicited local AEs include injection site erythema, injection site induration, injection 
site pain and injection site swelling. Solicited systemic AEs include body temperature ≥ 
38.0°C (as measured orally), loss of appetite, nausea, fatigue, generalized myalgia, 
generalized arthralgia, headache, chills, vomiting, diarrhea, generalized rash and 
urticaria. 
All AESIs will be reported in the same manner as SAEs. All AEs will be monitored until 
resolution or, if the AE becomes chronic, a cause is identified. If an AE is unresolved at 
the conclusion of the study, a clinical assessment will be made by the investigator and 
the medical monitor to determine whether or not continued follow-up of the AE is 
warranted. 
The relationship of the study treatment to any AE will be determined by the investigator 
as probably related, possibly related, or not related; the relationship of the study 
treatment to any SAE will be determined by the investigator as probably 
related/suspected, or not related. 
Safety Laboratory Parameters 
To assess laboratory AEs, blood and urine samples will be collected from each subject 
as outlined in Table 3 to perform blood chemistry, hematology, and urine analyses. 
Safety laboratory samples will be drawn from all subjects at pre-vaccination screening 
(between Day -28 and Day -3) at Day 1 (pre-vaccination), at Day 8 and at Day 29. Safety 
laboratory assessments will include sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, liver function tests (ALT, AST), a complete blood count and C-
reactive protein. A urine sample will be collected at the same time-points and will be 
assessed for the presence of protein, glucose and red blood cells. 
Primary and Secondary Immunogenicity Measurements 
Four blood samples per subject (i.e. at Day 1, Day 8, Day 29 and Day 181) will be 
collected for serum preparation and determination of antibody-mediated immune 
responses to MenC-CRM197 as outlined in Table 3 and Table 4. See section 7.3 for 
further details. 
 

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Version No. 2 / Version Date: December 2, 2013 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Exploratory Measurements 
In all subjects who agree by signing a separate Informed Consent, additional blood 
samples will be collected at Day 1, Day 4, Day 8, Day 29 and Day 181 for exploratory 
assays as outlined in Table 3 and Table 4. The purpose of these assays is to assess the 
systemic exposure of LHD153, to determine the frequency and quality of B- and T-cells 
specific for MenC polysaccharide and/or CRM197 and to evaluate biomarkers that may 
be predictive of safety and/or innate immune activation. Subsequently, MenC-CRM197 
specific B-cell repertoires as well as the MenC-CRM197 specific antibody functionalities 
will be analyzed in a selected subset of subjects, dependent on the results from primary 
and secondary immunogenicity measurements and the volume of whole blood (specific 
B cell repertoire) and serum (specific antibody functionality) remaining for additional 
testing. See section 7.4 for further details. All exploratory analyses may be performed 
after the Clinical Study Report (CSR) has been completed, in which case these data will 
be submitted as an addendum to the CSR. 
Number of Subjects planned: 
Approximately 80 adult subjects will be randomized, with anticipated dropout rates of 
5% by Day 181 (last serology time point), and 10%, by Day 366 (last safety time point). 
Sample size is not driven by statistical assumptions for formal hypothesis testing, but the 
proposed number of subjects will be sufficient to provide a descriptive summary of the 
safety and immunogenicity of the study vaccine. 
Study Population and Subject Characteristics: 
Healthy adult male and female volunteers between 18-45 years of age, inclusive. 
The list of inclusion and exclusion criteria is included in protocol section 4.0. 

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Version No. 2 / Version Date: December 2, 2013 
Study Vaccines: 
The MenC-CRM197 conjugate  is a lyophilized powder consisting of 10 µg of MenC 
polysaccharide conjugated to 12.5-25 µg CRM197 carrier protein. The MenC-CRM197 
lyophilized powder will be reconstituted with adjuvant by the unblinded designated site 
staff member who is to follow the procedure as described in the vaccine preparation  
 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
instructions in the Investigator Site File (i.e. the vaccine will be prepared in the clinic prior 
to administration). 
The lyophilized MenC-CRM197 powder will be reconstituted with either: 
(a) aluminium hydroxide adjuvant 
(b) Aluminium Hydroxide/LHD153R adjuvant with specified dosages of LHD153R 
(12.5, 25, 50 or 100 µg) 
The components for each formulation of MenC-CRM197 will be provided in a separate 
kit. 
Aluminium Hydroxide/LHD153R with specified dosages of LHD153R will be prepared  
by dilution of the highest Aluminium Hydroxide/LHD153R dosage (100 µg of 
LHD153R) with aluminium hydroxide. 
In each cohort, subjects will be randomized to receive one injection of MenC- 
CRM197/Aluminium Hydroxide/LHD153R adjuvant or aluminium hydroxide adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine. The 0.5 mL of vaccine will be injected 
IM in the deltoid muscle, with preference that the injection is administered in the 
nondominant arm. 

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Primary Safety Endpoint: 
Safety will be assessed by measuring the frequency of local and systemic solicited AEs, 
unsolicited AEs, SAEs, AESIs, NOCDs, and safety laboratory data for all subjects.  
Specifically, 
▫ The frequency and percentage of subjects with solicited local and systemic AEs 
through Day 14. Time intervals after vaccination that will be summarized are: 30 
min post-vaccination, Days 1-4 (without 30 min), Days 5-8, Days 8-14, Days 1-8 
(without 30 min) and Days 1-14 (without 30 min). 
▫ The frequency and percentage of subjects with any unsolicited AEs from the day of 
vaccination (Day 1) to Day 14. 
▫ The frequency and percentage of subjects with SAEs, medically attended AEs,  AEs  
 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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leading to study withdrawal, NOCDs, AESIs for the following time periods: day of 
signed informed consent until study completion (Day 366), day of vaccination (Day 
1) to Day 29 and Day 29 to study completion (Day 366). 
▫ The absolute values and changes in hematology, chemistry, and urinalysis parameters. 
▫ The frequency and percentage of subjects with abnormal laboratory parameter values 
as classified by investigator normal ranges (low, normal, high) and as classified by 
CBER toxicity grading scales, when available. 
Primary Immunogenicity Endpoint: 
Geometric mean titers (GMTs) measured by hSBA directed against MenC from samples 
collected on Day 1 (baseline, before vaccination) and Day 29 as well as the GMR of the 
titers (Day 29 / Day 1). 
Secondary Immunogenicity Endpoints: 
▫ GMTs and corresponding GMRs measured by hSBA directed against MenC for samples 
collected at Day 8 and Day181. 
▫ Percentage of subjects with hSBA seroresponse at Day 8, Day 29, and Day 181. 
seroresponse is defined as a post vaccination hSBA ≥8 for subjects with a baseline 
hSBA <4 or have an increase of at least 4 times the baseline hSBA level for subjects 
with pre-vaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against MenC measured by ELISA 
for samples collected on Day 1 (baseline, prior to vaccination), Day 8, Day 29, and 
Day 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations 
to MenC measured by ELISA on Day 8, Day 29, and Day 181 relative to baseline 
(Day 1). 
Exploratory Endpoints: 
Testing and analyses of exploratory endpoints may be performed after the Clinical Study  
Report (CSR) has been completed, in which case these data will be submitted as an  
 

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Version No. 2 / Version Date: December 2, 2013 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
addendum to the CSR. 
1. Serum concentration of LHD153 at Day 1 baseline (prior to vaccination), Day 1 (1h , 
2h, 4h, 8h, and 24h after vaccination) and Day 4 by LC-MS/MS. 
2. Frequency of MenC polysaccharide-specific and CRM197-specific B cells at Day 1 
(baseline), Day 8, Day 29, and Day 181 by ELISPOT. 
3. Diversity of the MenC polysaccharide-specific B-cell repertoire at Day 1 (baseline), 
Day 8, Day 29, and Day 181 by immunoglobulin cDNA sequencing. 
4. Functionality of antigen specific antibodies will be assessed at Day 1 (baseline), Day 
8, Day 29, and Day 181 by analysis of immunoglobulin isotype, glycosylation state 
and their ability to fix complement, to promote antibody-dependent cell mediated 
cytoxicity, to induce phagocytosis and to activate FcR+ cells. If the quantity of serum 
available for this specific exploratory objective is limited, assessments of 
immunoglobulin isotype, glycosylation state and complement fixing capacity will be 
prioritized over the other assessments. 
5. Frequency and quality of T cells specific for CRM197 at Day 1 (baseline), Day 8, and 
Day 29 by fluorescence activated cell sorting (FACS) analysis using intracellular 
staining with a panel of cytokines and surface markers to identify cell populations. 
6. Serum concentrations of a panel of 30 chemokines and cytokines at Day 1 baseline 
(prior to vaccination), Day 1 (6h and 24h after vaccination), Day 4, and Day 8 by 
electrochemo-luminescence based assay. 
7. Gene expression profile in whole blood at Day 1 baseline (prior to vaccination), Day 
1 (6h and 24h after vaccination), Day 4, and Day 8 by RNA micro array analysis. 

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Statistical Analyses: 
The study is exploratory in nature, thus analyses will be descriptive and no formal 
hypothesis testing will be performed. 
Primary Safety Analyses 
The primary safety analyses will be based on the safety set for solicited and unsolicited 
adverse events. There is no statistical null hypothesis associated with the safety  
 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
objective, which will be analyzed descriptively. 
Immunogenicity Analyses 
The primary immunogenicity analyses will be based on the per-protocol set (PPS) on 
Day 29. The primary analyses will also be performed using the Full Analysis Set (FAS) 
as a measure of the sensitivity/robustness of the results. All other immunogenicity 
assessments will be performed using the PPS or the appropriate subset of subjects. The 
antibody concentrations/titers will be summarized using GMC/GMTs and two-sided 
95% confidence intervals (CIs) constructed by exponentiation (base 10) of the least 
square means of the logarithmically transformed (base 10) antibody titer. The 95% CIs 
will be obtained from an analysis of covariance (ANCOVA) with baseline 
concentration/titer as a covariate. Additional details will be further described in the 
Statistical Analysis Plan. 
The immunogenicity endpoints based on subjects meeting criteria for seroconversion or 
achieving a certain threshold value will be summarized using frequencies and 
percentages and associated two-sided 95% Clopper-Pearson CIs. For analyses of 
seroconversion, separate summaries may be provided based on seropositivity status at 
baseline. 

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Interim Analysis: 
An Interim Analysis will be performed on the immunogenicity and safety data collected 
from all subjects until Day 29, after all cohorts have been enrolled. Further details 
regarding the interim analysis are contained in section 8.6. 
Data Monitoring Committee: 
A Data Monitoring Committee (DMC) will be implemented to review safety data during 
scheduled periodic reviews. The DMC will review safety data collected until Day 14, as 
described in the DMC charter and in the Statistical Analysis Plan, after enrollment of the 
first 5 subjects in each cohort, before proceeding with enrollment of the remaining 
subjects in each cohort. In addition, the DMC will review safety data collected until Day 
29 after enrollment for each cohort. Enrollment of subjects in subsequent cohorts will  
 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
only proceed after the DMC review is completed. The same enrollment sequence will be 
utilized for each cohort. Further information regarding the DMC is discussed in more 
detail in the protocol, section 3.7. 

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Table 3: 
Time and Events Table – Treatment Period (until Day 29) 
 
Visit Type 
Clinic Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
 
Study Day 
-28 to -3 
1 
4 
8 
15 
22 
29 
 
Visit Window (Days) 
n/a 
n/a 
n/a 
-1/+1 
+1 
n/a 
-2/+2 
 
Visit Number 
Screening  
1 
2 
3 
4 
5 
6 
Study Event 
References 
 
 
 
 
 
 
 
Study Treatment 
 
 
 
 
 
 
 
 
Vaccination 
Section 5.2 
 
X 
 
 
 
 
 
Screening and Safety 
 
 
 
 
 
 
 
 
Informed Consent  
Section 5.1.1 
X 
 
 
 
 
 
 
Demographic Data & Medical History 
Sections 5.1.2 
X 
 
 
 
 
 
 
Physical Exam 
Sections 5.1.2 and 5.2.1 
X 
Xa 
 
 
 
 
 
Safety Laboratory blood draw (10 ml) 
Section 7.1.7 
X 
Xa 
 
X 
 
 
X 
Urinalysis 
Sections 7.1.7 
X 
Xa 
 
X 
 
 
X 
Pregnancy Test 
Sections 5.1.2 and 5.2.1 
X 
Xa 
 
 
 
 
 
Exclusion/Inclusion Criteria 
Section 4.0 
X 
Xa 
 
 
 
 
 
Randomization 
Section 5.2.3 
 
Xa 
 
 
 
 
 
30 min and 24 hr Post Injection Assessment 
Section 5.2.5 
 
Xb 
 
 
 
 
 
Subject Diary Dispensed with Training 
Section 5.2.5 
 
X 
 
 
 
 
 
Subject Diary Reminder 
Section 5.2.5 
 
 
X 
X 
 
 
 

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Subject Diary Reviewed and Collected 
Section 5.3.1 
 
 
 
 
X 
 
 
Assess all solicited AEs 
Section 7.1.1 and 7.1.3 
 
 
 
 
X 
 
 
Assess all unsolicited AEs 
Sections 7.1.2 and 7.1.3 
X 
X 
X 
X 
X 
 
 
PRO-01 TEMP 06 / Atlas No. 293620 
Visit Type 
Clinic Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Study Day 
-28 to -3 
1 
4 
8 
15 
22 
29 
Visit Window (Days) 
n/a 
n/a 
n/a 
-1/+1 
+1 
n/a 
-2/+2 
Visit Number 
Screening  
1 
2 
3 
4 
5 
6 
Study Event 
References 
 
 
Assess SAEs 
Section 7.1.4 
X 
X 
X 
X 
X 
X 
X 
Assess AESIs 
Section 7.1.4.1 
X 
X 
X 
X 
X 
X 
X 
Assess NOCDs, medically attended AEs, 
AEs leading to withdrawal  
Sections 7.1.3 
X 
X 
X 
X 
X 
X 
X 
Assess relevant medications 
Sections 5.1.2 and 6.5 
X 
X 
X 
X 
X 
X 
X 
Blood draws for Immunogenicity and Exploratory Objectives 
 
Serum Blood Draw (Primary and Secondary 
Objectives; 10 mL)  
Section 3.5 
 
Xa 
 
X 
 
 
X 
Serum Blood Draw (Exploratory 
Objectives; 5 mL)  
Section 3.5 
 
Xc 
X 
X 
 
 
 
Whole Blood Draws (Exploratory 
Objectives; 2 mL) 
Section 3.5 
 
Xd 
X 
 
 
 
 
Whole Blood Draw (Exploratory Objectives; 
5 mL) 
Section 3.5 
 
Xe 
X 
X 
 
 
 

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Whole Blood Draw (Exploratory Objectives; 
50 mL) 
Section 3.5 
 
Xa 
 
X 
 
 
X 
Notes: 
a. Procedure must be performed prior to vaccination. 
b. Body temperature measurement must be performed at 30 min, 2, 4, 6, 8, 10, 12, 20 and 24 hours after vaccination.  
c. Three Serum Blood Draws (3 x 5ml) must be taken at Study Day 1, i.e. at baseline (prior to vaccination), at 6h and at 24h after vaccination. 
d. Six whole Blood Draws (6 x 2 mL) must be taken at Study Day 1, i.e. at baseline (prior to vaccination) and at 1, 2, 4, 8 and 24h after 
vaccination. 
e. Three Whole Blood Draw (3 x 5 mL) must be taken at Study Day 1, i.e. at baseline (prior to vaccination), at 6h and at 24h after vaccination 
 
PRO-01 TEMP 06 / Atlas No. 293620 
Table 4: 
Time and Events Table – Follow-up Period (until Day 366) 
Visit Type 
Clinic Visit 
Clinic Visit 
Clinic Visit 
Phone Call 
Phone Call 
Clinic Visit 
Study Day 
85 
113 
181 
209 
271 
366 
Visit Window (Days) 
-7 to +7 
-7 to +7 
-7 to +7 
-14 to +14 
-14 to +14 
-14 to +14 
Visit Number 
7 
8 
9 
10 
11 
12 
Study Event 
References 
 
 
Safety 
 
Assess SAEs 
Section 7.1.4 
X 
X 
X 
X 
X 
X 
Assess AESI 
Section 7.1.4.1 
X 
X 
X 
X 
X 
X 
Assess NOCDs, medically attended 
AEs, AEs leading to withdrawal 
Sections 7.1.3 
X 
X 
X 
X 
X 
X 
Assess relevant medications 
Sections 5.1.2 and 6.5 
X 
X 
X 
X 
X 
X 
Blood draws for Immunogenicity and Exploratory Objectives 
 
Serum Blood Draw (Secondary 
Objective; 10 mL) 
Section 3.5 
 
 
X 
 
 
 

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Whole Blood Draw  
(Exploratory Objectives; 50 mL) 
Section 3.5 
 
 
X 
 
 
 
Study Completion Procedures 
 
Study Terminationa 
Section 5.5 
 
 
 
 
 
X 
Notes: 
a. Subjects who terminate the study early are recommended to complete certain study-related procedures. See section 5.5 for further details. 
 
PRO-01 TEMP 06 / Atlas No. 293620 

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LIST OF ABBREVIATIONS 
ADCC 
Antibody-dependent cell mediated cytotoxicity 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BZN 
Benzonaphthyridines 
CBER 
Center for Biologics Evaluation and Research 
cDNA 
Complementary deoxyribonucleic acid 
CI 
Confidence interval 
CRF 
Case report form 
CRM197 
Cross Reacting Material 197 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
EC 
Ethics committee 
EDC 
Electronic data capture 
ELISA 
Enzyme-linked immunosorbent assay 
ELISPOT 
Enzyme-Linked ImmunoSpot 
EMA 
European Medicines Agency 
FACS 
Fluorescence-activated cell sorting 
FAS 
Full analysis set 
FDA 
Federal Drug Agency 
GCP 
Good clinical practice 
GMC 
Geometric mean concentration 
GMP 
Good manufacturing practice 

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GMT 
Geometric mean titer 
GMR 
Geometric mean ratio 
HEENT  
Head, ears, eyes, nose and throat 
HIV 
Human immunodeficiency virus 
 
HPV 
Human papillomavirus 
hSBA 
Human complement serum bactericidal assay 
ICF 
Informed consent form 
ICH 
International Committee for Harmonization 
IM 
Intramuscular 
IRB 
Institutional review board 
IV 
Intravenous 
LLQ 
Lower limit of quantification 
MenC 
Meningococcal type C 
MPL 
Monophosphoryl lipid A 
NCR 
No carbon required 
NOCD 
New Onset of Chronic Disease 
PEG 
Polyethylene glycol 
PO 
Per oral 
PP 
Per protocol 
RNA 
Ribonucleic acid (RNA 
SAE 
Serious Adverse Event 
SMIP 
Small molecule immune potentiator 
TLR 
Toll-like receptor 
VSAE 
Vaccine serious adverse event 
1.0  
BACKGROUND AND RATIONALE 
1.1  
Background 

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MenC-CRM197 Conjugate Vaccine 
Meningococcal disease worldwide is predominantly a disease of infants and young 
children. N. meningitidis serogroup B and C remain the most prevalent strains in North 
America and Europe, (Rosenstein, N. et al., 2001) and together cause more than 95% of 
reported cases of meningococcal disease in Europe (Connolly, M, et al., 1999). In Europe, 
N. meningitidis serogroup C (MenC) is one of the major serogroups causing invasive 
disease. Case fatality in Germany has ranged between 6% and 8% between 1999 and 
2006, and has remained generally consistent across the different European countries, 
varying between 6-11%, with the case fatality rate being notably higher for serogroup C 
disease than for serogroup B (European Centre for Disease Prevention and Control, 
2011). Since MenC vaccination was added to Germany’s routine schedule for children in 
2006, there has been a reported decline in MenC incidence. However, the decline was not 
as rapid when compared to other European countries (Hellenbrand, W. et al., 2013). 
The Novartis Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) comprises 
MenC oligosaccharides conjugated to the protein carrier, CRM197, a nontoxic mutant of 
diphtheria toxin. The vaccine has been shown to be safe and immunogenic and able to 
prime infants, toddlers and young children for immunological memory (see Novartis 
Meningococcal C-CRM197 Conjugate Vaccine Investigator’s Brochure).  
In Germany, the Standing Committee on Vaccination (STIKO) of the Robert Koch  
Institute recommends a single dose of MenC conjugate vaccine in children over the age of  
12 months as part of the routine vaccination campaign (Robert Koch Institute 
Epidemiologisches Bulletin, August 2013). For specific indications, e.g. in case of 
postexposure prophylaxis, the recommended schedule for primary immunization of 
infants between 2 to 12 months of age with a MenC conjugate vaccine is two dosages 
given with an interval of at least 2 months. 
Although the Novartis Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) 
represents an example of how vaccination with a well characterized, purified 
polysaccharide antigen can yield pivotal public health triumphs, there remains a need for 
further improvement of the MenC vaccine. A more potent MenC vaccine formulation 
might yield an increase in the magnitude of the antigen-specific immune response 
enabling a reduction of the antigen dosage. Furthermore, induction of a more rapid 
antigen-specific immune response may enable a reduction in the number of doses needed 
for post-exposure prophylaxis in infants. 

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Vaccine Adjuvants 
Immunization with purified protein or polysaccharide antigens typically results in the 
induction of a modest antibody response with little or no T cell response when compared 
to vaccines comprised of whole or killed bacteria or viruses that have inherent 
immunepotentiating activity. The need to increase the immunogenic response of 
wellcharacterized and purified antigens that display suboptimal immunogenicity when 
used alone affirms the essential role for the use of adjuvants. Vaccine adjuvants may 
significantly reduce the amount of antigen needed (Del Giudice, G, et al., 2013) and may 
induce a more rapid immune response enabling a reduction in the number of doses in a 
regimen. 
Besides reducing the antigen dosage or number of doses in the vaccine regimen, there is 
now an increased appreciation of the capacity of adjuvants to increase not just overall 
antibody titer but also to increase the number of functional antibodies and/or antibodies 
with higher affinity for vaccine antigens. Many pathogens, such as influenza viruses, 
HIV, human papilloma virus (HPV) and the malaria parasite, display substantial antigenic 
drift, subtype and/or strain variations. Therefore, the ability of adjuvants to broaden an 
immune response profile could be crucial to the success of vaccines against such targets. 
Previous studies have shown that the broadening effect of adjuvants may be mediated via 
expansion of B cell diversity, not merely through increased titers (Khurana, et al., 2010, 
2011). Clinically, antibody response broadening by adjuvants such as AS04 or oil-inwater 
emulsions has been demonstrated in HPV vaccines and influenza, respectively (Bissett, 
SL et al., 2014; Del Giudice, G et al., 2013). 
One unmet need is the development of vaccines for effective T cell responses. Several 
vaccines in development are aimed at eliciting T cell responses, which historically have 
not been induced by the most commonly used adjuvants in vaccines for human use, such 
as aluminium hydroxide. Therefore, an objective of many adjuvant discovery and 
development programs is to elicit more effective engagement of T-helper cells for 
optimizing the quality, breadth and durability of antibody responses, or, to induce effector 
CD4+ or CD8+ T cells to kill intracellular pathogens. One approach for new generation 
vaccines is the use of agonists for Toll-like receptors (TLRs) that activate innate immune 
receptors, mainly on antigen presenting cells, and facilitate the generation of T helper cell 
responses. 
Adjuvants that are currently employed in human vaccines licensed for use in the USA 
and/or Europe include aluminium salts, oil-in-water emulsions (MF59, AS03 and AF03), 
virosomes, and AS04 (Alving, CR, et al., 2012). Among the most advanced adjuvants 
systems is AS04 which is used in the Cervarix® HPV vaccine and consist of the TLR4 
ligand monophosphoryl lipid A (MPL) combined with aluminium salt. MPL, along with 

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QS21, is also part of the adjuvant system (AS01) in the RTS, S malaria vaccine from 
GlaxoSmithKline which has been evaluated in a Phase 3 clinical trial (Regules, JA, et al.,  
2011). Another clinically advanced adjuvant is CpG oligodeoxynucleotide (ODN), a 
TLR9 ligand contained in the Heplisav® vaccine candidate for hepatitis B from Dynavax, 
that has completed a Phase 3 clinical trial (Reed, SG, et al., 2013). 
Small molecule immune potentiators as a new class of vaccine adjuvants 
A new class of adjuvants, small molecule immune potentiators (SMIPs), has been 
identified that activate immune cells by targeting TLR7 and TLR8. Imiquimod and 
Resiquimod (R848) are clinically advanced TLR7 and/or TLR8 SMIPs that are used as 
immunotherapeutics. Although Imiquimod and Resiquimod have been studied 
extensively as vaccine adjuvants in preclinical models (Vasilakos et al. 2013), they were 
never optimized for this use and, in general, compare poorly to other pre-clinical and 
clinical adjuvant candidates. Furthermore, when Imiquimod is applied topically (it is a 
licensed topical treatment for viral and malignant skin lesions) it induces strong local and 
systemic inflammatory reactions, and is poorly tolerated (Bauza, et al. 2009; Campanelli, 
et al. 2005; Meyer, et al. 2008). 
Unlike traditional drugs, TLR7 SMIPs activate innate immunity and initiate a cascade of 
immune responses that can have systemic impact and endure after the compound has been 
cleared from the organism. For SMIPs as vaccine adjuvants this difference is highlighted 
further by the fact that 2-3 local IM injections drive antigen-specific B and T cell 
responses at distal sites and these can provide protection in the form of immunologic 
memory (Tacken,  et al. 2011; Ilyinskii, et al., 2014). Therefore, limiting the systemic 
exposure of the SMIP adjuvants has been postulated as an approach to both increase 
vaccine efficacy and minimize side effects associated with systemic and generalized 
inflammation. Novartis is currently developing a novel adjuvant, containing a SMIP from 
the benzonaphthryridines (BZN) series, LHD153, which targets TLR7. The objective 
driving the discovery of this new TLR7 ligand was to develop a vaccine adjuvant with 
high efficacy in increasing the vaccine specific immune response and with minimal side 
effects. To obtain this objective it was postulated that the ideal compound would remain 
localized at the site of injection to help trigger the immune reaction to vaccine antigens, 
yet maintain a low systemic distribution. At the same time this compound had to be 
soluble to make industrial scale-up and manufacturing feasible. Soluble BZN were 
engineered so that they could be formulated with aluminium salts with the aim of limiting 
their systemic exposure and keeping them localized in the muscle for short time after 
immunization. The strongest adsorption to aluminium hydroxide particles is obtained 
through ligand exchange of hydroxyl and/or phosphate groups on the surface of 
aluminium hydroxide or phosphate with soft anionic moieties such as phosphates, 
phosphonates, phosphites, sulfates and carboxylates. To drive the adsorption to 

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aluminium hydroxide through ligand exchange, LHD153 was functionalized with a 
polyethylene glycol (PEG) linker and a terminal phosphonate. Furthermore, LHD153 was 
stabilized with arginine salt to allow scale up for GMP manufacturing, yielding 
LHD153R. As predicted, unformulated LHD153R exhibited high levels of systemic 
exposure when injected IM in mice, rats and dogs, whereas the serum concentrations of 
LHD153R adsorbed to aluminium hydroxide (Aluminium Hydroxide/LHD153R) was 
dramatically reduced. Moreover, Aluminium Hydroxide/LHD153R remained localized to 
the injection site. 
Preclinical studies using Aluminium Hydroxide/LHD153R to date confirm the activation 
of the TLR7 pathway and subsequent boost of both the humoral and cellular immune 
response. Moreover, Aluminium Hydroxide/LHD153R displays a unique 
pharmacokinetic profile as demonstrated by its minimal systemic exposure, potentially 
minimizing any systemic inflammatory response associated with tolerability issues. 
Aluminium hydroxide/LHD153R has achieved proof of concept in animal models using 
several vaccine antigens including MenC, MenB, rabies, HIV and respiratory syncytial 
virus (RSV). In vitro toxicity of LDH153R has been assessed, and in vivo nonclinical 
tolerability and safety of LHD153R and Aluminium Hydroxide/LHD153R have been 
evaluated in rats, dogs and non-human primates. LHD153R was not phototoxic, 
genotoxic or mutagenic (Ames and chromosomal aberration tests), and did not cause local 
or systemic toxicity in dogs or rats. Furthermore, Aluminium Hydroxide/LHD153R was 
well tolerated in rhesus monkeys. 
1.2  
Rationale 
The aim of this study is to assess the safety of Aluminium Hydroxide/LHD153R 
adjuvanted MenC-CRM197 conjugate vaccine (MenC-CRM197/Aluminium  
Hydroxide/LHD153R) and to compare the antibody-mediated immune response elicited 
by MenC-CRM197/Aluminium Hydroxide/LHD153R with the licensed aluminium 
hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®). 
Furthermore, a comprehensive set of exploratory objectives has been selected to assess 
the systemic exposure of LHD153 after intramuscular injection and to evaluate the quality 
of the specific immune response against MenC-CRM197 in detail and to evaluate  
biomarkers that may be predictive of safety and/or innate immune activation. 
The licensed Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) has been 
chosen as the primary vaccine candidate to assess the safety and immunopotentiating 
properties of Aluminium Hydroxide/LHD153R for several reasons. Firstly, the safety and 
immunogenicity profiles of the Meningococcal C-CRM197 Conjugate Vaccine have been 
well established through years of commercial use. Secondly, a more potent 

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Meningococcal C-CRM197 Conjugate Vaccine might enable a reduction of the antigen 
dosage or the number of doses needed in infants between 2 and 12 months of age. Finally, 
the Meningococcal C-CRM197 conjugate is a well-characterized, single antigen 
preparation which provides an ideal setting to explore the potential of this new 
Aluminium Hydroxide/LHD153R adjuvant. 
2.0  
OBJECTIVES 
2.1  
Primary Objectives 
Primary Safety Objective 
To assess the safety of MenC-CRM197/Aluminium Hydroxide/LHD153R as compared to 
that of aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
Primary Immunogenicity Objective 
To compare the antibody responses of MenC-CRM197/Aluminium Hydroxide/LHD153R 
and aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at 
Day 29, as measured by human complement serum bactericidal assay (hSBA) directed 
against MenC. 
2.2  
Secondary Objectives 
Secondary Immunogenicity Objective(s) 
1. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine at Day 8 and Day 181 after vaccination, as measured by 
hSBA directed against MenC. Baseline antibody titers will also be measured by 
hSBA. 
2. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine, at Day 8, Day 29 and Day 181 after vaccination, as 
measured by an enzyme-linked immunosorbent assay (ELISA) to MenC. Baseline 
antibody concentrations will also be measured by ELISA. 
2.3  
Exploratory Objectives 

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1. To evaluate the systemic exposure of LHD153 at several early time-points after IM 
injection of MenC-CRM197/Aluminium Hydroxide/LHD153R or Meningococcal 
CCRM197 Conjugate Vaccine. 
2. To explore the frequency of B cells specific for MenC polysaccharide and CRM197 
protein at baseline (Day 1) and at Day 8, Day 29 and Day 181 after vaccination with 
MenC-CRM197/Aluminium Hydroxide/LHD153R or the aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. Subsequently, the B cell 
repertoire of the antigen specific B cells and the specific antibody functionality will 
be analyzed in a selected subset of subjects. 
3. To explore the baseline T cell mediated immunity to CRM197 and to evaluate the 
frequency and quality of CRM197 specific T cells induced by 
MenCCRM197/Aluminium Hydroxide/ LHD153R compared to aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at Day 8 and Day 29. 
4. To evaluate biomarkers that may be predictive for safety and/or innate immune 
activation. 
 

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3.0 
STUDY DESIGN 
3.1 
Overview of Study Design 
This is a Phase 1, randomized, observer blind, adjuvant dosage-escalation study. It will be 
performed at a single center. In total, approximately 80 healthy male and healthy 
nonpregnant female adults (18-45 years of age) will be enrolled in the study. 
Subjects will be randomized to receive a single IM vaccination of either the licensed 
aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine 
(Menjugate®) or the investigational vaccine, MenC-CRM197/Aluminium 
Hydroxide/LHD153R. 
The dosage of LHD153R will be escalated from 12.5 µg to 100 µg.  For the 
dosageescalation of LHD153R, the subjects will be enrolled into 1 of 4 cohorts, in a 
stepwise manner with 20 subjects per cohort. Subjects in all cohorts will be randomized 
in a 1:4 ratio, to receive either aluminium hydroxide adjuvanted Meningococcal C-
CRM197 Conjugate Vaccine (control) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R with increasing doses of LHD153R.Subjects assigned to MenC-
CRM197/Aluminium Hydroxide/LHD153R in Cohort 1 will receive 12.5 μg of LHD153R; 
Subjects in Cohort 2 will receive 25 μg of LHD153R; Subjects in Cohort 3 will receive 
50 μg of LHD153R; Subjects in Cohort 4 will receive 100 μg of LHD153R (Table 3.1-1). 
Table 3.1-1: Subjects Randomized per Cohort and Treatment Dose Group 
Cohort 
Group 
Subjects/ 
Group 
MenC 
Dosage* 
(µg) 
Adjuvant Dosages 
Total 
Volume/Dose 
Total 
Subjects/Group 
Aluminium  
Hydroxide  
(mg) 
LHD153R  
(µg) 
1 
A 
4 
10 
1 
0 
0.5 mL 
20 
 
 
 
 
 
 
 
B 
16 
10 
1 
12.5 
0.5 mL 
 
2 
A 
4 
10 
1 
0 
0.5 mL 
20 
C 
16 
10 
1 
25 
0.5 mL 
3 
A 
4 
10 
1 
0 
0.5 mL 
20 
D 
16 
10 
1 
50 
0.5 mL 
4 
A 
4 
10 
1 
0 
0.5 mL 
20 
E 
16 
10 
1 
100 
0.5 mL 
*Conjugated to 12.5-25 µg CRM197 
All cohorts will have a staggered entry. For each cohort, the first 5 subjects (i.e. the first  
1:4 randomization block) to receive either aluminium hydroxide adjuvanted  

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Meningococcal C-CRM197 Conjugate Vaccine (n=1) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R (n=4) will be vaccinated at rate of 1 subject each day. 
After entry of the first 5 subjects in each cohort, the enrollment will be paused. The 
remaining 15 subjects for each cohort will be enrolled only after DMC review of the 
safety results obtained through Day 14 has been finalized (Table 3.1-2). Furthermore, 
after entry of all 20 subjects in each cohort, enrollment will be paused again. Enrollment 
of the first 5 subjects in the next cohort will only proceed after the Day 29 safety results 
of the previous cohort have been reviewed by the DMC. 
Table 3.1-2: Overview of staggered entry of subjects for each cohort 
Cohort 
1st Stage of 
enrollment 
MenC- 
CRM197/ 
Aluminium 
Hydroxide 
MenC- 
CRM197/ 
Aluminium  
Hydroxide 
/LHD153R 
2nd Stage of 
enrollment 
MenC- 
CRM197/ 
Aluminium 
Hydroxide 
MenC- 
CRM197/ 
Aluminium 
Hydroxide  
/LHD153R 
1 
First 5 subjects 
with  
vaccination rate 
of 1 subject/day 
1 
4 
Remaining 15 
subjects, after  
DMC review of  
Day 14 safety 
results 
3 
12 
2 
1 
4 
3 
12 
3 
1 
4 
3 
12 
4 
1 
4 
3 
12 
Post-vaccination procedures include collection of urine specimens at Day 8 and Day 29 
for safety assessment and blood specimens at Day 8, Day 29 and Day 181 for safety 
assessment and evaluation of the primary and secondary immunogenicity endpoints. 
Furthermore, additional blood specimens will be collected for assessment of exploratory 
endpoints at Day 1, Day 4, Day 8, Day 29 and Day 181 from those subjects that signed an 
additional informed consent concerning blood collection for exploratory assessment. 
3.2  
Study Period 
Each subject should expect to participate in the study for approximately 12 months, from 
the time of enrolment through the last study visit. 
3.3  
Blinding Procedures 
This study is designed as an observer-blind study. For each dosage cohort, subjects, 
investigators, laboratories and the sponsor will be blinded to vaccine assignments. 
To maintain the blindness within each cohort, designated nurse(s) or physician(s) will be 
responsible for administering the study vaccines to the subjects, and will be instructed not 
to reveal the identity of the study vaccines neither to the subject nor to the investigative 

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site personnel (investigator, study nurse, monitor) involved in the conduct or monitoring 
of the trial. This (these) designated individual(s) will have no contact with the subjects 
after the administration of the study vaccine. Furthermore, unblinded monitors are 
assigned to reconcile actual vaccine treatment. 
Study unblinding, at the group level, is planned for an Interim Analysis of the safety and 
immunogenicity data obtained up to Day 29 after all cohorts are enrolled and for full 
unblinding at the End of Study. 
Except in the case of medical necessity, a subject’s treatment should not be unblinded 
without the approval of the Sponsor. In such instance of medical emergency, every effort 
should be made to contact the Sponsor prior to unblinding. If unblinding should occur (by 
either accidental unblinding or emergency unblinding for a serious adverse event) prior to 
completion of the study, the investigator must promptly contact the Sponsor and 
document the circumstances on the appropriate forms. Instructions regarding emergency 
unblinding will be provided to the investigator. 
3.4  
Data Collection 
3.4.1  
Data Collected from Subjects 
The following data will be collected from each subject over the duration of their study 
participation: 
▫ Demographic Information 
▫ Adverse Events 
▫ Medical History 
▫ Concomitant Medications 
▫ Vital signs 
All data collected must only be identified using the Subject ID, as described in section 
5.2.3. 
3.4.2  
Tools Used for Data Collection 
Data will be recorded in the Subject Diary and collected on Case Report Forms (CRFs). 
Subject Diary 

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Subject Diaries will be the only source document allowed for solicited local and systemic 
adverse events (including body temperature measurements), starting after the initial 24 
hours post-vaccination observation period at the clinic. The following additional rules 
apply to documentation of safety information collected in the Subject Diary: 
1. No corrections or additions to the Subject Diary will be allowed after it is delivered to 
the site. 
2. Any blank or illegible fields on the Subject Diary must be described as missing in the 
CRF. 
3. Any corrections to the Subject Diary must be performed by the person completing the 
Subject Diary and should include a single strike through line through the incorrect 
value or text with a brief explanation for each change, the initials of that person, and 
date of correction. 
Case Report Forms 
This study utilizes CRFs to collect study-related data from each subject. A qualified site 
staff member(s) is required to enter subject data in the CRFs in English based on the 
medical information available in each subject’s  record. The following additional rules 
apply to documentation of Subject Diary information collected in the CRFs: 
1. The site must enter all readable entries in the Subject Diary into the CRF, including 
those values that may be biologically implausible (e.g. body temperature: 400°C). 
2. Any illegible or implausible data should be reviewed with the subject. If an 
underlying solicited or unsolicited adverse event is described on review with the 
subject, this should be described in the source document and reported as an 
unsolicited adverse event in the appropriate CRF (e.g., if the subject above confirms 
body temperature of 40°C on the day in which body temperature: 400°C was written 
into his/her Subject Diary, this fever of 40°C should be recorded in the appropriate 
CRF). 
3. Any newly described safety information (including a solicited adverse event) must not 
be written into the Subject Diary and must be described in the study file as a verbally 
reported adverse event. Any adverse event reported in this fashion must be described 
as an unsolicited adverse event and therefore, entered in the appropriate CRF. 
Data should be entered into the CRF in a timely fashion following each subject’s clinic 
visit, study procedure, or phone call. Each subject’s CRF casebook will be compared with 
the subject’s source records by a Novartis-approved study monitor (or designee) over the 
duration of the study in order to ensure data collection accuracy. 

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3.5  
Collection of Clinical Specimens 
The following clinical specimens are required to be collected from each subject in this 
study: 
▫ Blood 
▫ Urine 
Processing of each specimen should be completed by a qualified site member. Testing of 
clinical specimens will be performed by a Novartis or designated laboratory. 
Blood Specimens 
Before Vaccination 
▫ At the Pre-vaccination Screening Visit (between Day -28 to -3) one sample of 
approximately 10 ml blood will be drawn from all subjects. 
▫ At Visit 1 (Day 1) - prior to vaccination – two samples of approximately 10 ml blood 
will be drawn from all subjects. 
▫ At Visit 1 (Day 1) - prior to vaccination - the following blood samples will be drawn 
from subjects that gave additional informed consent for blood collection for 
exploratory assays: 
- 
One sample of approximately 2 ml 
- 
Two samples of approximately 5 ml 
- 
One sample of approximately 50 ml 
After Vaccination 
▫ At Visit 1 (Day 1) - 1 hour after vaccination - one sample of approximately 2 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 2 hours after vaccination - one sample of approximately 2 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 4 hours after vaccination - one sample of approximately 2 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 

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▫ At Visit 1 (Day 1) - 6 hours after vaccination – two samples of approximately 5 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 8 hours after vaccination - one sample of approximately 2 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 24 hours after vaccination - the following blood samples will be 
drawn from subjects that gave additional informed consent for blood collection for 
exploratory assays: 
- 
One sample of approximately 2 ml 
- 
Two samples of  approximately 5 ml 
▫ At Visit 2 (Day 4) the following blood samples will be drawn from subjects that gave 
additional informed consent for blood collection for exploratory assays: 
- 
One sample of  approximately 2 ml 
- 
Two samples of  approximately 5 ml 
▫ At Visit 3 (Day 8) two samples of approximately 10 ml blood will be drawn from all 
subjects. 
▫ At Visit 3 (Day 8) the following blood samples will be drawn from subjects that gave 
additional informed consent for blood collection for exploratory assays 
- 
Two samples of approximately 5 ml 
- 
One sample of approximately 50 ml 
▫ At Visit 6 (Day 29) two samples of approximately 10 ml blood will be drawn from all 
subjects. 
▫ At Visit 6 (Day 29) one sample of approximately 50 ml blood will be drawn from 
subjects that gave additional informed consent for blood collection for exploratory 
assays. 
▫ At Visit 9 (Day 181) one sample of approximately 10 ml blood will be drawn from all 
subjects. 
▫ At Visit 9 (Day 181) one sample of approximately 50 ml blood will be drawn from 
subjects that gave additional informed consent for blood collection for exploratory 
assays. 

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The blood will be used for screening and safety laboratory assessments, immunological 
serology assays, pharmacokinetic analysis, cell mediated immunity assays and gene 
expression and protein production assays. See section 5.1.2, section 5.2.1 and section 7.0 
for additional details. 
Processing of each blood specimen should be completed in accordance with the study 
specific Clinical Specimen Laboratory Manual. 
The total amount of blood collected over the study period for all subjects will be 
approximately 80 ml. 
For subjects that signed an additional informed consent for blood collection for 
exploratory assays the total amount of blood collected over the study period will be 
approximately 344 ml. 
Urine Specimens 
Urine will be collected at the Pre-vaccination Screening Visit (between Day -28- to -3), at 
Visit 1 (Day 1; before vaccination), at Visit 3 (Day 8) and at Visit 6 (Day 29). Results 
will be recorded in the source document and CRF. 
Urine will be collected from all subjects for safety laboratory assessments and drugs-
ofabuse testing. Furthermore, urine will be collected for pregnancy testing in all females. 
3.6  
Stopping/Pausing Guidelines 
Stopping/pausing guidelines are predefined criteria that halt the conduct of a study (either 
a vaccine group or the entire study). These guidelines are used to ensure the safety of study 
subjects.  
The following criteria, based on FDA guidance and with grading scales adapted from the 
CBER Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive vaccine Clinical Trials”, will be used for this study: 
1. The study will be halted (no new enrollments and no further investigational product 
administered until a full safety review by the DMC and consultation with the IRB/EC 
and the health authorities is completed) if one of the following occurs 
a. One subject experiences a serious adverse event (SAE) assessed as possibly or 
probably related to investigational product or, 

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b. There is a subject death assessed as possibly or probably related to the 
investigational product. 
2. If one or more subjects experience a Grade 4 AE (see Appendix C, D, and E), vital 
sign or laboratory abnormality that cannot be clearly attributed to another cause, 
vaccination will be suspended until a full safety review by the DMC is performed. 
3. If six or more subjects experience a Grade 3 AE (see Appendix A, B, C, D, and E), 
vital sign or laboratory abnormality, dosage escalation will be suspended for that 
vaccine until a full safety review by the DMC is performed.  
The sponsor or the investigator (following consultation with the sponsor) has the right to 
discontinue the study at any time. If the clinical study is prematurely terminated, the 
investigator must promptly inform the study subjects and must assure appropriate therapy 
and follow-up for the subjects.  All procedures and requirements pertaining to the 
archiving of the documents must be followed.  All other study materials (such as study 
vaccines) must be returned to the sponsor or destroyed after sponsor approval. 
3.7  
Data Monitoring Committee 
A DMC will be formed to review safety data during scheduled periodic reviews. The 
DMC may also perform reviews on an ad hoc basis as needed. DMC membership will 
consist of at least 3 individuals who are external to the site and sponsor, and will include 
1 statistician who is independent from the study team.  
Subjects will be enrolled in a stepwise manner in each of the four vaccine dosage cohorts  
(Cohort 1: 12.5 μg LHD153R, Cohort 2: 25 μg of LHD153R, Cohort 3: 50 μg of  
LHD153R and Cohort 4: 100 μg of LHD153R). The DMC will review all safety data, as 
described in the DMC charter and in the Statistical Analysis Plan, after the first 5 subjects 
in each cohort have completed Visit 4 and their data are available for analysis, and before 
enrollment of the remaining subjects in each cohort. In addition, the DMC will review all 
safety data after enrollment in each cohort has been completed, after Visit 6 and their data 
are available for analysis/review and before proceeding with enrollment of the subsequent 
cohort. 
The specific roles and responsibilities of the DMC members and other personnel involved 
will be documented in the DMC charter. The DMC charter will be finalized before the 
start of the study and will outline in detail all pausing and stopping rules according to the 
Clinical Study Protocol. 
3.8  
Premature Withdrawal from Study 

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Subjects may withdraw at any time, or be dropped from the study at the discretion of the 
investigator should any untoward effects occur and/or for safety reasons. In addition, a 
subject may be withdrawn by the investigator or the Sponsor if he/she violates the study 
plan or for administrative reasons. The investigator or study coordinator must notify the 
Sponsor immediately when a subject has been withdrawn due to an adverse event. 
The circumstances above are referred to as premature withdrawal from the study, and the 
reason for premature withdrawal should be clearly documented and detailed in the source 
documentation. The investigator should make every attempt to evaluate the subject’s 
safety, including resolution of ongoing AEs, at the time of premature withdrawal. If a 
subject wants to withdraw from the study prior to the last planned study visit, the subject 
will be asked to be followed for safety for the duration of the study. When a subject 
withdraws, or is withdrawn, from the study, the procedures described in section 5.5.1 
should be completed if possible. 
The reasons for premature withdrawal from the study include: Adverse event, death, 
withdrawal of consent, lost to follow-up, administrative reason, and protocol deviation. 
These reasons are described in greater detail below. 
Adverse Event 
For any subject withdrawn from study participation prior to the planned Study  
Termination Visit, it is important to determine if an AE was associated with the reason for 
discontinuing the study. This AE must be identified on the appropriate CRF page by 
indicating “Withdrawn from study due to AE”. Any ongoing AEs at the time of study 
withdrawal must be followed until resolution or stabilization. 
Death 
For any subject withdrawn from study participation due to death, this should be noted on 
the appropriate CRF page and the associated SAE that led to the death must be reported. 
Withdrawal of consent 
The subject can withdraw consent for participation in the study at any time without 
penalty or loss of benefit to which the subject is otherwise entitled. Reason for early 
termination should be deemed as “withdrawal of consent” if the subject withdraws from 
participation due to a non-medical reason (i.e., reason other than AE). If the subject 
intends to withdraw consent from the study, the investigator should clarify if the subject 
will withdraw completely from the study or if the subject will continue study participation 
for safety, or a subset of other study procedures. If the subject requests complete 

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withdrawal from the study, no further study interventions will be performed with the 
subject. 
Lost to Follow-Up 
For subjects who fail to show up for study visits (clinic or telephone contacts), study staff 
is encouraged to make at least three documented attempts to contact the subject by 
telephone and at least one documented written attempt to contact the subject to encourage 
the completion of study termination procedures. These efforts to contact the subject must 
be recorded in the source document. The termination date for the subject to be captured 
on the appropriate CRF page is the date of the last contact (clinic visit or telephone) with 
the subject. 
Administrative Reason 
Examples for subjects withdrawn from the study due to administrative reason can include: 
Sponsor decision to terminate the study, subject meeting a pre-specified withdrawal 
criterion, subject discontinuation for insurance issues, moving, no time, etc. This reason 
should be noted in the appropriate CRF page and any ongoing AEs at the time of study 
withdrawal must be followed until resolution/stabilization. 
If the clinical study is prematurely terminated by the Sponsor, the investigator is to 
promptly inform the study subjects and local EC/IRB and should assure appropriate 
therapy and follow up for the subjects. All procedures and requirements pertaining to the 
archiving of study documents should be followed. All other study materials (study 
medication/vaccines, etc.) must be returned to the Sponsor. 
For subjects who are withdrawn from the study due to receipt of an excluded 
medication/vaccination or due to significant protocol non-compliance, this reason should 
be noted in the appropriate CRF page. 
Protocol Deviation 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. In general, subjects associated with protocol deviations 
may remain in the study unless continuation in the study jeopardizes the subject’s health, 
safety, or rights. 
Investigators will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring 
the study to request approval of a protocol deviation, as no authorized deviations are 

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permitted. If the investigator feels a change to the protocol would improve the conduct of 
the study this must be considered a protocol amendment, and unless such an amendment 
is agreed upon by Novartis and approved by the IRB/EC and health authorities it cannot 
be implemented. 
Any subject who becomes pregnant during the study should be encouraged to continue 
participating in the study for safety follow-up. The site must complete a Pregnancy 
Report CRF (initial report) as soon as possible after learning of pregnancy occurrence 
(see section 7.1.6 for further details). If the subject withdraws from the study for any of 
the above categories except death, the site will obtain permission from the subject to 
continue to remain in contact with her until the outcome of the pregnancy is known, even 
if the outcome is not known until after the subject reaches the end of the routine study 
period. 
3.9  
End of Study 
Most clinical trials intended to support the efficacy/immunogenicity and safety of an 
Investigational Product proceed to full completion of planned sample size accrual. 
A subject is considered to have completed this study when he/she has: (1) received the 
intended dose of study vaccine and (2) completed 365 days (Visit 12) of safety follow-up 
after receiving the study vaccine. 
Evaluation of the primary and secondary immunogenicity objectives requires the testing 
of biological samples from all study subjects, which can only be completed after all 
samples are collected. The last samples for the analysis of the primary and/or secondary 
objectives will be taken at Visit 9 (Day 181). For the purpose of this protocol, End of 
Study is defined as the completion of the testing of such biological samples, to be 
achieved no later than 8 months after collection of the last biological sample at Visit 9. 

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4.0  
SELECTION OF STUDY POPULATION 
4.1  
Inclusion Criteria 
In order to participate in this study, all subjects must meet all of the inclusion criteria 
described. 
1. Male or female individuals of 18 through 45 years of age on the day of informed 
consent. 
2. Healthy volunteers with good physical and mental health status, determined on the 
basis of the medical history, a physical examination and the results of the screening 
tests as judged by the investigator. 
3. Individuals who have voluntarily given written informed consent after the nature of 
the study has been explained according to local regulatory requirements, prior to 
study entry. 
4. Individuals who can comply with study procedures including follow-up1. 
5. Individuals that are able to understand, read and write German language. 
6. Females of childbearing potential who are using an effective birth control method2 
which they intend to use for at least 30 days after the study vaccination. 
4.2  
Exclusion Criteria 
Each subject must not have or must not be: 
1. Progressive, unstable or uncontrolled clinical conditions. 
2. Hypersensitivity, including allergy, to any component of vaccines, medicinal products 
or medical equipment whose use is foreseen in this study. 
                                                
1 A subject is considered to be compliant if the Investigator judges that the subject will complete the Subject 
Diary, return for all the follow-up visits and be available for telephone calls as scheduled in the study. 
2 The following birth control methods are considered effective: 
- 
Hormonal contraceptive (such as oral, injection, transdermal patch, implant) if used for at least 30 
days prior to informed consent 
- 
Diaphragm with spermicide, tubal occlusion device 
- 
Intrauterine device (IUD) 

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- 
Tubal ligation 
- 
Male partner using condom with spermicide 
- 
Male partner having been vasectomized at least six months prior to informed consent 
3. Clinical conditions representing a contraindication to intramuscular vaccination and 
blood draws. 
4. Abnormal function of the immune system resulting from: 
a. Clinical conditions. 
b. Systemic administration of corticosteroids (PO/IV/IM) for more than 14 
consecutive days within 90 days prior to informed consent. 
c. Administration of antineoplastic and prescription immunomodulating agents or 
radiotherapy within 90 days prior to informed consent. 
5. Received immunoglobulins or any blood products within 180 days prior to informed 
consent. 
6. Received an investigational or non-registered medicinal product within 30 days prior 
to informed consent or intend to participate in another clinical study at any time 
during the conduct of this study. 
7. Vulnerable subjects (e.g. persons kept in detention), study personnel or an immediate 
family or household member of study personnel, subjects with legal incapacity or 
limited legal capacity 
8. Any relevant deviation from the laboratory parameters at screening as judged by the 
investigator. 
9. Previously received any vaccine that included a MenC antigen. 
10. Previously suspected or confirmed disease caused by N. meningitides. 
11. Had household contact with and/or intimate exposure to an individual with culture 
proven MenC. 
12. A positive serum or urine pregnancy test prior to the study vaccine administration or 
are currently lactating. 
13. A positive drugs-of-abuse test prior to the study vaccine administration 
14. Received any other vaccines within 30 days prior to enrolment in this study or who 
are planning to receive any vaccine within 30 days from the administration of study 
vaccines. 

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15. Any other condition that, in the opinion of the investigator, might interfere with the 
results of the study or pose additional risk to the subject due to participation in the 
study. 
4.3  
Criteria for Delay of Vaccination or Blood Draw 
There may be instances when individuals meet all eligibility criteria for vaccination or 
blood draw yet have a transient clinical circumstance which may warrant delay of 
vaccination or blood draw. Under such circumstances, a subject may be considered 
eligible for study enrolment after the appropriate window for delay has passed and 
inclusion/exclusion criteria have been rechecked, and if the subject is confirmed to be 
eligible. 
Reasons for delay of vaccination include: 
▫ Body temperature elevation ≥38.0°C (measured orally) within 3 days prior to intended 
study vaccination. 
▫ Use of antipyretics and/or analgesic medications within 24 hours prior to vaccination. 
Reasons for delay of blood draw include: 
▫ Subject has received a dose of systemic antibiotics less than 6 days before blood 
collection for the hSBA directed against MenC. 
 

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5.0  
STUDY PROCEDURES 
The sections that follow provide an overview of the procedures that are to be followed in 
enrolling, evaluating, and following subjects who participate in this clinical study. Visits 
can be either clinic visits or safety follow-up telephone calls, as specified in the Table 
below and in the Time and Events Tables 3 and 4 of the Study Synopsis. 
Table 5.0-1: Study procedures 
Visit Category 
Procedures 
Pre-vaccination Clinic Visit 
Section 5.1 describes procedures to be followed 
prior to subject enrollment, including: informed 
consent and screening procedures. 
Vaccination Clinic Visit 
Section 5.2 describes procedures to be followed 
during the vaccination clinic visit, including: 
prevaccination procedures, enrolment, 
randomization, vaccination and post-vaccination 
procedures. 
Post-vaccination Visits 
Section 5.3 describes follow-up clinic visits and 
safety follow-up calls. 
Unscheduled Visits 
Section 5.4 describes possible procedures to be 
followed at unscheduled clinic visit. 
Study Termination Visit 
Section 5.5 describes procedures to be followed at 
the last study visit for a subject (may include early 
termination visit). 
5.1 
Pre-vaccination Clinic Visit(s) 
The Pre-vaccination Clinic Visit must be performed in the period between Day -28 and 
Day -3. 
This section describes the procedures that must be performed for each potential subject 
prior to enrollment, including obtaining informed consent and screening. 
5.1.1  
Informed Consent 
"Informed consent" is the voluntary agreement of an individual or his/her legal 
guardian(s) to participate in research. Consent must be given with free will of choice, and 
without undue inducement. The individual must have sufficient knowledge and 
understanding of the nature of the proposed research, the anticipated risks and potential 
benefits, and the requirements of the research to be able to make an informed decision. 

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Informed consent following local IRB/EC guidance must be obtained before conducting 
any study-specific procedure (i.e., all of the procedures described in the protocol). Prior to 
any additional blood sample collection for exploratory objectives, a secondary informed 
consent must be signed by subjects. The process of obtaining informed consent should be 
documented in the subject source document in addition to maintaining a copy of the 
signed and dated informed consent. 
5.1.2  
Screening 
After an individual has consented to participate in the study and informed consent is 
signed, that individual will be given a unique Screening Number. The subject’s unique 
Screening Number will be documented in the Screening and Enrolment log. The 
eligibility of the subject will be determined based on the inclusion and exclusion criteria 
listed in section 4.0 and evaluated during this screening procedure. 
Screening procedures at the Pre-vaccination Clinical Visit (between Day -28 and Day -3) 
will include the following: 
▫ Review of demographic data, including age, gender, race, body weight and height. 
▫ Review of medical history, including but not limited to any medical history, ongoing 
illnesses or injuries that may be relevant to subject eligibility for study participation. 
Relevant medical history can also include any medical history that contributes to the 
understanding of an adverse event that occurs during study participation, if it 
represents an exacerbation of an underlying disease/pre-existing problem. 
▫ Perform physical examination, including but not limited to: 
- 
Assessment of general appearance 
- 
Collection of vital signs, including body temperature, blood pressure, heart rate 
and respiratory rate 
- 
Examination of head, ears, eyes, nose and throat (HEENT) 
- 
Examination of skin 
- 
Auscultation of heart and lungs 
▫ Collection and review of prior and concomitant medications or vaccinations taken 
prior to start of study (refer to section 6.5 for further details). 
▫ Collection of any unsolicited AEs occurring prior to administration of the study 
vaccine. 

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▫ Blood draw (approximately 10 ml) for Safety Laboratory assessments, measurement of 
Hepatitis B surface antigen, anti-Hepatitis C virus antibodies, anti-HIV 1 and 2 
antibodies and serum pregnancy test (all women). 
▫ Urine sample for Safety Laboratory assessments and drugs-of-abuse testing. 
NOTE: A general physical examination is to be performed by a qualified health care 
practitioner. “Qualified health care practitioner” refers to any licensed health care 
professional who is permitted by institutional policy to perform physical examinations 
and who is identified within the Study Staff Signature Log. 
Data collected during the Pre-vaccination Screening Clinic Visit must be written in the 
source document (see section 9.1) and will be captured in the screening CRF Forms. In 
the event that the individual is determined ineligible for study participation, he/she is 
considered a screen failure. The reason for screen failure must be documented in the 
Screening and Enrolment log. 
5.2  
Vaccination Clinic Visit(s) 
This section describes the procedures to be performed at the Vaccination Clinic Visit 
(Visit 1, Day 1), including: pre-vaccination procedures, enrolment, randomization, 
prevaccination blood draw, vaccination and post-vaccination procedures. 
5.2.1  
Pre-vaccination Procedures 
During pre-vaccination procedures at Visit 1 (Day 1), the eligibility of the subject will be 
confirmed based on the inclusion and exclusion criteria listed in section 4.0. 
Pre-vaccination procedures at Visit 1 (Day 1) will include the following: 
▫ Review of systems by means of a structured interview that queries the subject as to any 
complaints the subject has experienced across each organ system. 
▫ Perform physical examination, including but not limited to: 
- 
Assessment of general appearance 
- 
Assessment of body weight and collection of vital signs, including body 
temperature, blood pressure, heart rate, and respiratory rate 
- 
Examination of head, ears, eyes, nose and throat (HEENT) 
- 
Examination of skin 

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- 
Auscultation of heart and lungs 
▫ Collection and review of prior and concomitant medications or vaccinations taken, or 
recalled, since the last visit (refer to section 6.5 for further details). 
▫ Collection of any unsolicited AEs occurring prior to administration of the study 
vaccine. 
▫ One blood sample (approximately 10 ml) will be drawn from all subjects for serology 
testing. 
▫ One blood sample (approximately 10 ml) will be drawn from all subjects for baseline 
Safety Laboratory assessments. 
▫ Urine sample for baseline Safety Laboratory assessments, pregnancy testing (all 
women) and drugs-of-abuse testing. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of blood draws are provided in section 3.5. 
NOTE: A general physical examination is to be performed by a qualified health care 
practitioner. “Qualified health care practitioner” refers to any licensed health care 
professional who is permitted by institutional policy to perform physical examinations 
and who is identified within the Study Staff Signature Log. 
Data collected during pre-vaccination procedures at Visit 1 must be written in the source 
document (see section 9.1). In the event that the individual is determined ineligible for 
study participation, he/she is considered a screen failure. The reason for screen failure 
must be documented in the Screening and Enrolment log. If the individual is determined 
to be eligible for the study, he/she can be enrolled into the study. 
5.2.2 
Enrolment 
After an individual is determined to be eligible for study participation, the investigator 
will enroll the subject into the Electronic Data Capture (EDC) system where the 
randomization to the treatment group will occur. The Screening Number ceases to be used 
and remains in the Screening and Enrolment Log only. 
If for any reason, after signing the informed consent form (ICF), the subject who is 
eligible and enrolled fails to be randomized, this is called a randomization failure. In this 
case the early termination study procedures must be applied. The reason for all 
randomization failures should be recorded in the Screening and Enrolment Log and in the 

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source document as specified in the Source Data Agreement. The information on subjects 
who are randomization failures should be kept distinct from subjects who are screen 
failures, as described in section 5.1.2 and section 5.2.1. 
5.2.3 
Randomization 
Enrolled subjects will be randomized and automatically assigned a unique Subject ID. 
The Subject ID will be the subject’s unique identification number for all CRFs and 
associated study documentation that will be used for the duration of the study. 
If for any reason, after signing the informed consent form (ICF), the eligible subject is 
enrolled and randomized but fails to undergo treatment, this is an Early Termination and 
the reason should be recorded in source document as specified in the Source Data 
Agreement/Source Data Verification Form. The information on these Early Termination 
subjects should be kept distinct in the source documentation from randomization failures, 
which are described in section 5.2.2. 
5.2.4 
Vaccination 
After completing the pre-vaccination procedures at Visit 1 (Day 1), administer the 
vaccine to the subject according to the procedures described in section 6.3. Observe the 
blinding procedures described in section 3.3. 
5.2.5 
Post-vaccination Procedures 
The following post-vaccination procedures will be performed at Visit 1 (Day 1): 
▫ After vaccination, the subject will be observed for at least 30 minutes for any 
immediate solicited and unsolicited AEs and a body temperature measurement at 30 
min after vaccination. All safety and body temperature data collected during this time 
are to be recorded in the subject’s source document. 
▫ After vaccination, the subject will be observed for at least 24 hours at the clinic 
including observation for solicited and unsolicited AEs and body temperature 
measurements . Body temperature measurements must be performed at 2, 4, 6, 8, 10, 
12, 20 and 24 hours after vaccination. All safety and body temperature data collected 
during this time are to be recorded in the subject’s source.. 
▫ From those subjects that signed an additional Informed Consent for exploratory assays, 
additional blood samples will be drawn in the first 24 hours after vaccination. Details 
regarding the number and volume of post-vaccination blood draws are provided in 
section 3.5. 

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After the initial 24 hours inpatient observation period, a Subject Diary will be used in this 
study to document solicited and unsolicited AEs until Day 14. The Subject Diary is the 
only source for collection of solicited AEs after the initial 24 hours inpatient observation 
period. Therefore, it is critical that the subject completes the Subject Diary correctly. 
The following training regarding completion of the Subject Diary must be provided: 
▫ The subject should be trained on how and when to complete each field of the Subject 
Diary. 
▫ The subject should be trained on how to self-measure local solicited adverse events 
and body temperature. The measurement of solicited local adverse events is to be 
performed using the ruler provided by the site. 
▫ The subject should be instructed how to perform body temperature measurement using 
the thermometer provided by the site. If the subject feels unusually hot or cold during 
the day, the subject should check their body temperature. If the subject has fever, the 
highest body temperature observed that day should be recorded in the Subject Diary. 
Subject Diary training should be directed at the individual(s) who will perform the 
measurements of adverse events and who will enter the information into the Subject 
Diary. This individual may not be the subject, but if a person other than the subject enters 
information into the Subject Diary, this person’s identity must be documented in the 
Subject Diary. Any individual that writes in the Subject Diary must receive training on 
completion of the Diary Card at the time of the visit. This training must be documented in 
the subject’s source record. 
The site should schedule the next study activity (clinic visit) with the subject. 
The subject will receive a written reminder of the next planned study activity. The subject 
will be reminded to complete the Subject Diary and to contact the site if there are any 
questions, and to contact the site immediately (or as soon as the subject is medically 
stable) if the subject has a medical condition that leads to a hospitalization or an 
emergency room visit. 
5.3  
Post-vaccination Visit(s) 
5.3.1 Subject Diary Reminder, Safety Follow-up and/or Post-vaccination Blood 
Draw Clinic Visits 

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Subject Diary reminder, Safety follow-up and/or post-vaccination blood draw clinic visits 
will be performed on Day 4 (Visit 2), Day 8 (Visit 3), Day 15 (Visit 4), Day 29 (Visit 6), 
Day 85 (Visit 7), Day 113 (Visit 8) and Day 181 (Visit 9) 
At Day 4 (Visit 2) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. All unsolicited AEs, SAEs, AESIs, 
medically attended AEs, AEs leading to study withdrawal and NOCD must be 
recorded on source documents. Any concomitant medications or vaccinations 
associated with those events must also be recorded on the source documents. 
▫ All subjects will be reminded to complete the Subject Diary and to contact the site if 
there are any questions, and to contact the site immediately (or as soon as the subject 
is medically stable) if the subject has a medical condition that leads to a 
hospitalization or an emergency room visit. No changes to the Subject Diary should 
be done at the clinic visit. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of blood draws are provided in section 3.5. 
▫ The site should schedule the next study activity (clinic visit) with the subject and the 
subject will receive a written reminder of the next planned study activity. 
At Day 8 (Visit 3) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. All unsolicited AEs, SAEs, AESIs, 
medically attended AEs, AEs leading to study withdrawal and NOCD must be 
recorded on source documents. Any concomitant medications or vaccinations 
associated with those events must also be recorded on the source documents. 
▫ The subject will be reminded to complete the Subject Diary and to contact the site if 
there are any questions, and to contact the site immediately (or as soon as the subject 
is medically stable) if the subject has a medical condition that leads to hospitalization 

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or an emergency room visit. No changes to the Subject Diary should be done at the 
clinic visit. Blood draw (approximately 10 ml) from all subjects for Safety Laboratory 
assessments. 
▫ Urine sample from all subjects for Safety Laboratory assessments. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of blood draws are provided in section 3.5. 
▫ The site should schedule the next study activity (clinic visit) with the subject and the 
subject will receive a written reminder of the next planned study activity. 
At Day 15 (Visit 4) the following procedures will be performed: 
▫ The Subject Diary will be collected and reviewed. No changes to the Subject Diary 
should be done at the clinic visit. For details on the Subject Diary see sections 3.4.2, 
and 5.2.5. The healthcare professional reviewing these data will discuss the symptoms 
(if any) reported by the subject and will determine if any additional diagnoses and/or 
adverse events are present. All unsolicited AEs until Day 14, solicited local and 
systemic AEs persisting at Day 14, SAEs, AESIs, medically attended AEs, AEs 
leading to study withdrawal and NOCD must be recorded on source documents. All 
concomitant medications or vaccinations associated with those events must also be 
recorded on the source documents. 
▫ The site should schedule the next study activity (safety phone call) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 29 (Visit 6) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. Any solicited local and systemic AEs 
continuing beyond Day 14, SAEs, AESIs, medically attended AEs, AEs leading to 
study withdrawal and NOCD must be recorded on source documents. All concomitant 

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medications or vaccinations associated with those events must also be recorded on the 
source documents. 
▫ Blood draw (approximately 10 ml) from all subjects for Safety Laboratory 
assessments. 
▫ Urine sample from all subjects for Safety Laboratory assessments. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of post-vaccination blood draws are provided in section 3.5. 
▫ The site should schedule the next study activity (clinic visit) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact  
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 85 and Day 113 (Visit 7 and Visit 8), the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. Any solicited local and systemic AEs 
continuing beyond Day 14, SAEs, AESIs, medically attended AEs, AEs leading to 
study withdrawal and NOCD must be recorded on source documents. All concomitant 
medications or vaccinations associated with those events must also be recorded on the 
source documents. 
▫ The site should schedule the next study activity (clinic visit) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 181 (Visit 9), the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 

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the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. Any solicited local and systemic AEs 
continuing beyond Day 14, SAEs, AESIs, medically attended AEs, AEs leading to 
study withdrawal and NOCD must be recorded on source documents. All concomitant 
medications or vaccinations associated with those events must also be recorded on the 
source documents. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of post-vaccination blood draws are provided in section 3.5. 
▫ The site should schedule the next study activity (safety phone call) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
5.3.2  
Safety Follow-up Calls 
Safety follow-up calls will be performed on Day 22 (Visit 5), Day 209 (Visit 10) and Day 
271 (Visit 11) and include the following procedures: 
▫ Safety follow-up calls are calls made to the subject by a healthcare professional 
designated on the site log. These calls will follow a script which will facilitate the 
collection of relevant safety information. The subject will be interviewed according to 
the script, and information relating to solicited local and systemic AEs persisting 
beyond Day 14 and unsolicited adverse events including SAEs, AESIs, medically 
attended AEs, AEs leading to study withdrawal, and/or NOCD and concomitant 
medications or vaccinations associated with those events. All safety information 
described by the subject must be written down in a designated location within the 
source document and not written on the script used for the telephone call. 
▫ The site should schedule the next study activity (clinic visit or study termination visit) 
with the subject. 
▫ The subject will be reminded to contact the site if there are any questions and to 
contact the site immediately (or as soon as the subject is medically stable) if the 
subject has a medical condition that leads to a hospitalization or an emergency room 
visit. 

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5.4  
Unscheduled Visits  
An unscheduled visit describes a non-routine study visit triggered by a specific event. 
These could include anticipated or unanticipated adverse events or interventions. 
The following procedures should be carried out for all unscheduled visits: 
1. Evaluate the subject’s vital signs body temperature, heart rate, and blood pressure and 
perform a symptom-directed physical examination. 
2. Record any observed AEs in the source documents. 
3. Record any concomitant medications or vaccinations associated with AEs in the 
source documents. 
5.5  
Study Termination Visit 
The study termination visit is scheduled on Day 366 (Visit 12). The termination visit is a 
clinic visit. For visit procedures to be performed for a subject whose planned study 
participation ends prematurely, please see section 5.5.1. 
At the Study Termination clinic visit the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. 
▫ The healthcare professional reviewing these data will discuss the symptoms (if any) 
reported by the subject and will determine if any additional diagnoses and/or adverse 
events are present. 
▫ Medically attended AEs, SAEs, NOCDs, or AESIs will be recorded on source 
documents. 
▫ All medications taken or vaccines received will also be recorded on the source 
documents. 
▫ The site will review with the subject the plan of when information relating to the 
subject’s participation in the study may be available (e.g., study results, treatment 
assignments). It will also be discussed how information relating to the subject’s 
participation in the study will be shared with the subject’s healthcare provider, if the 
subject chooses to share this information. 
▫ The site will complete the termination CRF page and this will mark the completion of 
the subject’s participation in the study. 

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5.5.1  
Early Termination Visit 
The date of termination is the date of the last contact in which the subject’s health status 
was assessed or, in cases where the subject does not agree to any further safety follow-up, 
it is the date consent is withdrawn. This date should be recorded on the appropriate CRF 
page. 
When a subject is withdrawn from treatment or withdraws from the study, the investigator 
will notify the Sponsor and, when possible, will perform the procedures listed below. 
The reason(s) for the early termination must be included in the subject’s source 
documentation. If the Early Termination Visit is a telephone call, collect as much 
information as possible. Early Termination Visits include subjects who were randomized 
but not treated. 
At the clinic visit or during the telephone call, the following procedures should be 
performed, when possible: 
▫ Collection and review of Subject Diary (if not already collected). 
▫ Interview of subject to collect unsolicited adverse events, medically attended AEs, 
AEs leading to withdrawal, SAEs, AESIs, and NOCD. 
▫ Interview of subject to collect concomitant medications and/or vaccinations. 
▫ Symptom-directed physical assessment, at least including measurement of vital signs 
(body temperature, respiratory rate, blood pressure, heart rate) and a check of general 
appearance (in case of clinic early termination visit). 
▫ Draw a blood sample (approximately 10 ml) and a urine sample for Safety Laboratory 
assessment (in case of clinic early termination visit). 
▫ The site will review with the subject the plan of when information relating to the 
subject’s participation in the study may be available (e.g., study results, treatment 
assignments). It will also be discussed how information relating to the subject’s 
participation in the study will be shared with the subject’s healthcare provider, if the 
subject chooses to share this information. 
▫ The site will complete the appropriate CRF page and this will mark the completion of 
the subject’s participation in the study. 
 

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6.0  
TREATMENT OF SUBJECTS 
All vaccines associated with this study are to be stored separately from other vaccines and 
medications in a secure location under appropriate storage conditions with temperature 
monitoring. All vaccines associated with this study must be checked for expiration 
date prior to use. Expired vaccines must not be administered to subjects. 
6.1  
Study Vaccine(s) 
The term ‘study vaccine’ refers to those vaccines provided by the Sponsor, which will be 
evaluated as part of the study objectives. The study vaccines specific to this study are 
described in Table 6.1-1. 
Table 6.1-1: Study Vaccine Composition 
Group A (Control) Meningococcal C-CRM197 Conjugate Vaccine 
 
Vaccine Component 
Quantity per 0.5 ml dose 
 
 
Vial Containing Vaccine Conjugate 
 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
 
Aluminum Hydroxide Solvent Components (for 0.5 mL dose) 
 
Aluminum hydroxide 
1.0 mg 
Sodium Chloride 
3.5 mg 
Sterile water for injection, up to 
0.5 ml 
 
 
Group B (12.5µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
 

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Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
12.5 µg 
Sodium Chloride 
3.4 mg 
Histidine  
0.1 mg 
Tris 
30 µg 
Sterile water for injection, up to 
0.5 ml 
 
 
Group C (25 µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
25 µg 
Sodium Chloride 
3.4 mg  
Histidine 
0.2 mg 
Tris 
61 µg 
Sterile water for injection, up to 
0.5 ml 

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Group D (50µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
50 µg 
Sodium Chloride 
3.2 mg 
Histidine 
0.4 mg 
Tris 
121 µg 
Sterile water for injection, up to 
0.5 ml 
 
Group E (100µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 

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Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
100 µg 
Sodium Chloride 
2.9 mg 
Histidine 
0.8 mg 
Tris 
243 µg 
Sterile water for injection, up to 
0.5 ml 
6.2  
Non-Study Vaccines 
The term ‘non-study vaccine’ refers to those vaccines which will be intentionally given to 
study subjects but not formally included in the analysis of study objectives. 
No non-study vaccines are planned for this study. Any non-study vaccines administered 
during the study conduct will be captured in the CRF as concomitant medications and/or 
vaccinations. 
6.3  
Vaccine Preparation and Administration 
The investigator or designee will be responsible for oversight of the administration of 
vaccine to subjects enrolled in the study according to the procedures stipulated in this 
study protocol. All vaccines will be administered only by unblinded personnel who are 
qualified to perform that function under applicable local laws and regulations for the 
specific study site. 
The vaccine components will be provided in 5 separate kits (i.e. one for the control and 
one for each of the 4 dosage groups). The vaccine components must be mixed prior to 
vaccination taking into account the appropriate aseptic procedures. Detailed vaccine 
preparation and administration instructions, including the maximal administration period, 
will be provided to investigators prior to study start and must be filed in the Investigator 
Site File. 
PRECAUTIONS TO BE OBSERVED IN ADMINISTERING STUDY VACCINE: 
- 
Prior to vaccination, subjects must be determined to be eligible for study vaccination 
and it must be clinically appropriate in the judgment of the investigator to vaccinate. 
Eligibility for vaccination prior to first study vaccine administration is determined by 
evaluating the entry criteria outlined in protocol sections 4.0. 

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- 
Study vaccines must not be administered to individuals with known hypersensitivity 
to any component of the vaccines. 
- 
Standard immunization practices are to be observed and care should be taken to 
administer the injection intramuscularly. Before administering vaccine, the 
vaccination site is to be disinfected with a skin disinfectant (e.g., 70% alcohol). Allow 
the skin to dry. DO NOT inject intravascularly. 
- 
As with all injectable vaccines, trained medical personnel and appropriate medical 
treatment must be readily available in case of anaphylactic reactions following 
vaccine administration. For example, epinephrine 1:1000, diphenhydramine, and/or 
other medications for treating anaphylaxis should be available. 
6.4 
Vaccine Administration Error or Overdose of Vaccine 
Vaccine administration error is defined as receiving a dose of study vaccine that was not 
reconstituted as instructed or administered by a different route from the intended route of 
administration. An overdose of study vaccine (whether accidental or intentional) is 
defined when a dosage higher than the recommended dosage is administered in one dose 
of study vaccine. 
Any vaccine administration error or overdose of study vaccine detailed in this protocol 
must be reported as an adverse event, and if the vaccine administration error or overdose 
is associated with a serious adverse event, it must be reported as such within 24 hours to 
the Sponsor. 
6.5 
Prior and Concomitant Medications and Vaccines 
All medications, vaccines and blood products taken or received by the subject within 180 
days prior to the start of the study are to be recorded in the appropriate CRF. 
Medications taken for prophylaxis are those intended to prevent the onset of symptoms. 
Medications taken for treatment are intended to reduce or eliminate the presence of 
symptoms that are present. 
NOTE: Use of antipyretics/analgesics within 24 hours prior to vaccine administration is a 
reason to delay study vaccination (see section 4.3). 
Concomitant medications include all medications (including vaccines) taken 
by/administered to the subject at and after enrolment and must be documented in the 
appropriate CRF. 

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When recording concomitant medications/vaccines, they should be checked against the 
study entry criteria in section 4.0, to ensure that the subject should be enrolled in the 
study. 
6.6  
Vaccine Supply, Labeling, Storage and Tracking 
The Sponsor will ensure the following: 
▫ Supply the study vaccines. 
▫ Appropriate labeling of all study vaccines provided that complies with the legal 
requirements of each country where the study is to be performed. 
The investigator must ensure the following: 
▫ Acknowledge receipt of the study vaccines by a designated staff member at the site, 
including: 
- 
Confirmation that the vaccines were received in good condition 
- 
Confirmation to the Sponsor of the temperature range during shipment from the  
Sponsor to the investigator’s designated storage location 
- 
Confirmation by the Sponsor that the vaccines are authorized for use. 
▫ Proper storage of the study vaccines, including: 
- 
Storage in a secure, locked, temperature-controlled location. 
- 
Proper storage according to the instructions specified on the labels. 
- 
Appropriate record keeping and inventory of the study vaccines, including regular 
documentation of adequate storage temperature. 
▫ Appropriate use of the study vaccines, including: 
- 
No use of vaccines prior to receipt of authorization for use from the Sponsor. 
- 
Use only in accordance with the approved protocol. 
- 
Proper handling, including confirmation that the vaccine has not expired prior to 
administration. 
- 
Appropriate documentation of administration of vaccines to study subjects 
including: 
▪ 
Date, dosage, batch/lot numbers, expiration dates, unique identifying 
numbers assigned to subjects and study vaccines, and time of vaccine 

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administration. This information will be maintained in an accountability log 
that will be reviewed by the site monitor. 
▪ 
Reconciliation of all vaccines received from the Sponsor. Reconciliation is 
defined as maintaining records of which and how many vaccines were 
received, which vaccines were administered to subjects, which vaccines 
were destroyed at the site, and which vaccines were returned to the Sponsor, 
as applicable. 
▫ Proper adherence to the local institutional policy with respect to destruction of study 
vaccines. 
▫ Complete record keeping of vaccine use, wastage, return or destruction, including 
documentation of: 
- 
Copy of the site’s procedure for destruction of hazardous material. 
- 
Number of doses destroyed, date of destruction, destruction code (if available), 
method of destruction, and name of individual performing destruction. 
Vaccines that have been stored differently from the manufacturer’s indications must not 
be used unless the Sponsor provides written authorization for use. In the event that the use 
cannot be authorized, the Sponsor will make every effort to replace the vaccine supply. 
All vaccines used in conjunction with this protocol must be stored separately from normal 
hospital/practice stocks to prevent unintentional use of study vaccines outside of the 
clinical study setting. 
Monitoring of vaccine accountability will be performed by the study monitor during site 
visits and at the completion of the study. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator must ensure that all unused study vaccines, packaging and supplementary 
labels are destroyed locally (upon approval from Sponsor) or returned to the Sponsor. 

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7.0 
ASSESSMENTS 
7.1 
Safety Assessment 
The measures of safety used in this study are based on previous study data and based on 
comparable routine clinical/laboratory procedures. They include a close vigilance for, and 
stringent reporting of selected local and systemic adverse events routinely monitored in 
vaccine studies as indicators of reactogenicity. 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product at any dose that does 
not necessarily have to have a causal relationship with this treatment. Therefore, an AE 
can be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the investigational product. 
This definition includes intercurrent illnesses or injuries and exacerbation of pre-existing 
conditions. 
The period of observation for AEs extends from the time the subject signs informed 
consent until he or she completes the specified safety follow-up period (Day 366) or 
terminates the study early (whichever comes first). AEs occurring after the informed 
consent form is signed but prior to receiving study vaccine/product will be documented as 
an adverse event and recorded within the source documents. However, any AEs occurring 
prior to receipt of any study vaccine will be analyzed separately from “treatment 
emergent” AEs (AEs occurring after administration of the first study vaccine). 
Adverse events are collected as either solicited or unsolicited adverse events. Solicited 
events are derived from organized data collection systems, such as Subject Diaries or 
interview. 
7.1.1 
Solicited Adverse Events 
The term “reactogenicity” refers to solicited signs and symptoms (“solicited adverse 
events”) occurring in the hours and days following a vaccination, to be collected by the 
subject after the first 24 hours inpatient observation period at Day 1until Day 14, using a 
pre-defined Subject Diary. 
The following solicited adverse events are included in the Subject Diary. Each adverse 
event is to be assessed using the scoring system shown in Appendix A (Solicited Local 
AEs) and Appendix B (Solicited Systemic AE): 

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Solicited Local Adverse Events 
Solicited local AEs include: 
- 
injection site erythema 
- 
injection site induration 
- 
injection site pain 
- 
injection site swelling Solicited Systemic Adverse Events 
Solicited systemic AEs include: 
- 
body temperature ≥38.0°C (as measured orally) 
- 
loss of appetite 
- 
nausea 
- 
fatigue 
- 
generalized myalgia 
- 
generalized arthralgia 
- 
headache 
- 
chills 
- 
vomiting 
- 
diarrhea 
- 
generalized rash 
- 
urticaria 
Other Solicited Data 
Other solicited data collected per Subject Diary include: 
▫ Use of analgesics/antipyretics recorded as “absent” or “present” and summarized by 
“for treatment” or “for prophylaxis” 
▫ Body temperature as recorded daily, ideally at same time, by the oral route 
The study staff must review the data entered into the Subject Diary as described in 
sections 3.4.2 and 5.3.1. 

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NOTE: Any solicited adverse event that meets any of the following criteria must be 
entered into the subjects’ source documents (see section 9.1) and also as an adverse event 
in the appropriate CRF: 
▫ Solicited local or systemic adverse event that continues beyond Day 14 after 
vaccination. 
▫ Solicited local or systemic adverse event that leads to a visit to a healthcare provider 
(medically attended adverse event, see section 7.1.3). 
▫ Solicited local or systemic adverse event leading to the subject withdrawing from the 
study or the subject being withdrawn from the study by the investigator (adverse event 
leading to withdrawal, see section 7.1.3). 
▫ Solicited local or systemic adverse event that otherwise meets the definition of a 
serious adverse event (see section 7.1.4). 
7.1.2  
Unsolicited Adverse Events 
An unsolicited adverse event is an adverse event that was not solicited using a Subject 
Diary and that was spontaneously communicated by a subject who has signed the 
informed consent. 
7.1.3  
Evaluation of Adverse Events 
Every effort should be made by the investigator to evaluate safety information reported by 
a subject for an underlying diagnosis and to capture this diagnosis as the event in the AE 
page. In other words, the practice of reporting only symptoms (e.g., “cough” or “ear 
pain”) are better reported according to the underlying cause (e.g., “asthma exacerbation” 
or “otitis media”). 
The severity of events reported on the appropriate CRF page will be determined by the 
investigator as: 
Mild: 
transient with no limitation in normal daily activity. 
Moderate: 
some limitation in normal daily activity. 
Severe: unable to perform normal daily activity. 
The relationship of the study treatment to an AE will be determined by the investigator 
based on the following definitions: 

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1. Not Related 
The AE is not related to an investigational vaccine if there is evidence that clearly 
indicates an alternative explanation. If the subject has not received the vaccine, the timing 
of the exposure to the vaccine and the onset of the AE are not reasonably related in time, 
or other facts, evidence or arguments exist that reasonably suggest an alternative 
explanation, then the AE is not related. 
2. Possibly Related 
The administration of the investigational vaccine and AE are considered reasonably 
related in time and the AE could be explained by exposure to the investigational vaccine 
or by other causes. 
3. Probably Related 
Exposure to the investigational vaccine and AE are reasonably related in time and no 
alternative explanation has been identified. 
The relationship of the study treatment to an unsolicited AE will be determined by the 
investigator.  
Note: solicited AEs will not be evaluated for relationship to study treatment. Grading for 
severity of solicited local and systemic AEs is described in Appendix A and Appendix B. 
Adverse events will also be evaluated by the investigator for the co-existence of any of 
the other following conditions: 
▫ “Medically attended adverse event”: an adverse event that leads to a visit to a 
healthcare provider. 
▫ “New onset of chronic disease” (NOCD): an adverse event that represents a new 
diagnosis of a chronic medical condition that was not present or suspected in a subject 
prior to study enrolment. 
▫ AEs leading to withdrawal: adverse events leading to study or vaccine withdrawal. 
All AEs, regardless of severity, will be monitored until resolution or until the investigator 
assesses them as chronic or stable. All subjects experiencing AEs - whether considered 
associated with the use of the study vaccine or not - must be monitored until symptoms 
subside and any abnormal laboratory values have returned to baseline, or until there is a 
satisfactory explanation for the changes observed, or until death, in which case a full 
pathologist’s report should be supplied, if possible. 

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7.1.4  
Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose results in one or more of the following: 
▫ Death. 
▫ Is life-threatening (i.e., the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred); it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
▫ Required or prolonged hospitalization. 
▫ Persistent or significant disability/incapacity (i.e., the event causes a substantial 
disruption of a person’s ability to conduct normal life functions). 
▫ Congenital anomaly/or birth defect. 
▫ An important and significant medical event that may not be immediately life 
threatening or resulting in death or hospitalization but, based upon appropriate 
medical judgment, may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed above. 
Adverse events which do not fall into these categories are defined as non-serious. 
It should be noted that a severe adverse event need not be serious in nature and that a 
serious adverse event need not, by definition, be severe. 
Serious adverse events will be captured both on the Vaccines Serious Adverse Event 
(VSAE) form as well as on the appropriate CRF page. All SAEs will be evaluated by the 
investigator for relationship of the event to study vaccine. SAEs that are judged to be 
possibly or probably related to the study vaccine should be reported to the Sponsor as 
related/suspected events. 
The relationship of the study treatment to an SAE will be determined by the investigator 
based on the following definitions: 
1. Related/suspected 
The SAE is judged by the investigator to be possibly or probably related to the study 
vaccine on the appropriate CRF page (see section 7.1.3). 

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2. Not Related 
The SAE is not related if exposure to the study vaccine has not occurred, or the 
occurrence of the SAE is not reasonably related in time, or the SAE is considered 
unlikely to be related to use of the study vaccine, i.e., there are no facts (evidence) or 
arguments to suggest a causal relationship. 
The relationship of the study vaccine to an SAE will be determined by the investigator. 
In addition, SAEs will be evaluated by the Sponsor or designee for “expectedness.” An 
unexpected AE is one that is not listed in the current Summary of Product Characteristics 
or the Investigator’s Brochure or an event that is by nature more specific or more severe 
than a listed event. 
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded on the appropriate CRF. If the onset of an event occurred before the subject 
entered the study (e.g., any pre-planned hospitalization for conditions like cosmetic 
treatments or for non-emergency routine visits for a pre-existing condition), the 
hospitalization would not lead to an AE being classified as serious unless, in the view of 
the investigator, hospitalization was prolonged as a result of participation in the clinical 
study or was necessary due to a worsening of the pre-existing condition. 
7.1.4.1  
Adverse Events of Special Interest 
Certain adverse events of special interest (AESIs) are monitored after the administration 
of immunostimulatory agents. All subjects enrolled in this study will be monitored for 
AESIs for the entire follow-up period. The AESIs will be defined according to MedDRA 
preferred terms. The investigator will be provided with a list of AESIs prior to study start. 
Receipt of this list will be notified and stored, along with the list of AESIs, in the 
Investigator Site File. During the course of the trial the list of AESIs may change. If this 
occurs, the investigators will be advised of the change and confirmation of receipt will be 
documented. The updated list of AESIs and documentation of receipt are also stored in 
the Investigator Site File. The occurrence of any of these adverse events will be treated as 
a serious adverse event (SAE), meeting the criterion of a “medically important event.” 
Subjects will be assessed for diagnosis of an AESI at the following visits: 
- 
Pre-vaccination clinic visit (Day -28 to Day -3)  
- 
Visit 1 (Day 1, pre-vaccination) 
- 
Visit 2 (Day 4) 

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- 
Visit 3 (Day 8) 
- 
Visit 4 (Day 15) 
- 
Visit 5 (Day 22; Safety Follow-Up Call) 
- 
Visit 6 (Day 29) 
- 
Visit 7 (Day 85) 
- 
Visit 8 (Day 113) 
- 
Visit 9 (Day 181) 
- 
Visit 10 (Day 209; Safety Follow-Up Call) 
- 
Visit 11 (Day 271; Safety Follow-Up Call) 
- 
Visit 12 (Day 366; Study Termination Visit) 
At these visits a qualified health care practitioner listed on the site’s responsibilities and 
delegation logs will conduct a review of organ systems and a targeted physical exam and 
will evaluate subjects for any new signs or symptoms that could indicate one of the 
AESIs as specified in the list of AESIs stored in the Investigator Site File. They will also 
interview the subject about recent medical history and any new diagnosis that could 
indicate an AESI. Medical records related to any new medical event or diagnosis will be 
requested, reviewed by the site staff, and recorded in the subject’s source documents. 
A diagnosis of an AESI will be reported in the same manner and time frame as an SAE 
using the VSAE form. The investigator must notify Novartis within 24 hours. The AESI 
diagnosis, as well as any medications taken to treat the condition, will be recorded in the 
subject’s source documents and on the appropriate CRF. 
7.1.5  
Methods for Recording Adverse Events and Serious Adverse Events 
All findings regarding Adverse Events must be reported on the appropriate CRF page and 
on the VSAE form, if applicable, which is part of the Investigator Site File. All findings 
in subjects experiencing AEs must be reported also in the subject's source document. 
All SAEs which occur during the course of the study, whether considered to be associated 
with the study vaccination or not, must be reported within 24 hours of the site becoming 
aware of the event to Novartis or its designee. Specific instructions and contact details 
for collecting and reporting SAEs to Novartis will be provided to the investigator. 

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All SAEs are also to be documented on the appropriate CRF page. Any medication or 
other therapeutic measures used to treat the AE will be recorded on the appropriate 
CRF(s) in addition to the outcome of the AE. 
After receipt of the initial report, representatives of Novartis or its designee will contact 
the investigator if it is necessary to obtain further information for assessment of the event. 
All SAEs must be reported by the investigator to his/her corresponding EC and applicable 
regulatory authorities in accordance with institutional policy/regulatory requirements and 
adequate documentation of this notification must be provided to the Sponsor. 
Novartis or its designee must also comply with the applicable regulatory requirement(s) 
related to the reporting of suspected unexpected serious adverse vaccine reactions (also 
known as SUSARs) to the regulatory authority(ies) and the IRB/EC. If a SUSAR or other 
safety signal relating to use of one of the study vaccines is reported to Novartis or its 
designee, the Sponsor will communicate the information to the investigator and the 
investigator will be responsible for submitting this information to the EC and other 
relevant authorities. 
7.1.5.1 
Post-Study Events 
Any suspected SAE that occurs outside of the protocol-specified follow-up period or after 
the end of the study but considered to be caused by the study vaccine must be reported to 
Novartis or its designee. These SAEs will be processed by Novartis or its designee as 
during the course of the study, until 3 months after the last scheduled study visit. 
Instructions and contact details for collecting and reporting these suspected SAEs will be 
provided to the investigator. 
7.1.6  
Pregnancies 
To ensure subjects’ safety, each pregnancy in a subject after study vaccination must be 
reported to Novartis within 72 hours of the site learning of its occurrence. If the subject 
agrees to submit this information, the pregnancy must be followed to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. This follow-up should occur even if intended duration of safety follow-up 
for the study has ended. 
Pregnancy data must be recorded on a Pregnancy Report CRF (initial report) and 
Pregnancy Follow-Up CRF (outcome report). 

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Any pregnancy outcome meeting the definition of a SAE (see section 7.1.4) must also be 
reported on the VSAE Report Form. 
7.1.7  
Safety Laboratory Measurements 
Blood and urine samples will be collected from all subjects at the Pre-vaccination 
Screening, at Visit 1, at Visit 3 and at Visit 6 as outlined in Time and Events Table 3. The 
blood safety laboratory assessments will include sodium, potassium, chloride, 
bicarbonate, blood urea nitrogen, creatinine, liver function tests (ALT, AST), a complete 
blood count and C-reactive protein. The urine safety laboratory assessments will include 
protein, glucose and red blood cells. An additional blood and urine sample will be 
collected in case of a clinic Early Termination Visit as outlined in section 5.5.1. 
All testing will be conducted by qualified and certified laboratories. Abnormal laboratory 
values will be defined following the FDA CBER Guidance for Industry “Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials” dated September 2007, or the institution’s normal ranges if they 
differ from CBER guidance. Please see Appendix C, D and E for further details on the 
Toxicity Grading Scales according to CBER. 
Retesting may be performed in case of abnormal values per guidance of the investigator.  
Retest results will not be captured in the CRF. 
7.2  
Efficacy Assessment 
Efficacy measurement will not be performed as part of this study. 
7.3  
Immunogenicity Assessment 
The measures to assess the primary and secondary immunogenicity endpoints for this 
study are standard, i.e., widely used and generally recognized as reliable, accurate, and 
relevant (able to describe the quality and extent of the immune response). 
The assay’s used in this study to assess the primary and immunogenicity endpoints are 
human serum bactericidal assay (hSBA) and ELISA specific for MenC 
The hSBA is a functional measure of the ability of specific antibodies, in conjunction 
with human complement, to kill MenC indicator strains, and is widely used and generally 
recognized as the serological correlate of protection. The specific ELISA will be used to 
measure the induction of antibodies directed against MenC following vaccination with the 
study vaccines. 

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Blood samples (approximately 10 ml) to obtain serum for hSBA and ELISA assays will 
be collected at Day 1, Day 8, Day 29 and Day 181 (refer to section 3.5 for detailed 
specimen collection procedures). 
Testing will be conducted by a Novartis or designated laboratory in a blinded manner 
towards the treatment group. Laboratory contact details are listed in the Protocol 
Ancillary Document. 
All data will be captured at the laboratory and transferred via Electronic Data Transfer  
(EDT) 
Details on all blood sample handling steps are described in the Clinical Specimen Lab 
Manual provided to the study site. 
7.4 
Exploratory Measurements 
In those subjects who agree to a separate Informed Consent, additional blood samples will 
be collected at Day 1, Day 4, Day 8, Day 29 and Day 181 for exploratory measurements. 
The purpose of these exploratory measurements is to assess the systemic exposure of 
LHD153, to further delineate vaccine induced antigen specific immune responses and to 
evaluate  biomarkers that may be predictive for safety and/or innate immune activation. 
All exploratory measurements will be conducted by a Novartis or a designated laboratory. 
Laboratory contact details are listed in the Protocol Ancillary Document. 
Exploratory measurements may be performed after the Clinical Study Report (CSR) has 
been completed, in which case these data will be submitted as an addendum to the CSR. 
Systemic exposure of LHD153 
Systemic exposure of LHD153 will be assessed by analyzing LHD153 blood plasma 
levels at Day 1 (baseline, 1, 2, 4, 8 and 24h after vaccination) and Day 4 using 
LC/MS/MS. Time-points for assessment of clinical exposure of LHD153 have been 
selected based on non-clinical data in dogs and rats. 
Vaccine-induced antigen-specific immune responses 
The frequency of B cells specific for MenC polysaccharide and CRM197 will be 
determined by enzyme-linked immunosorbent spot (ELISPOT) at Day 1, Day 8, Day 29 
and Day 181 in order to evaluate the baseline specific B-cell frequency (Day 1), the peak 
of plasmablast responses (Day 8), the peak of B cell memory responses (Day 29), and the 
persistence of memory B cell responses (Day 181). 

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Subsequently, the diversity of the antigen specific B-cell repertoire as well as the specific 
antibody functionality will be analyzed in a selected subset of subjects. The selection of 
the subset will be based on the most pronounced response to the study vaccines when 
compared to baseline as determined by the primary and secondary immunogenicity 
assessment. 
The diversity of the elicited B-cell receptors will be assessed through sequence analysis of 
complementary DNA (cDNA) generated from immunoglobulin (Ig) messenger RNA 
(mRNA). The Ig cDNAs will be analyzed from antigen-specific B cells obtained at Day 
1, Day 29 and/or Day 181 and plasmablasts isolated at Day 8. The analysis of the B-cell 
receptor diversity does not have the intent nor the capability to identify or rule out any 
genetic modifications in the RNA or DNA that are presumably linked to disease or 
predisposition to disease. 
To evaluate the functionality specific antibodies induced by the study vaccines, 
biochemical and cell-based assays will be performed on a selected subset of serology 
samples collected for the assessment of the primary and secondary immunogenicity 
endpoints at Day 1, Day 8, Day 29 and Day 181. The evaluation of antigen specific 
antibody functionality includes determination of the antibody isotype and the antibody 
glycosylation state. Furthermore, the ability of the MenC-specific antibodies to fix 
complement, to promote antibody-dependent cell mediated cytoxicity (ADCC), to induce 
phagocytosis and to activate FcR+ cells in vitro will be assessed. If the quantity of serum 
available for this specific exploratory objective is limited, assessments of isotype, 
glycosylation state and complement fixing capacity will be prioritized over the other 
assessments. 
The frequency of T cells specific for the CRM197 protein at baseline (Day 1), at Day 8 and 
at Day 29 after vaccination with the study vaccines will be determined by FACS analysis 
using intracellular staining with a panel of cytokines and surface markers to identify cell 
populations. 
Early Markers for Safety and Innate immune activation 
The evaluation of potential biomarkers of safety and innate immune activation will be 
performed on blood specimens collected at Day 1 (baseline, 6h and 24h after vaccination) 
and Day 4. 
The vaccine-induced production of inflammatory cytokines and chemokines will be 
monitored on serum samples using a commercially available electrochemoluminescence 
assay for a panel of pro-inflammatory cytokines and chemokines, including Eotaxin, 
Eotaxin-3, GM-CSF, IFN-g, IL-1a, IL-1b, IL-10, IL-12 p70, IL-12/IL-23p40, IL-13, 

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IL15, IL-16, IL-17A, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IP-10, MCP-1, MCP-
4, MDC, MIP-1a, MIP-1b, TARC, TNF-a, TNF-b, VEGF. 
The vaccine-induced expression of genes and gene families will be monitored on whole 
blood samples using of RNA microarrays by existing technologies. The RNA micro array 
analysis does not have the intent nor the capability to identify or rule out any genetic 
modifications in the RNA or DNA that are presumably linked to disease or predisposition 
to disease. 
8.0  
STATISTICAL CONSIDERATIONS 
8.1  
Endpoints 
8.1.1 
Primary Endpoint(s) 
8.1.1.1  
Primary Safety Endpoint(s) 
The measures for assessing safety and tolerability (by vaccine group within each cohort 
and by LHD153R adjuvant dosage group overall) are as follows: 
▫ The frequency and percentage of subjects with solicited local and systemic  AEs 
through Day 14. Time intervals after vaccination that will be summarized are:30 
minutes post-vaccination, Days 1-4 (without 30 minutes), Days 5-8, Days 8-14, Days 
1-8 (without 30 minutes) and Days 1-14 (without 30 minutes). 
▫ The frequency and percentage of subjects with any unsolicited AEs from the day of 
vaccination (Day 1) to Day 14. 
▫ The frequency and percentage of subjects with SAEs, medically attended AEs,  AEs 
leading to study withdrawal, NOCDs, AESIs for the following time periods: day of 
signed informed consent until study completion (Day 366), day of vaccination (Day 1) 
to Day 29, and Day 29 to study completion (Day 366). 
▫ The absolute values and changes in hematology, chemistry, and urinalysis parameters 
(see section 7.1.7). 
▫ The frequency and percentage of subjects with abnormal laboratory parameter values 
as classified by investigator normal ranges (low, normal, high) and as classified by 
CBER toxicity grading scales, when available. 
8.1.1.2  
Primary Efficacy Endpoint(s) 

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Not applicable. 
8.1.1.3  
Primary Immunogenicity Endpoint(s) 
The primary immunogenicity endpoints are the GMTs measured by hSBA directed 
against MenC from samples collected on Day 1 (baseline, before vaccination) and Day 29 
as well as the GMR of the titers (Day 29 / Day 1). 
8.1.2 
Secondary Endpoint(s) 
8.1.2.1  
Secondary Safety Endpoint(s) 
Not applicable. 
8.1.2.2  
Secondary Efficacy Endpoint(s) 
Not applicable. 
8.1.2.3  
Secondary Immunogenicity Endpoint(s) 
The secondary immunogenicity endpoints are: 
▫ GMTs and corresponding GMRs measured by hSBA directed against MenC for 
samples collected at Day 8 and Day181. 
▫ Percentage of subjects with hSBA seroresponse at Days 8, 29, and 181. Seroresponse 
is defined as a post vaccination hSBA ≥8 for subjects with a baseline hSBA <4 or 
have an increase of at least 4 times the baseline hSBA level for subjects with 
prevaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against MenC measured by ELISA 
for samples collected on Days 1 (baseline, prior to vaccination), 8, 29, and 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations to 
MenC as measured by ELISA on Day 8, 29, and 181 relative to baseline (Day 1). 
8.1.3  
Exploratory Endpoint(s) 
The exploratory  endpoints are based on results of testing which may not be performed 
until after the study report has been finalized and will be further refined prior to testing. 
They include the following: 

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▫ Serum concentration of LHD153 at Day 1 baseline (prior to vaccination), Day 1 (1h , 
2h, 4h, 8h, and 24h after vaccination), Day 4 by LC-MS/MS. 
▫ Frequency of MenC polysaccharide-specific and CRM197-specific B cells at Day 1 
(baseline), Day 8, Day 29, and Day 181 by ELISPOT. 
▫ Diversity of MenC polysaccharide-specific B-cell repertoire at Day 1 (baseline), Day 
8, Day 29, and Day 181 by immunoglobulin cDNA sequencing. 
▫ Functionality of antigen specific antibodies will be assessed at Day 1 (baseline), Day 
8, Day 29, and Day 181 by analysis of immunoglobulin isotype, glycosylation state 
and their ability to fix complement, to promote antibody-dependent cell mediated 
cytoxicity, to induce phagocytosis and to activate FcR+ cells. If the quantity of serum 
available for this specific exploratory objective is limited, assessments of 
immunoglobulin isotype, glycosylation state and complement fixing capacity will be 
prioritized over the other assessments. 
▫ Frequency and quality of T cells specific for CRM197 at Day 1 (baseline), Day 8, and  
Day 29 by fluorescence activated cell sorting (FACS) analysis using intracellular  
staining with a wide panel of cytokines and surface markers to identify cell 
populations. 
▫ Serum concentrations of a panel of 30 chemokines and cytokines at Day 1 baseline 
(prior to vaccination), Day 1 (6h and 24h after vaccination), Day 4, and Day 8 by 
multiplex Electro-chemo-luminescence based assay. 
▫ Gene expression profile in whole blood at Day 1 baseline (prior to vaccination), Day 1 
(6h and 24h after vaccination), Day 4, and Day 8 by RNA micro array analysis. 
8.2  
Success Criteria 
The study has no formal statistical hypotheses and will not be declared positive or 
negative according to given rules. The selection of an appropriate LHD153R adjuvant 
dosage for future studies will be determined by the joint evaluation of the 
immunogenicity and safety profiles of each dosage group. 8.2.1  
Success Criteria 
for Primary Objective(s) Not applicable. 
8.2.2  
Success Criteria for Secondary Objective(s) 
Not applicable. 

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8.3  
Analysis Sets 
8.3.1  
All Enrolled Set 
All screened subjects who provide informed consent and provide demographic and/or 
baseline screening assessments, regardless of the subject’s randomization and treatment 
status in the study and received a Subject ID. 
8.3.2  
All Exposed Set 
All subjects in the enrolled set who receive a study vaccination. 
8.3.3  
Safety Set 
Safety Set (solicited adverse events and other solicited reactions) 
All subjects in the Exposed Set who: 
▫ Provide post vaccination reactogenicity data. 
Safety Set (unsolicited adverse events) 
All subjects in the Exposed Set who: 
▫ Have post-vaccination unsolicited adverse event records. 
Safety Set (overall) 
All subjects in the Exposed Set who: 
▫ Have either post-vaccination adverse event or reactogenicity records. 
Subjects will be analyzed as “treated” (i.e., according to the vaccine a subject received, 
rather than the vaccine to which the subject may have been randomized). 
8.3.4  
Full Analysis Set (FAS) Efficacy/Immunogenicity Set 
All subjects in the Enrolled Set who: 
▫ Receive a study vaccination AND provide efficacy/immunogenicity data at relevant 
time points. 

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FAS sets will be analyzed “as randomized” (i.e., according to the vaccine a subject was 
designated to receive, which may be different from the vaccine the subject actually 
received). 
8.3.5  
Per Protocol (PP) Set Efficacy/Immunogenicity Set 
All subjects in the FAS efficacy/immunogenicity set who: 
▫ Are not excluded due to reasons (see section 8.3.8) defined prior to unblinding or 
analysis. 
PPS are subsets of FAS and should always be defined even if the objectives do not 
require it. 
Examples for subjects excluded due to other reasons than protocol deviations are: 
- 
Subjects who withdrew informed consent. 
- 
Premature withdrawal due to an adverse event. 
Exclusions need to be considered by objective/time point, i.e., sometimes not all data of a 
subject but only part of the subject's data will be removed from the PPS analysis. 
8.3.6  
Other Analysis Sets  
All subjects in the Enrolled Set who consent to additional blood draws, receive a study 
vaccination AND provide exploratory assay data at relevant time points will be included 
in an exploratory assay subset. 
8.3.7  
Subgroups 
Selected immunogenicity analyses may be provided based on seropositivity status at 
baseline. 
8.3.8  
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. A protocol deviation may be a reason to remove data from 
an analysis set at the time of analysis. Reportable protocol deviations will be defined as 
exclusionary from the analysis according to protocol objectives and endpoints, which will 
be specified in the Statistical Analysis Plan. In some cases exclusion of data may be due 
to a reason other than a protocol deviation, e.g. early termination. 

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8.4  
Statistical Analysis Plan 
This section provides a summary of the statistical methodology to be used. A more 
detailed description of analysis methods will be provided in a separate Statistical Analysis 
Plan which may also include additional exploratory analyses not explicitly mentioned in 
the following sections. 
8.4.1  
Analysis of Demographic and Baseline Characteristics 
Descriptive statistics (number of non-missing observations, mean, standard deviation, 
median, minimum and maximum) for age, height and weight at enrolment will be 
calculated overall and by vaccine group and LHD153R adjuvant dosage. 
Distributions of subjects by sex and ethnic origin will be summarized overall and by 
vaccine group and LHD153R adjuvant dosage. 
8.4.2  
Analysis of Primary Objective(s) 
8.4.2.1  
Analysis of Primary Safety Objective(s) 
Safety of the study vaccines will be assessed in all subjects in terms of the frequency and 
percentage of reported AEs as well as by changes in clinical laboratory values.  
8.4.2.1.1  
Analysis of Extent of Exposure 
The frequency and percentage of subjects with vaccinations will be summarized by 
vaccine group and LHD153R adjuvant dosage, by cohort and overall, for the Enrolled 
Set. 
8.4.2.1.2  
Analysis of Solicited Local, Systemic and Other Adverse Events 
All solicited adverse events will be summarized according to defined severity grading 
scales. Use of medication to prevent/treat fever will be summarized according to 
frequencies and percentages reporting “Yes” and “No”. 
Frequencies and percentages of subjects experiencing each adverse event will be 
presented for each symptom severity. Summary tables showing the occurrence of any 
local or systemic adverse event overall and at each time point will also be presented. 
Post-vaccination solicited adverse events reported from Day 1 to Day 14 will be 
summarized for the intervals Day 1-4 (without 30 minutes), Day 5-8, Day 1-8 (without 30 
minutes), Day 8-14 and Day 1-14 (without 30 minutes) by maximal severity and by 

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vaccine group and LHD153R adjuvant. The severity of solicited local adverse events, 
including injection-site erythema, swelling and induration will be summarized according 
to categories based on linear measurement: 25-50 mm, 51-100 mm, > 100 mm. 
Injection site pain and systemic reactions (except fever) occurring up to Day 14 will be 
summarized according to “mild”, “moderate” or “severe”. 
Each solicited local and systemic adverse event will also be further summarized as “none” 
versus “any”. 
Implausible measurements (for further definition see Statistical Analysis Plan) will be left 
out of the analysis. 
Use of antipyretics and analgesics will be summarized by frequency by type of use 
(prophylactic versus treatment) and percentage of subjects reporting use. The influence of 
antipyretics and analgesics use on the occurrence of specific adverse events (e.g., fever, 
pain) will be assessed. 
Body temperature will be summarized by 0.5 °C and 1.0 °C increments from 36.0 °C up 
to ≥40 °C. 
8.4.2.1.3  
Analysis of Unsolicited Adverse Events 
This analysis applies to all adverse events occurring during the study, judged either as 
probably related, possibly related, or not related to vaccination by the investigator, 
recorded in the CRF, with a start date on or after the date of first vaccination. AE starting 
prior to the first vaccination will only be listed. The original verbatim terms used by 
investigators to identify adverse events in the CRFs will be mapped to preferred terms 
using the MedDRA dictionary. The adverse events will then be grouped by MedDRA 
preferred terms into frequency tables according to system organ class. 
All reported adverse events, as well as adverse events judged by the investigator as at 
least possibly related to study vaccine, will be summarized according to system organ 
class and preferred term within system organ class. These summaries will be presented by 
vaccination group and LHD153R adjuvant dosage for each cohort and by interval of 
study observation. When an adverse event occurs more than once for a subject, the 
maximal severity and strongest relationship to the vaccine group will be counted. 
Separate summaries will be produced for the following categories: 
▫ Serious adverse events. 

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▫ Adverse events that are possibly or probably related to vaccine. 
▫ Adverse events of special interest. 
▫ New onset of chronic disease. 
▫ Adverse event leading to withdrawal. 
▫ Adverse events leading to a medically attended visit. 
▫ Adverse event by data source. 
Data listings of all adverse events will be provided by subject. In addition, adverse events 
in the categories above will be provided as listed data. 
8.4.2.1.4  
Analysis of Safety Laboratory Values 
The investigator must review all safety laboratory results (see Section 7.1.7). Abnormal 
laboratory values and clinically significant changes in values from pre-vaccination 
(Screening Visit) will be assessed, using medical judgment, based on the FDA CBER  
Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” dated September 2007, or the 
institution’s normal ranges if they differ from CBER guidance. Please see Appendix C, D 
and E for further details. 
The following information will be provided: 
▫ Change in absolute laboratory value from pre-vaccination (Screening Visit) and Day 1 
(Visit 1) baseline to Day 8 (Visit 3) and Day 29 (Visit 6) after vaccination. 
▫ The classification of laboratory values and/or their changes from pre-vaccination 
according to the CBER toxicity grading scale. 
▫ 3 x 3 shift tables by visit using the categorization of laboratory values according to 
institutional normal reference ranges (below, within, above). 8.4.2.2  
Analysis 
of Primary Efficacy Objective(s) 
Not applicable. 
8.4.2.3  
Analysis of Primary Immunogenicity Objective(s) 
8.4.2.3.1  
Statistical Hypotheses 

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There are no statistical hypotheses associated with the primary immunogenicity 
objectives. All analyses are descriptive. 
8.4.2.3.2  
Analysis Sets 
The primary immunogenicity analyses will be based on the per-protocol set (PPS) at Day 
29. The primary analyses will be repeated using the Full Analysis Set (FAS) as a measure 
of the sensitivity/robustness of the results (further details are given in section 8.3). 
8.4.2.3.3  
Statistical Methods 
Before any statistical analysis that assumes normally distributed observations, antibody 
titers will be log10-transformed. Individual titers below the limit of quantitation (LLQ) 
will be set to half that limit. 
Geometric Mean Titers 
The logarithmically (base 10) transformed antibody titers will be modeled using an 
analysis of covariance (ANCOVA) model with a qualitative factor for LHD153R 
adjuvant dosage (0 [for unadjuvanted MenC], 12.5, 25, 50 or 100 µg) and log (base 10) 
pre-vaccination titer as a covariate. The adjusted GMT and the two-sided, 95%, 
confidence intervals (CIs) of the GMT will be calculated based on this model as will the 
ratio of GMTs and corresponding CIs. The adjusted GMT and two-sided 95% CIs will be 
constructed by exponentiation (base 10) of the least square means of the logarithmically 
transformed (base 10) antibody titer. The ratio of GMTs (LHD153R adjuvant dosage 
minus Men C), and corresponding two-sided 95% CIs, will be constructed by 
exponentiation (base 10) of the least square differences obtained from this model. The 
model can be written as:  
log10 (yik) = µ + αi + βxik + εik 
where µ represents a common overall mean, αi represents the adjuvant dose group i effect, 
β represents the common slope for the log10 pre-vaccination titer, xik for subject k in 
adjuvant dose group I, and εik represents random error for subject k in adjuvant dose 
group i. 
Geometric Mean Ratios 
The logarithmically (base 10) transformed within subject ratio of antibody titers (Day 29 / 
pre-vaccination) will be modeled using an analysis of variance model with a qualitative 
factor for LHD153R adjuvant dosage (0 [for non-LHD153R adjuvanted MenC], 12.5, 25, 

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50 or 100 µg). The adjusted GMR and the two-sided, 95% CIs of the GMR will be 
calculated based on this model. The model can be written as: 
log10 (yik) = µ + αi + εik 
where µ represents a common overall mean, αi represents the adjuvant dose group i effect 
and εik represents random error for subject k in adjuvant dose group i. 
Handling of missing values 
For immunogenicity data, it may be reasonable to consider missing immunogenicity 
values as missing completely at random (MCAR), i.e., not informative. Therefore, the 
primary analysis will comprise a complete case analysis only, without introducing any 
bias. Imputation methods will not be used. 
8.4.3  Analysis of Secondary Objective(s) 8.4.3.1 
 Analysis of Secondary Safety Objective(s) Not 
applicable. 
8.4.3.2  
Analysis of Secondary Efficacy Objective(s) 
Not applicable. 
8.4.3.3  
Analysis of Secondary Immunogenicity Objective(s) 
8.4.3.3.1  
Statistical Hypotheses 
There are no statistical hypotheses associated with the secondary immunogenicity 
objectives. All analyses are descriptive. 
8.4.3.3.2  
Analysis Sets 
The secondary immunogenicity analyses will be based on the PPS (further details are 
given in section 8.3) or the appropriate subset of subjects. 
8.4.3.3.3  
Statistical Methods 
The secondary immunogenicity endpoints are: 
▫ GMTs and corresponding GMRs measured by hSBA directed against MenC for 
samples collected at Day 8 and Day181. 

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▫ Percentage of subjects with hSBA seroresponse at Days 8, 29, and 181. seroresponse is 
defined as a post vaccination hSBA ≥8 for subjects with a baseline hSBA <4 or have 
an increase of at least 4 times the baseline hSBA level for subjects with 
prevaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against MenC measured by ELISA 
for samples collected on Days 1 (baseline, prior to vaccination), 8, 29, and 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations to 
MenC as measured by ELISA on Day 8, 29, and 181 relative to baseline (Day 1). 
The GMTs for samples collected at Day 8 and Day 181 as well as the GMCs for samples 
collected at Day 1, Day 8, Day 29, and Day 181 will be analyzed using the same approach 
as for the primary immunogenicity endpoint. 
The remaining immunogenicity endpoints are based on subjects meeting criteria for 
seroconversion or achieving a certain threshold value. These endpoints will be 
summarized using frequencies and percentages by LHD153R adjuvant dosage (0 [for 
non-LHD153R adjuvanted MenC], 12.5, 25, 50 or 100 µg). Two-sided 95% 
ClopperPearson CIs will also be provided for percentages. For analyses of 
seroconversion, separate summaries may be provided based on seropositivity status at 
baseline. 
8.4.4  
Analysis of Exploratory Objectives 
Testing and analyses of exploratory endpoints may be performed after the Clinical Study 
Report (CSR) has been completed, in which case these data will be submitted as an 
addendum to the CSR. 
In general, concentration and titer results will be summarized for each LHD153R 
adjuvant dosage group using geometric means and associated 2-sided 95% confidence 
intervals; and, categorical data will be summarized using frequencies and percentages, 
with corresponding two-sided, 95% confidence intervals. 
8.5  
Sample Size and Power Considerations of Primary Objectives 
Sample size is not driven by statistical assumptions for formal hypothesis testing, but was 
based on the safety objective for the study. The table below provides the probability for 
various combinations of sample size (N) and presumed true frequency of a given event 
within an individual vaccine group  

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Frequency 
of Event 
Probability to Observe at Least 1 Subject with a Given Event For  
Various Choices of N 
4 
8 
12 
16 
0.05 
0.1855 
0.3366 
0.4596 
0.5599 
0.10 
0.3439 
0.5695 
0.7176 
0.8147 
0.15 
0.4780 
0.7275 
0.8577 
0.9257 
0.20 
0.5904 
0.8322 
0.9313 
0.9718 
0.30 
0.8250 
0.9423 
0.9862 
0.9967 
0.40 
0.8704 
0.9832 
0.9978 
0.9997 
The proposed combinations of sample sizes within each cohort are 4 aluminium 
hydroxide adjuvanted MenC-CRM197 and 16 MenC-CRM197 plus an assigned-level of 
LHD153R adsorbed to aluminium hydroxide. If all four cohorts are fully enrolled, there 
will be 16 subjects receiving aluminium hydroxide adjuvanted MenC-CRM197. 
With 16 subjects, events which occur at a frequency of 15% or more will be detected with 
at least 90% probability; and, events which occur at a frequency of 10% or more will be 
detected with 81% probability. With 4 subjects, events which occur at a frequency of 30% 
or more will be detected with at least 80% probability. Intermediate values of 8 and 12 
are provided to correspond to sample sizes in the MenC- CRM197 after cohort 2 and 
cohort 3 are fully enrolled. 
8.6  
Interim Analysis 
The DMC will be reviewing the accumulating safety data from the study in order to 
continue enrollment of subjects within a cohort and whether to enroll subjects into the 
next cohort. 
In addition to these periodic reviews, there will be a safety and immunogenicity interim 
analysis for the selection of an LHD153R adjuvant dosage based on the data collected 
through Day 29 from subjects enrolled in all cohorts. This analysis will be performed by 
personnel not involved in study decisions. The results will be unblinded at the group level 
thereby preserving the blind for individual subjects. No adjustment to the overall alpha 
will be performed as the data collected subsequent to this analysis involve secondary and 
exploratory endpoints. 
 

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9.0  
SOURCE DOCUMENTATION, STUDY MONITORING AND 
AUDITING 
Study monitoring and auditing will be standardized and performed in accordance with the 
Sponsor’s or delegated contract research organization’s (CRO) standard operating 
procedures and applicable regulatory requirements (e.g., FDA, EMA, and ICH 
guidelines). 
Prior to enrolment of the first study subject, Novartis or delegate will train investigators 
and/or their study staff on the study protocol, all applicable study procedures, 
documentation practices and all electronic systems. CRFs must be completed for each 
enrolled subject (see section 8.3.1 for definition of enrolled subject). Documentation of 
screened but not enrolled subjects must be maintained at the site and made available for 
review by the site monitor. 
9.1  
Source Documentation 
Prior to the start of the study, the site staff participating in the study conduct will be 
instructed on what documents will be required for review as source documents. The kinds 
of documents that will serve as source documents will be agreed between Sponsor or 
delegate and investigator and designees and specified in the SDA/Source Data 
Verification Form prior to subject enrolment. 
In addition, source documentation must include all of the following: subject identification 
(on each page), eligibility and participation, proper informed consent procedures, dates of 
visits, adherence to protocol procedures, adequate reporting and follow-up of adverse 
events, documentation of prior/concomitant medication/vaccines, study vaccine 
receipt/dispensing/return records, study vaccine administration information, any data 
collected by a telephone conversation with the subject and date of completion and reason. 
The subject must also allow access to the subject’s medical records. Each subject must be 
informed of this prior to the start of the study and consent for access to medical records 
may be required in accordance with local regulations. 
All safety data reported by subjects must be written down in source documents. If there 
are multiple sources of information (e.g., Subject Diary, verbal report of the subject, 
telephone contact details, medical chart) supporting the diagnosis of an adverse event, 
these sources must be identified in the source documents, discrepancies between sources 
clarified, the ultimate diagnosis must be justified and written in the source documents, 
and this diagnosis must be captured in the appropriate CRF page. The CRF must also 

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capture which source(s) of information were used to determine the adverse event (e.g., 
subject recall, medical chart, Subject Diary). 
9.2  
Study Monitoring, Auditing and Source Data Verification 
Prior to enrolment of the first study subject, Novartis or its designee (e.g., a CRO) will 
develop a Monitoring Plan to specify how centralized and/or on-site monitoring, 
including clinical specimens reconciliation, will be performed for the study. Study 
progress will be monitored as frequently as necessary to ensure: 
▫ that the rights and well-being of human subjects are protected, 
▫ the reported study data are accurate, complete, and verifiable from the source 
documents and 
▫ the conduct of the study is in compliance with the current approved 
protocol/amendment(s), GCP and applicable regulatory requirements. 
Contact details for the team involved in study monitoring will be provided to the 
investigator. Study data recorded on CRFs will be verified by checking the CRF entries 
against source documents in order to ensure data completeness and accuracy as required 
by study protocol. 
Additional documents such as the investigator site file, pharmacy records, and informed 
consent documentation must also be available for review if requested. Arrangements for 
monitoring visits will be made in advance in accordance with the monitoring plan, except 
in case of emergency. 
The investigator and/or site staff must make source documents of subjects enrolled in this 
study available for inspection at the time of each monitoring visit and Sponsor audits, 
when applicable. These documents must also be available for inspection, verification and 
copying, as required by regulations, by officials of the regulatory health authorities (e.g., 
FDA, EMA and others) and/or ECs/IRBs. The investigator and study site staff must 
comply with applicable privacy, data protection and medical confidentiality laws for use 
and disclosure of information related to the study and enrolled subjects. 
10.0  
DATA MANAGEMENT 
10.1 
Data Entry and Management 
In this study, all clinical data (including, but not limited to, AE/SAEs, concomitant 
medications, medical history, and physical assessments), safety data, and immunogenicity 
data will be entered into an EDC system, which is compliant with Title 21 Part 11 

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policies of the Code of Federal Regulations (FDA, 1997). The data system includes 
password protection and internal quality checks. The EDC system will be designed and 
validated by the Sponsor prior to activation for data entry by sites. The investigator or 
designated delegate must review data entered and electronically sign the CRFs to verify 
their accuracy. 
Access to the EDC system for data entry or review will require training and distinct 
individual access code assignments to those site staff members who will be entering study 
data and those involved in study oversight who may review study data. Data are collected 
within the EDC system, to which the Sponsor and site monitors have exclusively “read 
only” access. 
Paper CRFs will be provided for each pregnant subject by the Sponsor. All appropriate 
pregnant subject data collected will be recorded on this form. One copy must be retained 
by the investigator, and all other copies (including the original copy) will be returned as 
directed by the Sponsor. Instructions on how to complete this form will be provided to the 
investigator. 
10.2  
Data Clarification 
As part of the conduct of the trial, the Sponsor may have questions about the data entered 
by the site, referred to as queries. The monitors and the Sponsor are the only parties that 
can generate a query. All corrections and clarifications will be entered into the EDC 
system and will be identified by the person entering the information, the reason for the 
change, as well as the time of the changes made. If changes are made to a previously and 
electronically signed CRF, the investigator must confirm and endorse the changes 
10.3  
Data Protection 
Novartis respects the subjects’ rights to privacy and will ensure the confidentiality of their 
medical information in accordance with all applicable laws and regulations. 
The Sponsor as Data Controller according to the European Directive on the protection of 
individuals with regard to the processing of personal data and on the free movement of 
such data (95/46/EC) confirms herewith compliance to Directive 95/46/EC in all stages of 
Data Management. 
 

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11.0  
RECORD RETENTION 
Investigators must retain all study records required by Novartis and by the applicable 
regulations in a secure and safe facility. The investigator must consult a Novartis 
representative before disposal of any study records, and must notify the Sponsor of any 
change in the location, disposition, or custody of the study files. Essential documents 
must be retained for 15 years. “Essential documents” are defined as documents that 
individually and collectively permit evaluation of the conduct of a study and the quality 
of the data produced. These documents should be retained for a longer period, however, if 
required by the applicable national regulatory or institutional requirements.  
These principles of record retention will also be applied to the storage of laboratory 
samples, provided that the integrity of the stored sample permits testing. 
 

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12.0  
USE OF INFORMATION AND PUBLICATION 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov, and in compliance with current regulations. 
Novartis also assures that key results of this clinical study will be posted in a publicly 
accessible database within the required time-frame from the End of Study as defined in 
section 3.9. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
Novartis must be notified of any intent to publish data collected from the study and prior 
approval from Novartis must be obtained prior to submission for publication. 

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13.0  
ETHICS 
13.1  
Regulatory and Ethical Compliance 
The study will be conducted in compliance with the protocol, GCP and applicable 
regulatory requirement(s). 
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, European 
Directive 2001/20/EC, Novartis codes on protection of human rights, and with the ethical 
principles laid down in the Declaration of Helsinki (European Council 2001, US Code of 
Federal Regulations, ICH 1997). 
13.2  
Informed Consent Procedures 
Eligible subjects may only be included in the study after providing written informed 
consent or assent, as described in section 5.1.1. Before the start of the study, the 
investigator will have the informed consent and any other materials that will be provided 
to the subjects reviewed and approved by the IRB/EC. This review and approval will be 
documented and stored with other study documents. The investigator or designee must 
fully inform the subject or legal guardian of all pertinent aspects of the study. A copy of 
the written informed consent will be given to the subject or the designee. The 
subject/designee must be allowed ample time to ask about the details of the study and to 
make a decision as to whether or not to participate in the study. The subject and/or legal 
guardian(s) must sign the consent form indicating their agreement to participate in the 
study before any study-related procedures are conducted. The informed consent process 
may be conducted up to 23 days prior to vaccination on Day 1. If the subject is unable to 
read and write, a witness must be present during the informed consent discussion and at 
the time of informed consent signature. 
Prior to the start of the study, Novartis will provide to investigators a proposed informed 
consent form that complies with the ICH GCP guideline and regulatory requirements and 
is considered appropriate for this study. Any changes to the proposed consent form 
suggested by the investigator must be agreed to by Novartis before submission to the 
IRB/EC and a copy of the approved version must be provided to Novartis after IRB/EC 
approval. 
Women of childbearing potential should be informed that taking the study medication 
may involve unknown risks to the fetus if pregnancy were to occur during the study and 
agree that in order to participate in the study they must adhere to the contraception 

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requirements indicated in the protocol for the duration of the study. In case of doubt on 
the ability of a subject to adhere to these requirements, that subject should not be allowed 
in the study 
13.3  
Responsibilities of the Investigator and IRB/EC 
The protocol and the proposed informed consent form must be reviewed and approved by 
a properly constituted IRB/EC before study start. Properly constituted IRB/EC is defined 
in ICH Guideline for Good Clinical Practice E6 (R1), Section 3 (ICH, 1997). A signed 
and dated statement that the protocol and informed consent have been approved by the 
IRB/EC must be given to Novartis before study initiation. Prior to study start and at any 
time the protocol is amended during study conduct, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance 
with these documents and all of the instructions and procedures found in this protocol and 
to give access to all relevant data and records to Novartis monitors, auditors, Novartis 
Clinical Quality Assurance representatives, designated agents of Novartis, IRBs/ECs, and 
regulatory authorities as required. If an inspection of the clinical site is requested by a 
regulatory authority, the investigator must inform Novartis immediately that this request 
has been made. 
The investigator also responsible for the following: 
▫ Maintaining a list of appropriately qualified persons to whom the investigator has 
delegated significant study-related duties. 
▫ Demonstrating the capability of recruiting the required number of suitable subjects 
within the recruitment period. 
▫ Demonstrating sufficient time and staffing to properly conduct and complete the study 
within the agreed study period. 
▫ Ensuring that all persons assisting with the study are adequately informed about the 
protocol, the investigational product(s), and their study-related duties and functions 
▫ Ensuring that appropriately trained health care professionals are responsible for all 
study-related medical decisions and for ensuring appropriate medical care of subjects 
experiencing any adverse event related to the study. 
▫ If permission to do so is given by the subject, ensuring that the subject’s primary 
healthcare provider is informed of the subject’s participation in the study. 
The investigator should not implement any deviation from, or changes of the protocol 
without agreement by the Sponsor and prior review and documented approval/favourable 

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opinion from the IRB/IEC of an amendment, except where necessary to eliminate an 
immediate hazard(s) to study subjects, or when the change(s) involves only logistical or 
administrative aspects of the study (e.g., change in monitor(s), change of telephone 
number(s)). In addition, the investigator, or person designated by the investigator, should 
document and explain any deviation from the approved protocol. 
The investigator may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior IRB/IEC 
approval/favourable opinion. As soon as possible, the implemented deviation or change, 
the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be 
submitted: 
(a) to the IRB/IEC for review and approval/favourable opinion, 
(b) to the Sponsor for agreement and, if required, 
(c) to the regulatory authority(ies). 
13.4  
Protocol Amendments 
An amendment is a written description of change(s) to or formal clarification of a study 
protocol which may impact on the conduct of the clinical study, potential benefit of the 
clinical study, or may affect subject safety, including changes of study objectives, study 
design, subject population, sample sizes, study procedures, or significant administrative 
aspects. An administrative change of a study protocol is a minor correction or 
clarification that has no significant impact on the way the clinical study is to be conducted 
and no effect on subject safety (e.g., change of telephone number(s), logistical changes). 
Protocol amendments must be approved by Novartis, health authorities where required, 
and the IRB/EC. In cases when the amendment is required in order to protect the subject 
safety, the amendment can be implemented prior to IRB/EC approval. Notwithstanding, 
the need for formal approval of a protocol amendment, the investigator is expected to take 
any immediate action required for the safety of any subject included in this study, even if 
this action represents a deviation from the protocol. In such cases, Novartis should be 
notified of this action, the IRB/EC at the study site, and, if required by local regulations, 
the relevant health authority should be informed within 10 working days. 
14.0  
REFERENCE LIST 
Alving CR, Peachman KK, Rao M, Reed SG. Adjuvants for human vaccines. Curr Opin 
Immunol. 2012 Jun; 24(3):310-5 

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Bauza, A et al., Pemphigus-like lesions induced by imiquimod. Clin Exp Dermatol 2009, 
34, e60-62 
Bissett SL, Draper E, Myers RE, Godi A, Beddows S. Cross-neutralizing antibodies 
elicited by the Cervarix(®) human papillomavirus vaccine display a range of Alpha-9 
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Campanelli, A et al., Topical application of imiquimod and associated fever in children. J 
Am Acad Dermatol 2005,52, E1. 
Code of Federal Regulations (1997): Food and Drug Administration, U.S. Department of 
Health and Human Services: Title 21, Part 11: Electronic Records Electronic Signatures. 
Federal Register 62: 13464 
Connolly M and Noah N, Is group C meningococcal disease increasing in Europe? A 
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Del Giudice G, Fragapane E, Della Cioppa G, et al. Aflunov®: a vaccine tailored for 
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European Centre for Disease Prevention and Control. Surveillance of invasive bacterial 
diseases in Europe 2008/2009. Stockholm: ECDC 2011 
European Parliament (1995): Directive 95/46/EC of the European Parliament and of the 
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European Parliament (2001): Directive 2001/20/EC of the European Parliament and of the 
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Hellenbrand W, Elias J, Wichmann O et al. Epidemiology of invasive meningococcal 
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ICH (1997) ICH Harmonised Tripartite ICH Guideline for Good Clinical Practices E6  
(R1). Federal Register, 62 (90): 25691-25709 
ICH (1998) ICH Harmonised Tripartite ICH Guideline for Statistical Principles for 
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Ilyinskii, PO, et al., Adjuvant-carrying synthetic vaccine particles augment the immune 
response to encapsulated antigen and exhibit strong local immune activation without 
inducing systemic cytokine release. Vaccine, available online 1 March 2014. 
Khurana, S., W. Chearwae, F. Castellino, J. Manischewitz, L.R. King, A. Honorkiewicz, 
M.T. Rock, K.M. Edwards, G. Del Giudice, R. Rappuoli, and H. Golding. 2010. 
MF59adjuvanted vaccines expand antibody repertoires targeting protective sites of 
pandemic H5N1 influenza virus. Science Transl. Med. 2: 15ra5: 1-8. 
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Meyer, T et al., Clinical investigations of Toll-like receptor agonists. Expert Opin Investig 
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Recommendations of the Standing Committee on Vaccination (STIKO) at the Robert  
Koch Institute / Effective: August 2013; Robert Koch Institut Epidemiologisches Bulletin 
34, 26 August 2013 
Reed SG, Orr MT, Fox CB. Key roles of adjuvants in modern vaccines. Nat Med. 
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Regules JA, Cummings, JF and Ockenhouse CF. The RTS, S vaccine candidate for 
malaria. Expert Rev Vaccines 2011; 10:589-599. 
Rosenstein N, Perkins B, Stephens DS, et al. N. Engl. J. Med. 2001; 344: 1378-1388. 
Tacken, PJ et al., Targeted delivery of TLR ligands to human and mouse dendritic cells 
strongly enhances adjuvanticity. Blood 2011, 118:6836-6844. 
Takeda K, Kaisho T, Akira S Toll-like receptors. Annu.Rev.Immunol. 2003; 21: 335-76. 
U.S. Department of Health and Human Services, Food and Drug Administration, CBER  
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Vasilakos JP, and Tomai MA. The use of Toll-like receptor 7/8 agonists as vaccine 
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Brazil 
 

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APPENDIX A: GRADING SCALES FOR SOLICITED LOCAL ADVERSE  
EVENTS* 
(Adapted from CBER 2007b) 
Adverse event Following  
Administration of  
Injectable Product  
Mild (Grade 
1)  
Moderate 
(Grade 2)  
Severe 
(Grade 3)  
Pain 
present but does not 
interfere with activity 
interferes with activity 
prevents daily activity 
Induration / Swelling /  
Erythema 
25 – 50 mm 
51 – 100 mm  
> 100 mm  
*This toxicity grading scale is adapted from CBER 2007 to enable ease of reporting by Subjects in the 
source documents for ‘patient reported’ solicited adverse events. This toxicity grading scale is a Novartis 
standard that is used for patient reporting. ‘Grade 4’ is not listed here but will be defined in the Statistical 
Analysis Plan as necessary. 
 

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APPENDIX B: GRADING SCALES FOR SOLICITED SYSTEMIC ADVERSE  
EVENTS* 
(Adapted from CBER 2007b) 
Systemic  
Adverse event 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Fever 
°C 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 - 102 
39.0 – 40 
102.1 - 104 
°F 
Chills 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Loss of Appetite 
Loss of appetite without 
decreased oral intake  
decreased oral intake  
without weight loss 
decreased oral intake with 
weight loss 
Nausea 
Nausea present but not 
interfering with oral intake 
Nausea leading to decreased 
oral intake 
Nausea leading to minimal to 
no oral intake 
Vomiting 
1-2 episodes/24 hours 
>2 episodes/24 hours 
requires outpatient 
hydratation 
Diarrhea 
2-3 loose stools /24 hours 
4-5 loose stools /24 hours 
6 or more watery stools /24 
hours or requires outpatient 
IV hydration 
Generalized  
Myalgia 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Generalized  
Arthralgia 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Headache 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Fatigue 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Generalized  
Rash 
localized area of the skin (1 
extremity only) 
moderate area of the skin 
(2 or more body regions 
without whole body 
involvement) 
most of the skin 
Urticaria 
localized area of the skin (1 
extremity only) 
moderate area of the skin 
(2 or more body regions 
without whole body 
involvement) 
most of the skin 
*This toxicity grading scale is adapted from CBER 2007b to enable ease of reporting by Subjects in the 
source documents for ‘patient reported’ solicited adverse events. This toxicity grading scale is a Novartis 

Novartis Vaccines and Diagnostics  Protocol V132_01EXP 10 SEP 14 Version 2 Confidential 
Page 
107 of 103 
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Version No. 2 / Version Date: December 2, 2013 
standard that is used for patient reporting. ‘Grade 4’ is not listed here but will be defined in the statistical 
analysis plan as necessary 

Novartis Vaccines and Diagnostics  
Protocol V132_01EXP 
10 SEP 14 Version 2 
Confidential 
Page 108 of 103 
TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
PRO-01 TEMP 06 / Atlas No. 293620 
Version No. 2 / Version Date: December 2, 2013 
APPENDIX C:  
(SERUM CLINICAL CHEMISTRY)  
Serum*,** 
Mild (Grade 1)  
Moderate 
(Grade 2)  
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)*** 
Sodium – Hyponatremia 
mEq/L  
132 – 134  
130 – 131  
125 – 129  
< 125  
Sodium – Hypernatremia 
mEq/L  
144 – 145  
146 – 147  
148 – 150  
> 150  
Potassium – Hypokalemia 
mEq/L  
3.5 – 3.6  
3.3 – 3.4  
3.1 – 3.2  
< 3.1  
Potassium – Hyperkalemia 
mEq/L  
5.1 – 5.2  
5.3 – 5.4  
5.5 – 5.6  
> 5.6  
Blood Urea Nitrogen  
BUN mg/dL  
23 – 26  
27 – 31  
> 31  
Requires dialysis  
Creatinine – mg/dL  
1.5 – 1.7  
1.8 – 2.0  
2.1 – 2.5  
> 2.5 or requires 
dialysis  
Liver Function Tests –ALT,  
AST  
increase by factor  
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN  
5.1 – 10 x ULN  
> 10 x ULN  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 

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10 SEP 14 Version 2 
Confidential 
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TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
PRO-01 TEMP 06 / Atlas No. 293620 
Version No. 2 / Version Date: December 2, 2013 
**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 
***The clinical signs or symptoms associated with laboratory abnormalities might result in characterization 
of the laboratory abnormalities as Potentially Life Threatening (Grade 4). For example. a low sodium value 
that falls within a grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia event if 
the subject had a new seizure associated with the low sodium value. “ULN” = the upper limit of the normal 
range. 
APPENDIX D:  
(HEMATOLOGY) 
Hematology*,** 
Mild (Grade 
1)  
Moderate  
(Grade 2)  
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)  
Hemoglobin (Female) 
gm/dL  
11.0 – 12.0  
9.5 – 10.9  
8.0 – 9.4  
< 8.0  
Hemoglobin (Female) 
change from baseline 
value - gm/dL  
Any decrease – 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
Hemoglobin (Male) 
gm/dL  
12.5 – 13.5  
10.5 – 12.4  
8.5 – 10.4  
< 8.5  
Hemoglobin (Male) 
change from baseline 
value – gm/dL  
Any decrease – 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
WBC Increase - cell/mm3 
10,800 – 15,000  
15,001 – 20,000  
20,001 – 25, 000  
> 25,000  
WBC Decrease cell/mm3 
2,500 – 3,500  
1,500 – 2,499  
1,000 – 1,499  
< 1,000  

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10 SEP 14 Version 2 
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TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
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Platelets Decreased 
cell/mm3 
125,000 – 140,000 
100,000 – 124,000 
25,000 – 99,000  
< 25,000  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate.  
**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 
APPENDIX E:  
(URINE) 
Urine*,** 
Mild (Grade 
1)  
Moderate  
(Grade 2)  
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)  
Protein  
Trace  
1+  
2+  
Hospitalization or 
dialysis  
Glucose  
Trace  
1+  
2+  
Hospitalization for 
hyperglycemia  
Blood (microscopic) – 
red blood cells per high 
power field (rbc/hpf)  
1 - 10  
11 – 50  
> 50 and/or gross 
blood  
Hospitalization or 
packed red blood 
cells (PRBC) 
transfusion  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 
**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 

 
 
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Novartis Vaccines  
Clinical Study Protocol V132_01EXP Amendment 2 
17 DEC 14 
Confidential 
Page 1 of 2 
 
CLINICAL STUDY PROTOCOL AMENDMENT 
Study Number: V132_01EXP 
Protocol Title:  A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study 
to Evaluate the Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R 
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium  
Hydroxide Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy 
Adults (18-45 years of age) 
Amendment Number 2 
Revised Protocol version 3.0 issued on 17 DEC 2014 
The present amendment reflects changes to the Protocol version 2.0 issued on 
10SEP14   
Property of Novartis Vaccines  
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of Novartis Vaccines 

 
 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 
Novartis Vaccines 
Clinical Study Protocol V132_01EXP Amendment 2 
17 DEC 14 
Page 2 of 2 
 
DESCRIPTION OF CHANGE(S) AND RATIONALE: 
CHANGE 
LOCATION(S) OF  
CHANGE 
RATIONALE FOR  
CHANGE 
Escalation of the LHD153 
dosage will be based on 
DMC review of Day 14  
safety results of the first 5 
subjects in the previous 
dosage cohort. Furthermore, 
all available Day 14 and 
Day 29 safety results will be 
included in DMC reviews 
between the different 
enrollment stages. 
Previously escalation to the 
next dosage was based on 
DMC review of Day 29 
safety data of the entire 
previous dosage cohort.         
Synopsis, 
Study 
Design 
(Page 11; Table 2) 
Synopsis, Data Monitoring 
Committee (Page 18-19)  
Section 3.1 ‘Study Design’  
(Page 32; Table 3.1-2)   
Section 3.7 ’Data  
Monitoring Committee’  
(Page 38)   
 
Opportunity to reduce the 
enrollment period by 
reducing the number of 
DMC reviews without 
impact on subject safety 
(i.e. no change in 
enrollment rate of first 5 
subjects, no change in 
criteria of enrollment of the 
remaining 15 subjects in 
each cohort, no change in 
the safety assessments, no 
change in stopping rules). 
Deletion of ‘complement 
fixing capacity’ from the list 
of prioritized antibody 
functionality assessments as  
part of Exploratory 
Endpoint #4.    
Synopsis, Exploratory 
Endpoint #4, Page 17 
Section 7.4 ‘Exploratory  
Measurements’ (Page 74) 
Section 8.1.3 ‘Exploratory  
Endpoints’ (Page 76) 
Antibody 
functionality 
assessments 
as 
part 
of 
Exploratory Endpoints will 
be performed on serum 
samples that are left-over 
from 
the 
primary 
and 
secondary immunogenicity 
end-point 
assessments.   
“Complement 
fixing 
capacity” has been deleted 
from the list of prioritized 
assessments as it is not 
essential for determining the 
antibody functionality and 
we may experience limited 
quantity of serum available 
for this analysis. 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 

 
 
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PRO-01 TEMP 06 / Atlas No. 293620 
Version No. 2 / Version Date: December 2, 2013 
CLINICAL STUDY PROTOCOL V132_01EXP Version 3 
A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study to Evaluate the 
Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R Adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium Hydroxide  
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy Adults (18-45 
years of age) 
EUDRACT No. 2014-002430-31 
Property of Novartis Vaccines and Diagnostics (hereafter referred to as Novartis) 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of Novartis. 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................ 2 
PROTOCOL SYNOPSIS V132_01EXP.......................................................................... 7 
LIST OF ABBREVIATIONS........................................................................................ 23 
1.0  
BACKGROUND AND RATIONALE............................................................... 25 

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1.1  
Background.................................................................................................... 25 
 
1.2  
Rationale........................................................................................................ 28 
2.0  
OBJECTIVES.................................................................................................... 29 
 
2.1  
Primary Objectives......................................................................................... 29 
 
2.2  
Secondary Objectives..................................................................................... 29 
 
2.3  
Exploratory Objectives................................................................................... 29 
3.0  
STUDY DESIGN .............................................................................................. 31 
 
3.1  
Overview of Study Design............................................................................. 31 
 
3.2  
Study Period .................................................................................................. 32 
 
3.3  
Blinding Procedures....................................................................................... 33 
 
3.4  
Data Collection.............................................................................................. 33 
 
3.4.1  
Data Collected from Subjects ................................................................. 33 
 
3.4.2  
Tools Used for Data Collection .............................................................. 34 
 
3.5  
Collection of Clinical Specimens ................................................................... 35 
 
3.6  
Stopping/Pausing Guidelines.......................................................................... 37 
 
3.7  
Data Monitoring Committee........................................................................... 38 
 
3.8  
Premature Withdrawal from Study................................................................. 38 
 
3.9  
End of Study.................................................................................................. 41 
4.0  
SELECTION OF STUDY POPULATION......................................................... 42 
 
4.1  
Inclusion Criteria ........................................................................................... 42 
 
4.2  
Exclusion Criteria .......................................................................................... 42 
 
4.3  
Criteria for Delay of Vaccination or Blood Draw........................................... 44 
5.0  
STUDY PROCEDURES ................................................................................... 45 
 
5.1  
Pre-vaccination Clinic Visit(s) ....................................................................... 45 
 
5.1.1  
Informed Consent................................................................................... 45 
 
5.1.2  
Screening ............................................................................................... 46 
 
5.2  
Vaccination Clinic Visit(s)............................................................................. 47 

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5.2.1  
Pre-vaccination Procedures..................................................................... 47 
 
5.2.2  
Enrolment .............................................................................................. 48 
 
5.2.3  
Randomization ....................................................................................... 48 
 
5.2.4  
Vaccination............................................................................................ 49 
 
5.2.5  
Post-vaccination Procedures................................................................... 49 
 
5.3  
Post-vaccination Visit(s) ................................................................................ 50 
 
5.3.1  
Subject Diary Reminder, Safety Follow-up and/or Post-vaccination Blood  
Draw Clinic Visits ................................................................................................. 50 
 
5.3.2  
Safety Follow-up Calls........................................................................... 54 
 
5.4  
Unscheduled Visits ........................................................................................ 54 
 
5.5  
Study Termination Visit................................................................................. 54 
 
5.5.1  
Early Termination Visit.......................................................................... 55 
6.0  
TREATMENT OF SUBJECTS.......................................................................... 57 
 
6.1  
Study Vaccine(s)............................................................................................ 57 
 
6.2  
Non-Study Vaccines ...................................................................................... 60 
 
6.3  
Vaccine Preparation and Administration ........................................................ 60 
 
6.4  
Vaccine Administration Error or Overdose of Vaccine................................... 61 
 
6.5  
Prior and Concomitant Medications and Vaccines.......................................... 61 
 
6.6  
Vaccine Supply, Labeling, Storage and Tracking ........................................... 61 
7.0  
ASSESSMENTS................................................................................................ 64 
 
7.1  
Safety Assessment ......................................................................................... 64 
 
7.1.1  
Solicited Adverse Events........................................................................ 64 
 
7.1.2  
Unsolicited Adverse Events.................................................................... 66 
 
7.1.3  
Evaluation of Adverse Events................................................................. 66 
 
7.1.4  
Serious Adverse Events.......................................................................... 67 
 
7.1.4.1  
Adverse Events of Special Interest...................................................... 69 
 
7.1.5  
Methods for Recording Adverse Events and Serious Adverse Events ..... 70 

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7.1.5.1  
Post-Study Events .............................................................................. 71 
 
7.1.6  
Pregnancies............................................................................................ 71 
 
7.1.7  
Safety Laboratory Measurements ........................................................... 71 
 
7.2  
Efficacy Assessment ...................................................................................... 72 
 
7.3  
Immunogenicity Assessment.......................................................................... 72 
 
7.4  
Exploratory Measurements............................................................................. 73 
8.0  
STATISTICAL CONSIDERATIONS................................................................ 75 
 
8.1  
Endpoints....................................................................................................... 75 
 
8.1.1  
Primary Endpoint(s)............................................................................... 75 
 
8.1.1.1  
Primary Safety Endpoint(s) ................................................................ 75 
 
8.1.1.2  
Primary Efficacy Endpoint(s) ............................................................. 75 
 
8.1.1.3  
Primary Immunogenicity Endpoint(s)................................................. 75 
 
8.1.2  
Secondary Endpoint(s) ........................................................................... 75 
 
8.1.2.1  
Secondary Safety Endpoint(s)............................................................. 75 
 
8.1.2.2  
Secondary Efficacy Endpoint(s) ......................................................... 76 
 
8.1.2.3  
Secondary Immunogenicity Endpoint(s)............................................. 76 
 
8.1.3  
Exploratory Endpoint(s)......................................................................... 76 
 
8.2  
Success Criteria ............................................................................................. 77 
 
8.2.1  
Success Criteria for Primary Objective(s)............................................... 77 
 
8.2.2  
Success Criteria for Secondary Objective(s) ........................................... 77 
 
8.3  
Analysis Sets ................................................................................................. 77 
 
8.3.1  
All Enrolled Set...................................................................................... 77 
 
8.3.2  
All Exposed Set...................................................................................... 77 
 
8.3.3  
Safety Set............................................................................................... 77 
 
8.3.4  
Full Analysis Set (FAS) Efficacy/Immunogenicity Set ........................... 78 
 
8.3.5  
Per Protocol (PP) Set Efficacy/Immunogenicity Set................................ 78 
 
8.3.6  
Other Analysis Sets................................................................................ 79 

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8.3.7  
Subgroups.............................................................................................. 79 
 
8.3.8  
Protocol Deviations................................................................................ 79 
 
8.4  
Statistical Analysis Plan................................................................................. 79 
 
8.4.1  
Analysis of Demographic and Baseline Characteristics........................... 79 
 
8.4.2  
Analysis of Primary Objective(s)............................................................ 79 
 
8.4.2.1  
Analysis of Primary Safety Objective(s)............................................. 79 
 
8.4.2.1.1  
Analysis of Extent of Exposure.................................................... 80 
 
8.4.2.1.2  Analysis of Solicited Local, Systemic and Other Adverse Events. 80 
 
8.4.2.1.3  
Analysis of Unsolicited Adverse Events....................................... 81 
 
8.4.2.1.4  
Analysis of Safety Laboratory Values .......................................... 81 
 
8.4.2.2  
Analysis of Primary Efficacy Objective(s).......................................... 82 
 
8.4.2.3  
Analysis of Primary Immunogenicity Objective(s) ............................. 82 
 
8.4.2.3.1  
Statistical Hypotheses .................................................................. 82 
 
8.4.2.3.2  
Analysis Sets................................................................................ 82 
 
8.4.2.3.3  
Statistical Methods....................................................................... 82 
 
8.4.3  
Analysis of Secondary Objective(s)........................................................ 83 
 
8.4.3.1  
Analysis of Secondary Safety Objective(s) ......................................... 83 
 
8.4.3.2  
Analysis of Secondary Efficacy Objective(s)...................................... 83 
 
8.4.3.3  
Analysis of Secondary Immunogenicity Objective(s).......................... 84 
 
8.4.3.3.1  
Statistical Hypotheses .................................................................. 84 
 
8.4.3.3.2  
Analysis Sets................................................................................ 84 
 
8.4.3.3.3  
Statistical Methods....................................................................... 84 
 
8.4.4  
Analysis of Exploratory Objectives ........................................................ 85 
 
8.5  
Sample Size and Power Considerations of Primary Objectives....................... 85 
 
8.6  
Interim Analysis............................................................................................. 86 
9.0  
SOURCE DOCUMENTATION, STUDY MONITORING AND AUDITING... 87 
 
9.1  
Source Documentation................................................................................... 87 

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9.2  
Study Monitoring, Auditing and Source Data Verification ............................. 88 
10.0  
DATA MANAGEMENT................................................................................... 89 
 
10.1  
Data Entry and Management.......................................................................... 89 
 
10.2  
Data Clarification........................................................................................... 89 
 
10.3  
Data Protection .............................................................................................. 89 
11.0  
RECORD RETENTION.................................................................................... 91 
12.0  
USE OF INFORMATION AND PUBLICATION ............................................. 92 
13.0  
ETHICS............................................................................................................. 93 
 
13.1  
Regulatory and Ethical Compliance ............................................................... 93 
 
13.2  
Informed Consent Procedures ........................................................................ 93 
 
13.3  
Responsibilities of the Investigator and IRB/EC............................................. 94 
 
13.4  
Protocol Amendments.................................................................................... 95 
14.0  
REFERENCE LIST........................................................................................... 96 
APPENDIX A:  
GRADING SCALES FOR SOLICITED LOCAL ADVERSE  
EVENTS 
....................................................................................................... 99 
APPENDIX B:  
GRADING SCALES FOR SOLICITED SYSTEMIC ADVERSE  
EVENTS 
..................................................................................................... 100 
APPENDIX C:  
TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(SERUM CLINICAL CHEMISTRY).......................................................................... 101 
APPENDIX D:  
TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(HEMATOLOGY) ..................................................................................................... 102 
APPENDIX E:  
TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(URINE) 
..................................................................................................... 103 
PROTOCOL SYNOPSIS V132_01EXP 

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Version No. 2 / Version Date: December 2, 2013 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Title of Study: A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study to  
Evaluate the Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R 
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium  
Hydroxide Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy Adults 
(18-45 years of age) 
Study Period: Approximately 12 months for 
each subject 
Clinical Phase: Phase 1 
Background and Rationale: 
Neisseria meningitidis (N. meningitides)serogroup C (MenC) is one of the major 
serogroups causing invasive meningocococcal disease. Case fatality in Germany has 
ranged between 6% and 8% between 1999 and 2006, and has remained generally 
consistent across the different European countries, varying between 6-11%, with the case 
fatality rate being notably higher for serogroup C disease than for serogroup B. The 
safety and immunogenicity of the Novartis Meningococcal C-CRM197 Conjugate 
Vaccine (Menjugate®) has been confirmed through years of commercial use. For children 
over the age of 12 months, for adolescents and for adults a single dose is recommended. 
For infants between 2 and 12 months of age, the recommended schedule for primary 
immunization with the Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) is 
two doses given with an interval of at least 2 months (Novartis Meningococcal C-
CRM197 Conjugate Vaccine Investigator Brochure). 
A more potent Meningococcal C-CRM197 Conjugate Vaccine formulation might enable a 
reduction of the antigen dosage and/or a reduction in the number of doses needed in 
infants. One approach to achieve more potent well-characterized sub-unit vaccines - like 
the Novartis Meningococcal C-CRM197 Conjugate Vaccine - is the use of new adjuvants 
that activate the Toll-like receptor (TLR) pathway. 
Novartis is developing a small molecule immune potentiator (SMIP) LHD153 that is an 
agonist for  TLR7. The objective driving the development of LHD153 is to achieve a 
vaccine adjuvant with strong immunopotentiating properties and minimal side effects. In 

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line with this objective, it has been postulated that the ideal SMIP should remain local 
and target innate immune cells at the injection site. To this end, LHD153 contains a  
 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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functional phosphonate group to allow for adsorption to aluminium hydroxide. The 
arginine salt derivative of this compound is LHD153R. Preclinical results from animal 
models for bacterial and viral antigens, including MenC, MenB, rabies, HIV and 
respiratory syncytial virus (RSV) showed increased functional antibodies and 
antigenspecific T-cells with LHD153R adsorbed to aluminium hydroxide (Aluminium  
Hydroxide/LHD153R) when compared to aluminium hydroxide adjuvanted controls. In 
vitro toxicity screens confirmed that LHD153R is not phototoxic, genotoxic or 
mutagenic. Furthermore, toxicology studies in dog and rats showed that intramuscular 
(IM) injection of Aluminium Hydroxide/LHD153R was well tolerated. Importantly, in 
contrast to free LHD153R, toxicokinetic analysis in rats and dogs confirmed very 
limited exposure of LHD153 when LHD153R was adsorbed to aluminium hydroxide 
after IM injection. 
The aim of this Phase 1 clinical study is to assess the safety of Aluminium  
Hydroxide/LHD153R adjuvanted MenC-CRM197 conjugate vaccine 
(MenCCRM197/Aluminium Hydroxide/LHD153R) and to compare the antibody-
mediated immune response elicited by MenC-CRM197/Aluminium Hydroxide/LHD153R 
with the licensed aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate 
Vaccine (Menjugate®). Furthermore, a comprehensive set of exploratory objectives has 
been selected to assess the systemic exposure of LHD153 after intramuscular injection of 
MenC-CRM197/Aluminium Hydroxide/LHD153R, to evaluate the quality of the specific 
immune response against MenC-CRM197 in detail and to evaluate  biomarkers that may 
be predictive of safety and/or innate immune activation. 
The licensed Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) has been 
selected as the primary vaccine candidate to assess the safety and immunopotentiating 
properties of Aluminium Hydroxide/LHD153R for several reasons. Firstly, the safety 
and immunogenicity profiles of the Meningococcal C-CRM197 Conjugate Vaccine 
(Menjugate®) have been well established through years of commercial use. Secondly, a 
more potent MenC-CRM197 conjugate vaccine might enable a reduction of the antigen 
dosage or the number of doses needed in infants. Finally, the MenC-CRM197 conjugate 
is a well-characterized, single antigen preparation which provides an ideal setting to 
evaluate the potential of this new Aluminium Hydroxide/LHD153R adjuvant. 
 

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Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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Study Objectives: 
Primary Safety Objective: 
To assess the safety of MenC-CRM197/Aluminium Hydroxide/LHD153R as compared to 
that of aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
Primary Immunogenicity Objective: 
To compare the antibody responses of MenC-CRM197/Aluminium Hydroxide/LHD153R 
and aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at 
Day 29, as measured by human complement serum bactericidal assay (hSBA) directed 
against MenC. 
Secondary Immunogenicity Objectives: 
1. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine, at Day 8 and Day 181 after vaccination, as measured 
by hSBA directed against MenC. Baseline antibody titers will also be measured by 
hSBA. 
2. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine at Day 8, Day 29 and Day 181 after vaccination, as 
measured by an enzyme-linked immunosorbent assay (ELISA) to MenC. Baseline 
antibody concentrations will also be measured by ELISA. 
Exploratory Objectives: 
1. To evaluate the systemic exposure of LHD153 at several early time-points after IM 
injection of MenC-CRM197/Aluminium Hydroxide/LHD153R or aluminium 
hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
2. To explore the frequency of B cells specific for MenC polysaccharide and CRM197 
protein at baseline (Day 1) and at Day 8, Day 29 and Day 181 after vaccination with  
 

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Version No. 2 / Version Date: December 2, 2013 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
MenC-CRM197/Aluminium Hydroxide/LHD153R or the aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. Subsequently, the B cell 
repertoire of the antigen specific B cells and the specific antibody functionality will 
be analyzed in a selected subset of subjects. 
3. To explore the baseline T cell mediated immunity to CRM197 and to evaluate the 
frequency and quality of CRM197 specific T cells induced by MenC- 
CRM197/Aluminium Hydroxide/ LHD153R compared to aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at Day 8 and Day 29. 
4. To evaluate biomarkers that may be predictive for safety and/or innate immune 
activation. 

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Study Design: 
This Phase 1, randomized, observer-blind, dosage-escalation study will be performed at 
a single center. In total, approximately 80 healthy male and healthy non-pregnant female 
adults (18-45 years of age) will be enrolled in the study. Subjects will be randomized to 
receive a single IM vaccination of either the licensed aluminium hydroxide adjuvanted 
Meningococcal C-CRM197 Conjugate Vaccine (i.e. 10 µg MenC conjugated to CRM197,  
adjuvanted with 1 mg aluminium hydroxide) or one of four dosages of the 
investigational vaccine, MenC-CRM197/Aluminium Hydroxide/LHD153R (i.e. 10 µg 
MenC conjugated to CRM197,  adjuvanted with 1 mg aluminium hydroxide and one of 
four dosages [12.5, 25, 50 or 100 µg] of LHD153R). 
For the dosage-escalation of LHD153R, the subjects will be enrolled into 1 of 4 cohorts, 
in a stepwise manner with 20 subjects per cohort. Subjects in all cohorts will be 
randomized in a 1:4 ratio, to receive either aluminium hydroxide adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine (control) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R with increasing doses of LHD153R.Cohort 1 will receive 12.5 μg 
of LHD153R; Cohort 2 will receive 25 μg of LHD153R; Cohort 3 will receive 50 μg of 
LHD 153; and Cohort 4 will receive 100 μg of LHD153R (Table 1). 
 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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Table 1. Subjects Randomized per Cohort and Treatment Dose Group 
Cohort 
Group 
Subjects/ 
Group 
MenC  
Dosage*  
(µg) 
Adjuvant Dosages  
Total 
Volume/Dose 
Total 
Subjects/Group 
Aluminium  
Hydroxide  
(mg) 
LHD153R  
(µg) 
1 
A 
4 
10 
1 
0 
0.5 mL 
20 
B 
16 
10 
1 
12.5 
0.5 mL 
2 
A 
4 
10 
1 
0 
0.5 mL 
20 
C 
16 
10 
1 
25 
0.5 mL 
3 
A 
4 
10 
1 
0 
0.5 mL 
20 
D 
16 
10 
1 
50 
0.5 mL 
4 
A 
4 
10 
1 
0 
0.5 mL 
20 
E 
16 
10 
1 
100 
0.5 mL 
*Conjugated to 12.5-25 µg CRM197 
After vaccination, all subjects will be confined to the clinical site for 24 hours for 
clinical observation, including but not limited to observations for solicited and 
unsolicited adverse events, body temperature measurements and blood sampling for 
exploratory endpoint measurements. 
Importantly, all cohorts will have a staggered entry based on Data Monitoring 
Committee (DMC) reviews. 
▫ For each cohort, the first 5 subjects (i.e. the first 1:4 randomization block) to receive 
either aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate 
Vaccine (n=1) or MenC-CRM197/Aluminium Hydroxide/LHD153R (n=4) will be 
treated at a vaccination rate of 1 subject each day. 
▫ After entry of the first 5 subjects in each cohort, the enrollment will be paused. The 
remaining 15 subjects for each cohort will be enrolled only after DMC review of the 
safety results obtained through Day 14 has been finalized (Table 2). 
▫ In addition, enrollment of the first 5 subjects in the next cohort will only proceed after 
the Day 14 safety results of the first 5 subjects of the previous cohort have been 
reviewed by the DMC (Table 2). 
 

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Version No. 2 / Version Date: December 2, 2013 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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▫ Furthermore, all available Day 14 and Day 29 safety results will be included in DMC 
reviews between the different enrollment stages. 
Table 2. Overview of staggered entry of subjects based on DMC reviews 
Stage 
Dosage Cohort 
MenC-CRM197/ 
Aluminium Hydroxide (n) 
MenC-CRM197/ 
Aluminium Hydroxide 
/LHD153R (n) 
1   
1  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 14 Safety Results 
2 
1  
3 
12 
2  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 29 and Stage 2 Day 14 Safety Results 
3 
2  
3 
12 
3  
1 
4 
Enrollment pause until DMC review of Stage 2 Day 29 and Stage 3 Day 14 Safety Results 
4 
3  
3 
12 
4  
1 
4 
Enrollment pause until DMC review of Stage 3 Day 29 and Stage 4 Day 14 Safety Results 
5 
4  
3 
12 
The DMC review will be performed according to predefined stopping/pausing guidelines 
used to ensure the safety of study subjects. These stopping/pausing guidelines are based 
on FDA guidance and with grading scales from the CBER Guidance for Industry 
“Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials”. See protocol section 3.6 for further details. 
Safety Measurements 
Schedule of safety data collection: 
▫ Solicited local and systemic adverse events (AEs), body temperature and all 
unsolicited AEs will be collected until Day 14. 
▫ All serious adverse events (SAEs), medically attended AEs, AEs leading to study 
withdrawal, new onset of chronic disease (NOCDs), and adverse events of special  
 

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Version No. 2 / Version Date: December 2, 2013 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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interest (AESIs) will be collected from the date of signed informed consent to study 
completion at Day 366. 
▫ All concomitant medications administered in relation to the reported AEs will be 
collected from vaccination to study completion at Day 366. 
Solicited local AEs include injection site erythema, injection site induration, injection 
site pain and injection site swelling. Solicited systemic AEs include body temperature ≥ 
38.0°C (as measured orally), loss of appetite, nausea, fatigue, generalized myalgia, 
generalized arthralgia, headache, chills, vomiting, diarrhea, generalized rash and 
urticaria. 
All AESIs will be reported in the same manner as SAEs. All AEs will be monitored until 
resolution or, if the AE becomes chronic, a cause is identified. If an AE is unresolved at 
the conclusion of the study, a clinical assessment will be made by the investigator and 
the medical monitor to determine whether or not continued follow-up of the AE is 
warranted. 
The relationship of the study treatment to any AE will be determined by the investigator 
as probably related, possibly related, or not related; the relationship of the study 
treatment to any SAE will be determined by the investigator as probably 
related/suspected, or not related. 
Safety Laboratory Parameters 
To assess laboratory AEs, blood and urine samples will be collected from each subject as 
outlined in Table 3 to perform blood chemistry, hematology, and urine analyses. 
Safety laboratory samples will be drawn from all subjects at pre-vaccination screening 
(between Day -28 and Day -3) at Day 1 (pre-vaccination), at Day 8 and at Day 29. Safety 
laboratory assessments will include sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, liver function tests (ALT, AST), a complete blood count and C-
reactive protein. A urine sample will be collected at the same time-points and will be 
assessed for the presence of protein, glucose and red blood cells. 
 

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Version No. 2 / Version Date: December 2, 2013 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Primary and Secondary Immunogenicity Measurements 
Four blood samples per subject (i.e. at Day 1, Day 8, Day 29 and Day 181) will be 
collected for serum preparation and determination of antibody-mediated immune 
responses to MenC-CRM197 as outlined in Table 3 and Table 4. See section 7.3 for 
further details. 
Exploratory Measurements 
In all subjects who agree by signing a separate Informed Consent, additional blood 
samples will be collected at Day 1, Day 4, Day 8, Day 29 and Day 181 for exploratory 
assays as outlined in Table 3 and Table 4. The purpose of these assays is to assess the 
systemic exposure of LHD153, to determine the frequency and quality of B- and T-cells 
specific for MenC polysaccharide and/or CRM197 and to evaluate biomarkers that may 
be predictive of safety and/or innate immune activation. Subsequently, MenC-CRM197 
specific B-cell repertoires as well as the MenC-CRM197 specific antibody functionalities 
will be analyzed in a selected subset of subjects, dependent on the results from primary 
and secondary immunogenicity measurements and the volume of whole blood (specific 
B cell repertoire) and serum (specific antibody functionality) remaining for additional 
testing. See section 7.4 for further details. All exploratory analyses may be performed 
after the Clinical Study Report (CSR) has been completed, in which case these data will 
be submitted as an addendum to the CSR. 
Number of Subjects planned: 
Approximately 80 adult subjects will be randomized, with anticipated dropout rates of 
5% by Day 181 (last serology time point), and 10%, by Day 366 (last safety time point). 
Sample size is not driven by statistical assumptions for formal hypothesis testing, but the 
proposed number of subjects will be sufficient to provide a descriptive summary of the 
safety and immunogenicity of the study vaccine. 

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Version No. 2 / Version Date: December 2, 2013 
Study Population and Subject Characteristics: 
Healthy adult male and female volunteers between 18-45 years of age, inclusive. 
The list of inclusion and exclusion criteria is included in protocol section 4.0. 
 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Study Vaccines: 
The MenC-CRM197 conjugate is a lyophilized powder consisting of 10 µg of MenC 
polysaccharide conjugated to 12.5-25 µg CRM197 carrier protein. The MenC-CRM197 
lyophilized powder will be reconstituted with adjuvant by the unblinded designated site 
staff member who is to follow the procedure as described in the vaccine preparation 
instructions in the Investigator Site File (i.e. the vaccine will be prepared in the clinic 
prior to administration). 
The lyophilized MenC-CRM197 powder will be reconstituted with either: 
(a) aluminium hydroxide adjuvant 
(b) Aluminium Hydroxide/LHD153R adjuvant with specified dosages of LHD153R 
(12.5, 25, 50 or 100 µg) 
The components for each formulation of MenC-CRM197 will be provided in a separate 
kit. 
Aluminium Hydroxide/LHD153R with specified dosages of LHD153R will be prepared  
by dilution of the highest Aluminium Hydroxide/LHD153R dosage (100 µg of 
LHD153R) with aluminium hydroxide. 
In each cohort, subjects will be randomized to receive one injection of MenC- 
CRM197/Aluminium Hydroxide/LHD153R adjuvant or aluminium hydroxide adjuvanted  

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Meningococcal C-CRM197 Conjugate Vaccine. The 0.5 mL of vaccine will be injected 
IM in the deltoid muscle, with preference that the injection is administered in the 
nondominant arm. 
Primary Safety Endpoint: 
Safety will be assessed by measuring the frequency of local and systemic solicited AEs, 
unsolicited AEs, SAEs, AESIs, NOCDs, and safety laboratory data for all subjects.  
Specifically, 
▫ The frequency and percentage of subjects with solicited local and systemic AEs 
through Day 14. Time intervals after vaccination that will be summarized are: 30 
min post-vaccination, Days 1-4 (without 30 min), Days 5-8, Days 8-14, Days 1-8 
 

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Version No. 2 / Version Date: December 2, 2013 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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(without 30 min) and Days 1-14 (without 30 min). 
▫ The frequency and percentage of subjects with any unsolicited AEs from the day of 
vaccination (Day 1) to Day 14. 
▫ The frequency and percentage of subjects with SAEs, medically attended AEs,  AEs 
leading to study withdrawal, NOCDs, AESIs for the following time periods: day of 
signed informed consent until study completion (Day 366), day of vaccination (Day 
1) to Day 29 and Day 29 to study completion (Day 366). 
▫ The absolute values and changes in hematology, chemistry, and urinalysis parameters. 
▫ The frequency and percentage of subjects with abnormal laboratory parameter values 
as classified by investigator normal ranges (low, normal, high) and as classified by 
CBER toxicity grading scales, when available. 
Primary Immunogenicity Endpoint: 
Geometric mean titers (GMTs) measured by hSBA directed against MenC from samples 
collected on Day 1 (baseline, before vaccination) and Day 29 as well as the GMR of the 
titers (Day 29 / Day 1). 
Secondary Immunogenicity Endpoints: 
▫ GMTs and corresponding GMRs measured by hSBA directed against MenC for samples 
collected at Day 8 and Day181. 
▫ Percentage of subjects with hSBA seroresponse at Day 8, Day 29, and Day 181. 
seroresponse is defined as a post vaccination hSBA ≥8 for subjects with a baseline 
hSBA <4 or have an increase of at least 4 times the baseline hSBA level for subjects 
with pre-vaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against MenC measured by ELISA 
for samples collected on Day 1 (baseline, prior to vaccination), Day 8, Day 29, and 
Day 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations 
to MenC measured by ELISA on Day 8, Day 29, and Day 181 relative to baseline 
 

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Version No. 2 / Version Date: December 2, 2013 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
(Day 1). 
Exploratory Endpoints: 
Testing and analyses of exploratory endpoints may be performed after the Clinical Study 
Report (CSR) has been completed, in which case these data will be submitted as an 
addendum to the CSR. 
1. Serum concentration of LHD153 at Day 1 baseline (prior to vaccination), Day 1 (1h , 
2h, 4h, 8h, and 24h after vaccination) and Day 4 by LC-MS/MS. 
2. Frequency of MenC polysaccharide-specific and CRM197-specific B cells at Day 1 
(baseline), Day 8, Day 29, and Day 181 by ELISPOT. 
3. Diversity of the MenC polysaccharide-specific B-cell repertoire at Day 1 (baseline), 
Day 8, Day 29, and Day 181 by immunoglobulin cDNA sequencing. 
4. Functionality of antigen specific antibodies will be assessed at Day 1 (baseline), Day 
8, Day 29, and Day 181 by analysis of immunoglobulin isotype, glycosylation state 
and their ability to fix complement, to promote antibody-dependent cell mediated 
cytoxicity, to induce phagocytosis and to activate FcR+ cells. If the quantity of serum 
available for this specific exploratory objective is limited, assessments of 
immunoglobulin isotype and glycosylation state will be prioritized over the other 
assessments. 
5. Frequency and quality of T cells specific for CRM197 at Day 1 (baseline), Day 8, and 
Day 29 by fluorescence activated cell sorting (FACS) analysis using intracellular 
staining with a panel of cytokines and surface markers to identify cell populations. 
6. Serum concentrations of a panel of 30 chemokines and cytokines at Day 1 baseline 
(prior to vaccination), Day 1 (6h and 24h after vaccination), Day 4, and Day 8 by 
electrochemo-luminescence based assay. 
7. Gene expression profile in whole blood at Day 1 baseline (prior to vaccination), Day 
1 (6h and 24h after vaccination), Day 4, and Day 8 by RNA micro array analysis. 

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Statistical Analyses: 
The study is exploratory in nature, thus analyses will be descriptive and no formal  
 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
hypothesis testing will be performed. 
Primary Safety Analyses 
The primary safety analyses will be based on the safety set for solicited and unsolicited 
adverse events. There is no statistical null hypothesis associated with the safety 
objective, which will be analyzed descriptively. 
Immunogenicity Analyses 
The primary immunogenicity analyses will be based on the per-protocol set (PPS) on 
Day 29. The primary analyses will also be performed using the Full Analysis Set (FAS) 
as a measure of the sensitivity/robustness of the results. All other immunogenicity 
assessments will be performed using the PPS or the appropriate subset of subjects. The 
antibody concentrations/titers will be summarized using GMC/GMTs and two-sided 
95% confidence intervals (CIs) constructed by exponentiation (base 10) of the least 
square means of the logarithmically transformed (base 10) antibody titer. The 95% CIs 
will be obtained from an analysis of covariance (ANCOVA) with baseline 
concentration/titer as a covariate. Additional details will be further described in the 
Statistical Analysis Plan. 
The immunogenicity endpoints based on subjects meeting criteria for seroconversion or 
achieving a certain threshold value will be summarized using frequencies and 
percentages and associated two-sided 95% Clopper-Pearson CIs. For analyses of 
seroconversion, separate summaries may be provided based on seropositivity status at 
baseline. 

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Interim Analysis: 
An Interim Analysis will be performed on the immunogenicity and safety data collected 
from all subjects until Day 29, after all cohorts have been enrolled. Further details 
regarding the interim analysis are contained in section 8.6. 
Data Monitoring Committee: 
A DMC will be implemented to review safety data during scheduled periodic reviews.  
 
Name of Sponsor: 
Novartis Pharma  
Services AG 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
The DMC will review safety data collected until Day 14, as described in the DMC 
charter and in the Statistical Analysis Plan, after enrollment of the first 5 subjects in each 
cohort, before proceeding with enrollment of the remaining 15 subjects in each cohort. In 
addition, enrollment of the first 5 subjects of the next cohort will only proceed after the 
Day 14 safety results of the first 5 subjects of the previous cohort have been reviewed. 
Furthermore, all available Day 14 and Day 29 safety results will be included in DMC 
reviews between the different enrollment stages. Further information regarding the DMC 
is discussed in more detail in the protocol, section 3.7. 

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Table 3: 
Time and Events Table – Treatment Period (until Day 29) 
 
Visit Type 
Clinic Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
 
Study Day 
-28 to -3 
1 
4 
8 
15 
22 
29 
 
Visit Window (Days) 
n/a 
n/a 
n/a 
-1/+1 
+1 
n/a 
-2/+2 
 
Visit Number 
Screening  
1 
2 
3 
4 
5 
6 
Study Event 
References 
 
 
 
 
 
 
 
Study Treatment 
 
 
 
 
 
 
 
 
Vaccination 
Section 5.2 
 
X 
 
 
 
 
 
Screening and Safety 
 
 
 
 
 
 
 
 
Informed Consent  
Section 5.1.1 
X 
 
 
 
 
 
 
Demographic Data & Medical History 
Sections 5.1.2 
X 
 
 
 
 
 
 
Physical Exam 
Sections 5.1.2 and 5.2.1 
X 
Xa 
 
 
 
 
 
Safety Laboratory blood draw (10 ml) 
Section 7.1.7 
X 
Xa 
 
X 
 
 
X 
Urinalysis 
Sections 7.1.7 
X 
Xa 
 
X 
 
 
X 
Pregnancy Test 
Sections 5.1.2 and 5.2.1 
X 
Xa 
 
 
 
 
 
Exclusion/Inclusion Criteria 
Section 4.0 
X 
Xa 
 
 
 
 
 
Randomization 
Section 5.2.3 
 
Xa 
 
 
 
 
 
30 min and 24 hr Post Injection Assessment 
Section 5.2.5 
 
Xb 
 
 
 
 
 
Subject Diary Dispensed with Training 
Section 5.2.5 
 
X 
 
 
 
 
 
Subject Diary Reminder 
Section 5.2.5 
 
 
X 
X 
 
 
 

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Subject Diary Reviewed and Collected 
Section 5.3.1 
 
 
 
 
X 
 
 
Assess all solicited AEs 
Section 7.1.1 and 7.1.3 
 
 
 
 
X 
 
 
Assess all unsolicited AEs 
Sections 7.1.2 and 7.1.3 
X 
X 
X 
X 
X 
 
 
PRO-01 TEMP 06 / Atlas No. 293620 
Visit Type 
Clinic Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Study Day 
-28 to -3 
1 
4 
8 
15 
22 
29 
Visit Window (Days) 
n/a 
n/a 
n/a 
-1/+1 
+1 
n/a 
-2/+2 
Visit Number 
Screening  
1 
2 
3 
4 
5 
6 
Study Event 
References 
 
 
Assess SAEs 
Section 7.1.4 
X 
X 
X 
X 
X 
X 
X 
Assess AESIs 
Section 7.1.4.1 
X 
X 
X 
X 
X 
X 
X 
Assess NOCDs, medically attended AEs, 
AEs leading to withdrawal  
Sections 7.1.3 
X 
X 
X 
X 
X 
X 
X 
Assess relevant medications 
Sections 5.1.2 and 6.5 
X 
X 
X 
X 
X 
X 
X 
Blood draws for Immunogenicity and Exploratory Objectives 
 
Serum Blood Draw (Primary and Secondary 
Objectives; 10 mL)  
Section 3.5 
 
Xa 
 
X 
 
 
X 
Serum Blood Draw (Exploratory 
Objectives; 5 mL)  
Section 3.5 
 
Xc 
X 
X 
 
 
 
Whole Blood Draws (Exploratory 
Objectives; 2 mL) 
Section 3.5 
 
Xd 
X 
 
 
 
 
Whole Blood Draw (Exploratory Objectives; 
5 mL) 
Section 3.5 
 
Xe 
X 
X 
 
 
 

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Whole Blood Draw (Exploratory Objectives; 
50 mL) 
Section 3.5 
 
Xa 
 
X 
 
 
X 
Notes: 
a. Procedure must be performed prior to vaccination. 
b. Body temperature measurement must be performed at 30 min, 2, 4, 6, 8, 10, 12, 20 and 24 hours after vaccination.  
c. Three Serum Blood Draws (3 x 5ml) must be taken at Study Day 1, i.e. at baseline (prior to vaccination), at 6h and at 24h after vaccination. 
d. Six whole Blood Draws (6 x 2 mL) must be taken at Study Day 1, i.e. at baseline (prior to vaccination) and at 1, 2, 4, 8 and 24h after vaccination. 
e. Three Whole Blood Draw (3 x 5 mL) must be taken at Study Day 1, i.e. at baseline (prior to vaccination), at 6h and at 24h after vaccination 
 
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Table 4: 
Time and Events Table – Follow-up Period (until Day 366) 
Visit Type 
Clinic Visit 
Clinic Visit 
Clinic Visit 
Phone Call 
Phone Call 
Clinic Visit 
Study Day 
85 
113 
181 
209 
271 
366 
Visit Window (Days) 
-7 to +7 
-7 to +7 
-7 to +7 
-14 to +14 
-14 to +14 
-14 to +14 
Visit Number 
7 
8 
9 
10 
11 
12 
Study Event 
References 
 
 
Safety 
 
Assess SAEs 
Section 7.1.4 
X 
X 
X 
X 
X 
X 
Assess AESI 
Section 7.1.4.1 
X 
X 
X 
X 
X 
X 
Assess NOCDs, medically attended 
AEs, AEs leading to withdrawal 
Sections 7.1.3 
X 
X 
X 
X 
X 
X 
Assess relevant medications 
Sections 5.1.2 and 6.5 
X 
X 
X 
X 
X 
X 
Blood draws for Immunogenicity and Exploratory Objectives 
 
Serum Blood Draw (Secondary 
Objective; 10 mL) 
Section 3.5 
 
 
X 
 
 
 

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Whole Blood Draw  
(Exploratory Objectives; 50 mL) 
Section 3.5 
 
 
X 
 
 
 
Study Completion Procedures 
 
Study Terminationa 
Section 5.5 
 
 
 
 
 
X 
Notes: 
a. Subjects who terminate the study early are recommended to complete certain study-related procedures. See section 5.5 for further details. 
 
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LIST OF ABBREVIATIONS 
ADCC 
Antibody-dependent cell mediated cytotoxicity 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BZN 
Benzonaphthyridines 
CBER 
Center for Biologics Evaluation and Research 
cDNA 
Complementary deoxyribonucleic acid 
CI 
Confidence interval 
CRF 
Case report form 
CRM197 
Cross Reacting Material 197 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
EC 
Ethics committee 
EDC 
Electronic data capture 
ELISA 
Enzyme-linked immunosorbent assay 
ELISPOT 
Enzyme-Linked ImmunoSpot 
EMA 
European Medicines Agency 
FACS 
Fluorescence-activated cell sorting 
FAS 
Full analysis set 
FDA 
Federal Drug Agency 
GCP 
Good clinical practice 
GMC 
Geometric mean concentration 
GMP 
Good manufacturing practice 

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GMT 
Geometric mean titer 
GMR 
Geometric mean ratio 
HEENT  
Head, ears, eyes, nose and throat 
HIV 
Human immunodeficiency virus 
 
HPV 
Human papillomavirus 
hSBA 
Human complement serum bactericidal assay 
ICF 
Informed consent form 
ICH 
International Committee for Harmonization 
IM 
Intramuscular 
IRB 
Institutional review board 
IV 
Intravenous 
LLQ 
Lower limit of quantification 
MenC 
Meningococcal type C 
MPL 
Monophosphoryl lipid A 
NCR 
No carbon required 
NOCD 
New Onset of Chronic Disease 
PEG 
Polyethylene glycol 
PO 
Per oral 
PP 
Per protocol 
RNA 
Ribonucleic acid (RNA 
SAE 
Serious Adverse Event 
SMIP 
Small molecule immune potentiator 
TLR 
Toll-like receptor 
VSAE 
Vaccine serious adverse event 
1.0  
BACKGROUND AND RATIONALE 
1.1  
Background 

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MenC-CRM197 Conjugate Vaccine 
Meningococcal disease worldwide is predominantly a disease of infants and young 
children. N. meningitidis serogroup B and C remain the most prevalent strains in North 
America and Europe, (Rosenstein, N. et al., 2001) and together cause more than 95% of 
reported cases of meningococcal disease in Europe (Connolly, M, et al., 1999). In Europe, 
N. meningitidis serogroup C (MenC) is one of the major serogroups causing invasive 
disease. Case fatality in Germany has ranged between 6% and 8% between 1999 and 
2006, and has remained generally consistent across the different European countries, 
varying between 6-11%, with the case fatality rate being notably higher for serogroup C 
disease than for serogroup B (European Centre for Disease Prevention and Control, 
2011). Since MenC vaccination was added to Germany’s routine schedule for children in 
2006, there has been a reported decline in MenC incidence. However, the decline was not 
as rapid when compared to other European countries (Hellenbrand, W. et al., 2013). 
The Novartis Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) comprises 
MenC oligosaccharides conjugated to the protein carrier, CRM197, a nontoxic mutant of 
diphtheria toxin. The vaccine has been shown to be safe and immunogenic and able to 
prime infants, toddlers and young children for immunological memory (see Novartis 
Meningococcal C-CRM197 Conjugate Vaccine Investigator’s Brochure).  
In Germany, the Standing Committee on Vaccination (STIKO) of the Robert Koch  
Institute recommends a single dose of MenC conjugate vaccine in children over the age of  
12 months as part of the routine vaccination campaign (Robert Koch Institute 
Epidemiologisches Bulletin, August 2013). For specific indications, e.g. in case of 
postexposure prophylaxis, the recommended schedule for primary immunization of 
infants between 2 to 12 months of age with a MenC conjugate vaccine is two dosages 
given with an interval of at least 2 months. 
Although the Novartis Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) 
represents an example of how vaccination with a well characterized, purified 
polysaccharide antigen can yield pivotal public health triumphs, there remains a need for 
further improvement of the MenC vaccine. A more potent MenC vaccine formulation 
might yield an increase in the magnitude of the antigen-specific immune response 
enabling a reduction of the antigen dosage. Furthermore, induction of a more rapid 
antigen-specific immune response may enable a reduction in the number of doses needed 
for post-exposure prophylaxis in infants. 

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Vaccine Adjuvants 
Immunization with purified protein or polysaccharide antigens typically results in the 
induction of a modest antibody response with little or no T cell response when compared 
to vaccines comprised of whole or killed bacteria or viruses that have inherent 
immunepotentiating activity. The need to increase the immunogenic response of 
wellcharacterized and purified antigens that display suboptimal immunogenicity when 
used alone affirms the essential role for the use of adjuvants. Vaccine adjuvants may 
significantly reduce the amount of antigen needed (Del Giudice, G, et al., 2013) and may 
induce a more rapid immune response enabling a reduction in the number of doses in a 
regimen. 
Besides reducing the antigen dosage or number of doses in the vaccine regimen, there is 
now an increased appreciation of the capacity of adjuvants to increase not just overall 
antibody titer but also to increase the number of functional antibodies and/or antibodies 
with higher affinity for vaccine antigens. Many pathogens, such as influenza viruses, 
HIV, human papilloma virus (HPV) and the malaria parasite, display substantial antigenic 
drift, subtype and/or strain variations. Therefore, the ability of adjuvants to broaden an 
immune response profile could be crucial to the success of vaccines against such targets. 
Previous studies have shown that the broadening effect of adjuvants may be mediated via 
expansion of B cell diversity, not merely through increased titers (Khurana, et al., 2010, 
2011). Clinically, antibody response broadening by adjuvants such as AS04 or oil-inwater 
emulsions has been demonstrated in HPV vaccines and influenza, respectively (Bissett, 
SL et al., 2014; Del Giudice, G et al., 2013). 
One unmet need is the development of vaccines for effective T cell responses. Several 
vaccines in development are aimed at eliciting T cell responses, which historically have 
not been induced by the most commonly used adjuvants in vaccines for human use, such 
as aluminium hydroxide. Therefore, an objective of many adjuvant discovery and 
development programs is to elicit more effective engagement of T-helper cells for 
optimizing the quality, breadth and durability of antibody responses, or, to induce effector 
CD4+ or CD8+ T cells to kill intracellular pathogens. One approach for new generation 
vaccines is the use of agonists for Toll-like receptors (TLRs) that activate innate immune 
receptors, mainly on antigen presenting cells, and facilitate the generation of T helper cell 
responses. 
Adjuvants that are currently employed in human vaccines licensed for use in the USA 
and/or Europe include aluminium salts, oil-in-water emulsions (MF59, AS03 and AF03), 
virosomes, and AS04 (Alving, CR, et al., 2012). Among the most advanced adjuvants 
systems is AS04 which is used in the Cervarix® HPV vaccine and consist of the TLR4 
ligand monophosphoryl lipid A (MPL) combined with aluminium salt. MPL, along with 

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QS21, is also part of the adjuvant system (AS01) in the RTS, S malaria vaccine from 
GlaxoSmithKline which has been evaluated in a Phase 3 clinical trial (Regules, JA, et al.,  
2011). Another clinically advanced adjuvant is CpG oligodeoxynucleotide (ODN), a 
TLR9 ligand contained in the Heplisav® vaccine candidate for hepatitis B from Dynavax, 
that has completed a Phase 3 clinical trial (Reed, SG, et al., 2013). 
Small molecule immune potentiators as a new class of vaccine adjuvants 
A new class of adjuvants, small molecule immune potentiators (SMIPs), has been 
identified that activate immune cells by targeting TLR7 and TLR8. Imiquimod and 
Resiquimod (R848) are clinically advanced TLR7 and/or TLR8 SMIPs that are used as 
immunotherapeutics. Although Imiquimod and Resiquimod have been studied 
extensively as vaccine adjuvants in preclinical models (Vasilakos et al. 2013), they were 
never optimized for this use and, in general, compare poorly to other pre-clinical and 
clinical adjuvant candidates. Furthermore, when Imiquimod is applied topically (it is a 
licensed topical treatment for viral and malignant skin lesions) it induces strong local and 
systemic inflammatory reactions, and is poorly tolerated (Bauza, et al. 2009; Campanelli, 
et al. 2005; Meyer, et al. 2008). 
Unlike traditional drugs, TLR7 SMIPs activate innate immunity and initiate a cascade of 
immune responses that can have systemic impact and endure after the compound has been 
cleared from the organism. For SMIPs as vaccine adjuvants this difference is highlighted 
further by the fact that 2-3 local IM injections drive antigen-specific B and T cell 
responses at distal sites and these can provide protection in the form of immunologic 
memory (Tacken,  et al. 2011; Ilyinskii, et al., 2014). Therefore, limiting the systemic 
exposure of the SMIP adjuvants has been postulated as an approach to both increase 
vaccine efficacy and minimize side effects associated with systemic and generalized 
inflammation. Novartis is currently developing a novel adjuvant, containing a SMIP from 
the benzonaphthryridines (BZN) series, LHD153, which targets TLR7. The objective 
driving the discovery of this new TLR7 ligand was to develop a vaccine adjuvant with 
high efficacy in increasing the vaccine specific immune response and with minimal side 
effects. To obtain this objective it was postulated that the ideal compound would remain 
localized at the site of injection to help trigger the immune reaction to vaccine antigens, 
yet maintain a low systemic distribution. At the same time this compound had to be 
soluble to make industrial scale-up and manufacturing feasible. Soluble BZN were 
engineered so that they could be formulated with aluminium salts with the aim of limiting 
their systemic exposure and keeping them localized in the muscle for short time after 
immunization. The strongest adsorption to aluminium hydroxide particles is obtained 
through ligand exchange of hydroxyl and/or phosphate groups on the surface of 
aluminium hydroxide or phosphate with soft anionic moieties such as phosphates, 
phosphonates, phosphites, sulfates and carboxylates. To drive the adsorption to 

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aluminium hydroxide through ligand exchange, LHD153 was functionalized with a 
polyethylene glycol (PEG) linker and a terminal phosphonate. Furthermore, LHD153 was 
stabilized with arginine salt to allow scale up for GMP manufacturing, yielding 
LHD153R. As predicted, unformulated LHD153R exhibited high levels of systemic 
exposure when injected IM in mice, rats and dogs, whereas the serum concentrations of 
LHD153R adsorbed to aluminium hydroxide (Aluminium Hydroxide/LHD153R) was 
dramatically reduced. Moreover, Aluminium Hydroxide/LHD153R remained localized to 
the injection site. 
Preclinical studies using Aluminium Hydroxide/LHD153R to date confirm the activation 
of the TLR7 pathway and subsequent boost of both the humoral and cellular immune 
response. Moreover, Aluminium Hydroxide/LHD153R displays a unique 
pharmacokinetic profile as demonstrated by its minimal systemic exposure, potentially 
minimizing any systemic inflammatory response associated with tolerability issues. 
Aluminium hydroxide/LHD153R has achieved proof of concept in animal models using 
several vaccine antigens including MenC, MenB, rabies, HIV and respiratory syncytial 
virus (RSV). In vitro toxicity of LDH153R has been assessed, and in vivo nonclinical 
tolerability and safety of LHD153R and Aluminium Hydroxide/LHD153R have been 
evaluated in rats, dogs and non-human primates. LHD153R was not phototoxic, 
genotoxic or mutagenic (Ames and chromosomal aberration tests), and did not cause local 
or systemic toxicity in dogs or rats. Furthermore, Aluminium Hydroxide/LHD153R was 
well tolerated in rhesus monkeys. 
1.2  
Rationale 
The aim of this study is to assess the safety of Aluminium Hydroxide/LHD153R 
adjuvanted MenC-CRM197 conjugate vaccine (MenC-CRM197/Aluminium  
Hydroxide/LHD153R) and to compare the antibody-mediated immune response elicited 
by MenC-CRM197/Aluminium Hydroxide/LHD153R with the licensed aluminium 
hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®). 
Furthermore, a comprehensive set of exploratory objectives has been selected to assess 
the systemic exposure of LHD153 after intramuscular injection and to evaluate the quality 
of the specific immune response against MenC-CRM197 in detail and to evaluate  
biomarkers that may be predictive of safety and/or innate immune activation. 
The licensed Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) has been 
chosen as the primary vaccine candidate to assess the safety and immunopotentiating 
properties of Aluminium Hydroxide/LHD153R for several reasons. Firstly, the safety and 
immunogenicity profiles of the Meningococcal C-CRM197 Conjugate Vaccine have been 
well established through years of commercial use. Secondly, a more potent 

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Meningococcal C-CRM197 Conjugate Vaccine might enable a reduction of the antigen 
dosage or the number of doses needed in infants between 2 and 12 months of age. Finally, 
the Meningococcal C-CRM197 conjugate is a well-characterized, single antigen 
preparation which provides an ideal setting to explore the potential of this new 
Aluminium Hydroxide/LHD153R adjuvant. 
2.0  
OBJECTIVES 
2.1  
Primary Objectives 
Primary Safety Objective 
To assess the safety of MenC-CRM197/Aluminium Hydroxide/LHD153R as compared to 
that of aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
Primary Immunogenicity Objective 
To compare the antibody responses of MenC-CRM197/Aluminium Hydroxide/LHD153R 
and aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at 
Day 29, as measured by human complement serum bactericidal assay (hSBA) directed 
against MenC. 
2.2  
Secondary Objectives 
Secondary Immunogenicity Objective(s) 
1. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine at Day 8 and Day 181 after vaccination, as measured by 
hSBA directed against MenC. Baseline antibody titers will also be measured by 
hSBA. 
2. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine, at Day 8, Day 29 and Day 181 after vaccination, as 
measured by an enzyme-linked immunosorbent assay (ELISA) to MenC. Baseline 
antibody concentrations will also be measured by ELISA. 
2.3  
Exploratory Objectives 

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1. To evaluate the systemic exposure of LHD153 at several early time-points after IM 
injection of MenC-CRM197/Aluminium Hydroxide/LHD153R or Meningococcal 
CCRM197 Conjugate Vaccine. 
2. To explore the frequency of B cells specific for MenC polysaccharide and CRM197 
protein at baseline (Day 1) and at Day 8, Day 29 and Day 181 after vaccination with 
MenC-CRM197/Aluminium Hydroxide/LHD153R or the aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. Subsequently, the B cell 
repertoire of the antigen specific B cells and the specific antibody functionality will 
be analyzed in a selected subset of subjects. 
3. To explore the baseline T cell mediated immunity to CRM197 and to evaluate the 
frequency and quality of CRM197 specific T cells induced by 
MenCCRM197/Aluminium Hydroxide/ LHD153R compared to aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at Day 8 and Day 29. 
4. To evaluate biomarkers that may be predictive for safety and/or innate immune 
activation. 
 

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3.0 
STUDY DESIGN 
3.1 
Overview of Study Design 
This is a Phase 1, randomized, observer blind, adjuvant dosage-escalation study. It will be 
performed at a single center. In total, approximately 80 healthy male and healthy 
nonpregnant female adults (18-45 years of age) will be enrolled in the study. 
Subjects will be randomized to receive a single IM vaccination of either the licensed 
aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine 
(Menjugate®) or the investigational vaccine, MenC-CRM197/Aluminium 
Hydroxide/LHD153R. 
The dosage of LHD153R will be escalated from 12.5 µg to 100 µg.  For the 
dosageescalation of LHD153R, the subjects will be enrolled into 1 of 4 cohorts, in a 
stepwise manner with 20 subjects per cohort. Subjects in all cohorts will be randomized 
in a 1:4 ratio, to receive either aluminium hydroxide adjuvanted Meningococcal C-
CRM197 Conjugate Vaccine (control) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R with increasing doses of LHD153R.Subjects assigned to MenC-
CRM197/Aluminium Hydroxide/LHD153R in Cohort 1 will receive 12.5 μg of LHD153R; 
Subjects in Cohort 2 will receive 25 μg of LHD153R; Subjects in Cohort 3 will receive 
50 μg of LHD153R; Subjects in Cohort 4 will receive 100 μg of LHD153R (Table 3.1-1). 
Table 3.1-1: Subjects Randomized per Cohort and Treatment Dose Group 
Cohort 
Group 
Subjects/ 
Group 
MenC 
Dosage* 
(µg) 
Adjuvant Dosages 
Total 
Volume/Dose 
Total 
Subjects/Group 
Aluminium  
Hydroxide  
(mg) 
LHD153R  
(µg) 
1 
A 
4 
10 
1 
0 
0.5 mL 
20 
 
 
 
 
 
 
 
B 
16 
10 
1 
12.5 
0.5 mL 
 
2 
A 
4 
10 
1 
0 
0.5 mL 
20 
C 
16 
10 
1 
25 
0.5 mL 
3 
A 
4 
10 
1 
0 
0.5 mL 
20 
D 
16 
10 
1 
50 
0.5 mL 
4 
A 
4 
10 
1 
0 
0.5 mL 
20 
E 
16 
10 
1 
100 
0.5 mL 
*Conjugated to 12.5-25 µg CRM197 
All cohorts will have a staggered entry. For each cohort, the first 5 subjects (i.e. the first  
1:4 randomization block) to receive either aluminium hydroxide adjuvanted  

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Meningococcal C-CRM197 Conjugate Vaccine (n=1) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R (n=4) will be vaccinated at rate of 1 subject each day. 
After entry of the first 5 subjects in each cohort, the enrollment will be paused. The 
remaining 15 subjects for each cohort will be enrolled only after DMC review of the 
safety results obtained through Day 14 has been finalized (Table 3.1-2). In addition, 
enrollment of the first 5 subjects of the next cohort will only proceed after the Day 14 
safety results of the first 5 subjects of the previous cohort have been reviewed by the 
DMC. Furthermore, all available Day 14 and Day 29 safety results will be included in 
DMC review between the different enrollment stages. 
Table 3.1-2: Overview of staggered entry of subjects based on DMC reviews 
Stage 
Dosage Cohort 
MenC-CRM197/ 
Aluminium Hydroxide (n) 
MenC-CRM197/ 
Aluminium Hydroxide 
/LHD153R (n) 
1   
1  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 14 Safety Results 
2 
1  
3 
12 
2  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 29 and Stage 2 Day 14 Safety Results 
3 
2  
3 
12 
3  
1 
4 
Enrollment pause until DMC review of Stage 2 Day 29 and Stage 3 Day 14 Safety Results 
4 
3  
3 
12 
4  
1 
4 
Enrollment pause until DMC review of Stage 3 Day 29 and Stage 4 Day 14 Safety Results 
5 
4  
3 
12 
Post-vaccination procedures include collection of urine specimens at Day 8 and Day 29 
for safety assessment and blood specimens at Day 8, Day 29 and Day 181 for safety 
assessment and evaluation of the primary and secondary immunogenicity endpoints. 
Furthermore, additional blood specimens will be collected for assessment of exploratory 
endpoints at Day 1, Day 4, Day 8, Day 29 and Day 181 from those subjects that signed an 
additional informed consent concerning blood collection for exploratory assessment. 
3.2  
Study Period 
Each subject should expect to participate in the study for approximately 12 months, from 
the time of enrolment through the last study visit. 

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3.3  
Blinding Procedures 
This study is designed as an observer-blind study. For each dosage cohort, subjects, 
investigators, laboratories and the sponsor will be blinded to vaccine assignments. 
To maintain the blindness within each cohort, designated nurse(s) or physician(s) will be 
responsible for administering the study vaccines to the subjects, and will be instructed not 
to reveal the identity of the study vaccines neither to the subject nor to the investigative 
site personnel (investigator, study nurse, monitor) involved in the conduct or monitoring 
of the trial. This (these) designated individual(s) will have no contact with the subjects 
after the administration of the study vaccine. Furthermore, unblinded monitors are 
assigned to reconcile actual vaccine treatment. 
Study unblinding, at the group level, is planned for an Interim Analysis of the safety and 
immunogenicity data obtained up to Day 29 after all cohorts are enrolled and for full 
unblinding at the End of Study. 
Except in the case of medical necessity, a subject’s treatment should not be unblinded 
without the approval of the Sponsor. In such instance of medical emergency, every effort 
should be made to contact the Sponsor prior to unblinding. If unblinding should occur (by 
either accidental unblinding or emergency unblinding for a serious adverse event) prior to 
completion of the study, the investigator must promptly contact the Sponsor and 
document the circumstances on the appropriate forms. Instructions regarding emergency 
unblinding will be provided to the investigator. 
3.4  
Data Collection 
3.4.1  
Data Collected from Subjects 
The following data will be collected from each subject over the duration of their study 
participation: 
▫ Demographic Information 
▫ Adverse Events 
▫ Medical History 
▫ Concomitant Medications 
▫ Vital signs 

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All data collected must only be identified using the Subject ID, as described in section 
5.2.3. 
3.4.2  
Tools Used for Data Collection 
Data will be recorded in the Subject Diary and collected on Case Report Forms (CRFs). 
Subject Diary 
Subject Diaries will be the only source document allowed for solicited local and systemic 
adverse events (including body temperature measurements), starting after the initial 24 
hours post-vaccination observation period at the clinic. The following additional rules 
apply to documentation of safety information collected in the Subject Diary: 
1. No corrections or additions to the Subject Diary will be allowed after it is delivered to 
the site. 
2. Any blank or illegible fields on the Subject Diary must be described as missing in the 
CRF. 
3. Any corrections to the Subject Diary must be performed by the person completing the 
Subject Diary and should include a single strike through line through the incorrect 
value or text with a brief explanation for each change, the initials of that person, and 
date of correction. 
Case Report Forms 
This study utilizes CRFs to collect study-related data from each subject. A qualified site 
staff member(s) is required to enter subject data in the CRFs in English based on the 
medical information available in each subject’s  record. The following additional rules 
apply to documentation of Subject Diary information collected in the CRFs: 
1. The site must enter all readable entries in the Subject Diary into the CRF, including 
those values that may be biologically implausible (e.g. body temperature: 400°C). 
2. Any illegible or implausible data should be reviewed with the subject. If an 
underlying solicited or unsolicited adverse event is described on review with the 
subject, this should be described in the source document and reported as an 
unsolicited adverse event in the appropriate CRF (e.g., if the subject above confirms 
body temperature of 40°C on the day in which body temperature: 400°C was written 
into his/her Subject Diary, this fever of 40°C should be recorded in the appropriate 
CRF). 

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3. Any newly described safety information (including a solicited adverse event) must not 
be written into the Subject Diary and must be described in the study file as a verbally 
reported adverse event. Any adverse event reported in this fashion must be described 
as an unsolicited adverse event and therefore, entered in the appropriate CRF. 
Data should be entered into the CRF in a timely fashion following each subject’s clinic 
visit, study procedure, or phone call. Each subject’s CRF casebook will be compared with 
the subject’s source records by a Novartis-approved study monitor (or designee) over the 
duration of the study in order to ensure data collection accuracy. 
3.5  
Collection of Clinical Specimens 
The following clinical specimens are required to be collected from each subject in this 
study: 
▫ Blood 
▫ Urine 
Processing of each specimen should be completed by a qualified site member. Testing of 
clinical specimens will be performed by a Novartis or designated laboratory. 
Blood Specimens 
Before Vaccination 
▫ At the Pre-vaccination Screening Visit (between Day -28 to -3) one sample of 
approximately 10 ml blood will be drawn from all subjects. 
▫ At Visit 1 (Day 1) - prior to vaccination – two samples of approximately 10 ml blood 
will be drawn from all subjects. 
▫ At Visit 1 (Day 1) - prior to vaccination - the following blood samples will be drawn 
from subjects that gave additional informed consent for blood collection for 
exploratory assays: 
- 
One sample of approximately 2 ml 
- 
Two samples of approximately 5 ml 
- 
One sample of approximately 50 ml 

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After Vaccination 
▫ At Visit 1 (Day 1) - 1 hour after vaccination - one sample of approximately 2 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 2 hours after vaccination - one sample of approximately 2 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 4 hours after vaccination - one sample of approximately 2 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 6 hours after vaccination – two samples of approximately 5 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 8 hours after vaccination - one sample of approximately 2 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 24 hours after vaccination - the following blood samples will be 
drawn from subjects that gave additional informed consent for blood collection for 
exploratory assays: 
- 
One sample of approximately 2 ml 
- 
Two samples of  approximately 5 ml 
▫ At Visit 2 (Day 4) the following blood samples will be drawn from subjects that gave 
additional informed consent for blood collection for exploratory assays: 
- 
One sample of  approximately 2 ml 
- 
Two samples of  approximately 5 ml 
▫ At Visit 3 (Day 8) two samples of approximately 10 ml blood will be drawn from all 
subjects. 
▫ At Visit 3 (Day 8) the following blood samples will be drawn from subjects that gave 
additional informed consent for blood collection for exploratory assays 
- 
Two samples of approximately 5 ml 
- 
One sample of approximately 50 ml 

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▫ At Visit 6 (Day 29) two samples of approximately 10 ml blood will be drawn from all 
subjects. 
▫ At Visit 6 (Day 29) one sample of approximately 50 ml blood will be drawn from 
subjects that gave additional informed consent for blood collection for exploratory 
assays. 
▫ At Visit 9 (Day 181) one sample of approximately 10 ml blood will be drawn from all 
subjects. 
▫ At Visit 9 (Day 181) one sample of approximately 50 ml blood will be drawn from 
subjects that gave additional informed consent for blood collection for exploratory 
assays. 
The blood will be used for screening and safety laboratory assessments, immunological 
serology assays, pharmacokinetic analysis, cell mediated immunity assays and gene 
expression and protein production assays. See section 5.1.2, section 5.2.1 and section 7.0 
for additional details. 
Processing of each blood specimen should be completed in accordance with the study 
specific Clinical Specimen Laboratory Manual. 
The total amount of blood collected over the study period for all subjects will be 
approximately 80 ml. 
For subjects that signed an additional informed consent for blood collection for 
exploratory assays the total amount of blood collected over the study period will be 
approximately 344 ml. 
Urine Specimens 
Urine will be collected at the Pre-vaccination Screening Visit (between Day -28- to -3), at 
Visit 1 (Day 1; before vaccination), at Visit 3 (Day 8) and at Visit 6 (Day 29). Results 
will be recorded in the source document and CRF. 
Urine will be collected from all subjects for safety laboratory assessments and drugs-
ofabuse testing. Furthermore, urine will be collected for pregnancy testing in all females. 
3.6  
Stopping/Pausing Guidelines 

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Stopping/pausing guidelines are predefined criteria that halt the conduct of a study (either 
a vaccine group or the entire study). These guidelines are used to ensure the safety of study 
subjects.  
The following criteria, based on FDA guidance and with grading scales adapted from the 
CBER Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive vaccine Clinical Trials”, will be used for this study: 
1. The study will be halted (no new enrollments and no further investigational product 
administered until a full safety review by the DMC and consultation with the IRB/EC 
and the health authorities is completed) if one of the following occurs 
a. One subject experiences a serious adverse event (SAE) assessed as possibly or 
probably related to investigational product or, 
b. There is a subject death assessed as possibly or probably related to the 
investigational product. 
2. If one or more subjects experience a Grade 4 AE (see Appendix C, D, and E), vital 
sign or laboratory abnormality that cannot be clearly attributed to another cause, 
vaccination will be suspended until a full safety review by the DMC is performed. 
3. If six or more subjects experience a Grade 3 AE (see Appendix A, B, C, D, and E), 
vital sign or laboratory abnormality, dosage escalation will be suspended for that 
vaccine until a full safety review by the DMC is performed.  
The sponsor or the investigator (following consultation with the sponsor) has the right to 
discontinue the study at any time. If the clinical study is prematurely terminated, the 
investigator must promptly inform the study subjects and must assure appropriate therapy 
and follow-up for the subjects.  All procedures and requirements pertaining to the 
archiving of the documents must be followed.  All other study materials (such as study 
vaccines) must be returned to the sponsor or destroyed after sponsor approval. 
3.7  
Data Monitoring Committee 
A DMC will be formed to review safety data during scheduled periodic reviews. The 
DMC may also perform reviews on an ad hoc basis as needed. DMC membership will 
consist of at least 3 individuals who are external to the site and sponsor, and will include 
1 statistician who is independent from the study team.  
Subjects will be enrolled in a stepwise manner in each of the four vaccine dosage cohorts  
(Cohort 1: 12.5 μg LHD153R, Cohort 2: 25 μg of LHD153R, Cohort 3: 50 μg of  

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LHD153R and Cohort 4: 100 μg of LHD153R). The DMC will review all safety data, as 
described in the DMC charter and in the Statistical Analysis Plan, after the first 5 subjects 
in each cohort have completed Visit 4 and their data are available for analysis, and before 
enrollment of the remaining subjects in the respective cohort and before enrollment of the 
first 5 subjects in the subsequent cohort. In addition, in between the different enrollment 
stages, the DMC will review all available safety data of subjects that have completed 
Visit 4 and all available safety data of subjects that have completed Visit 6. 
The specific roles and responsibilities of the DMC members and other personnel involved 
will be documented in the DMC charter. The DMC charter will be finalized before the 
start of the study and will outline in detail all pausing and stopping rules according to the 
Clinical Study Protocol. 
3.8  
Premature Withdrawal from Study 
Subjects may withdraw at any time, or be dropped from the study at the discretion of the 
investigator should any untoward effects occur and/or for safety reasons. In addition, a 
subject may be withdrawn by the investigator or the Sponsor if he/she violates the study 
plan or for administrative reasons. The investigator or study coordinator must notify the 
Sponsor immediately when a subject has been withdrawn due to an adverse event. 
The circumstances above are referred to as premature withdrawal from the study, and the 
reason for premature withdrawal should be clearly documented and detailed in the source 
documentation. The investigator should make every attempt to evaluate the subject’s 
safety, including resolution of ongoing AEs, at the time of premature withdrawal. If a 
subject wants to withdraw from the study prior to the last planned study visit, the subject 
will be asked to be followed for safety for the duration of the study. When a subject 
withdraws, or is withdrawn, from the study, the procedures described in section 5.5.1 
should be completed if possible. 
The reasons for premature withdrawal from the study include: Adverse event, death, 
withdrawal of consent, lost to follow-up, administrative reason, and protocol deviation. 
These reasons are described in greater detail below. 
Adverse Event 
For any subject withdrawn from study participation prior to the planned Study  
Termination Visit, it is important to determine if an AE was associated with the reason for 
discontinuing the study. This AE must be identified on the appropriate CRF page by 
indicating “Withdrawn from study due to AE”. Any ongoing AEs at the time of study 
withdrawal must be followed until resolution or stabilization. 

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Death 
For any subject withdrawn from study participation due to death, this should be noted on 
the appropriate CRF page and the associated SAE that led to the death must be reported. 
Withdrawal of consent 
The subject can withdraw consent for participation in the study at any time without 
penalty or loss of benefit to which the subject is otherwise entitled. Reason for early 
termination should be deemed as “withdrawal of consent” if the subject withdraws from 
participation due to a non-medical reason (i.e., reason other than AE). If the subject 
intends to withdraw consent from the study, the investigator should clarify if the subject 
will withdraw completely from the study or if the subject will continue study participation 
for safety, or a subset of other study procedures. If the subject requests complete 
withdrawal from the study, no further study interventions will be performed with the 
subject. 
Lost to Follow-Up 
For subjects who fail to show up for study visits (clinic or telephone contacts), study staff 
is encouraged to make at least three documented attempts to contact the subject by 
telephone and at least one documented written attempt to contact the subject to encourage 
the completion of study termination procedures. These efforts to contact the subject must 
be recorded in the source document. The termination date for the subject to be captured 
on the appropriate CRF page is the date of the last contact (clinic visit or telephone) with 
the subject. 
Administrative Reason 
Examples for subjects withdrawn from the study due to administrative reason can include: 
Sponsor decision to terminate the study, subject meeting a pre-specified withdrawal 
criterion, subject discontinuation for insurance issues, moving, no time, etc. This reason 
should be noted in the appropriate CRF page and any ongoing AEs at the time of study 
withdrawal must be followed until resolution/stabilization. 
If the clinical study is prematurely terminated by the Sponsor, the investigator is to 
promptly inform the study subjects and local EC/IRB and should assure appropriate 
therapy and follow up for the subjects. All procedures and requirements pertaining to the 
archiving of study documents should be followed. All other study materials (study 
medication/vaccines, etc.) must be returned to the Sponsor. 

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For subjects who are withdrawn from the study due to receipt of an excluded 
medication/vaccination or due to significant protocol non-compliance, this reason should 
be noted in the appropriate CRF page. 
Protocol Deviation 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. In general, subjects associated with protocol deviations 
may remain in the study unless continuation in the study jeopardizes the subject’s health, 
safety, or rights. 
Investigators will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring 
the study to request approval of a protocol deviation, as no authorized deviations are 
permitted. If the investigator feels a change to the protocol would improve the conduct of 
the study this must be considered a protocol amendment, and unless such an amendment 
is agreed upon by Novartis and approved by the IRB/EC and health authorities it cannot 
be implemented. 
Any subject who becomes pregnant during the study should be encouraged to continue 
participating in the study for safety follow-up. The site must complete a Pregnancy 
Report CRF (initial report) as soon as possible after learning of pregnancy occurrence 
(see section 7.1.6 for further details). If the subject withdraws from the study for any of 
the above categories except death, the site will obtain permission from the subject to 
continue to remain in contact with her until the outcome of the pregnancy is known, even 
if the outcome is not known until after the subject reaches the end of the routine study 
period. 
3.9  
End of Study 
Most clinical trials intended to support the efficacy/immunogenicity and safety of an 
Investigational Product proceed to full completion of planned sample size accrual. 
A subject is considered to have completed this study when he/she has: (1) received the 
intended dose of study vaccine and (2) completed 365 days (Visit 12) of safety follow-up 
after receiving the study vaccine. 
Evaluation of the primary and secondary immunogenicity objectives requires the testing 
of biological samples from all study subjects, which can only be completed after all 
samples are collected. The last samples for the analysis of the primary and/or secondary 
objectives will be taken at Visit 9 (Day 181). For the purpose of this protocol, End of 

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Study is defined as the completion of the testing of such biological samples, to be 
achieved no later than 8 months after collection of the last biological sample at Visit 9. 

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4.0  
SELECTION OF STUDY POPULATION 
4.1  
Inclusion Criteria 
In order to participate in this study, all subjects must meet all of the inclusion criteria 
described. 
1. Male or female individuals of 18 through 45 years of age on the day of informed 
consent. 
2. Healthy volunteers with good physical and mental health status, determined on the 
basis of the medical history, a physical examination and the results of the screening 
tests as judged by the investigator. 
3. Individuals who have voluntarily given written informed consent after the nature of 
the study has been explained according to local regulatory requirements, prior to 
study entry. 
4. Individuals who can comply with study procedures including follow-up1. 
5. Individuals that are able to understand, read and write German language. 
6. Females of childbearing potential who are using an effective birth control method2 
which they intend to use for at least 30 days after the study vaccination. 
4.2  
Exclusion Criteria 
Each subject must not have or must not be: 
1. Progressive, unstable or uncontrolled clinical conditions. 
2. Hypersensitivity, including allergy, to any component of vaccines, medicinal products 
or medical equipment whose use is foreseen in this study. 
                                                
1 A subject is considered to be compliant if the Investigator judges that the subject will complete the Subject 
Diary, return for all the follow-up visits and be available for telephone calls as scheduled in the study. 
2 The following birth control methods are considered effective: 
- 
Hormonal contraceptive (such as oral, injection, transdermal patch, implant) if used for at least 30 
days prior to informed consent 
- 
Diaphragm with spermicide, tubal occlusion device 
- 
Intrauterine device (IUD) 

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- 
Tubal ligation 
- 
Male partner using condom with spermicide 
- 
Male partner having been vasectomized at least six months prior to informed consent 
3. Clinical conditions representing a contraindication to intramuscular vaccination and 
blood draws. 
4. Abnormal function of the immune system resulting from: 
a. Clinical conditions. 
b. Systemic administration of corticosteroids (PO/IV/IM) for more than 14 
consecutive days within 90 days prior to informed consent. 
c. Administration of antineoplastic and prescription immunomodulating agents or 
radiotherapy within 90 days prior to informed consent. 
5. Received immunoglobulins or any blood products within 180 days prior to informed 
consent. 
6. Received an investigational or non-registered medicinal product within 30 days prior 
to informed consent or intend to participate in another clinical study at any time 
during the conduct of this study. 
7. Vulnerable subjects (e.g. persons kept in detention), study personnel or an immediate 
family or household member of study personnel, subjects with legal incapacity or 
limited legal capacity 
8. Any relevant deviation from the laboratory parameters at screening as judged by the 
investigator. 
9. Previously received any vaccine that included a MenC antigen. 
10. Previously suspected or confirmed disease caused by N. meningitides. 
11. Had household contact with and/or intimate exposure to an individual with culture 
proven MenC. 
12. A positive serum or urine pregnancy test prior to the study vaccine administration or 
are currently lactating. 
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14. Received any other vaccines within 30 days prior to enrolment in this study or who 
are planning to receive any vaccine within 30 days from the administration of study 
vaccines. 
15. Any other condition that, in the opinion of the investigator, might interfere with the 
results of the study or pose additional risk to the subject due to participation in the 
study. 
4.3  
Criteria for Delay of Vaccination or Blood Draw 
There may be instances when individuals meet all eligibility criteria for vaccination or 
blood draw yet have a transient clinical circumstance which may warrant delay of 
vaccination or blood draw. Under such circumstances, a subject may be considered 
eligible for study enrolment after the appropriate window for delay has passed and 
inclusion/exclusion criteria have been rechecked, and if the subject is confirmed to be 
eligible. 
Reasons for delay of vaccination include: 
▫ Body temperature elevation ≥38.0°C (measured orally) within 3 days prior to intended 
study vaccination. 
▫ Use of antipyretics and/or analgesic medications within 24 hours prior to vaccination. 
Reasons for delay of blood draw include: 
▫ Subject has received a dose of systemic antibiotics less than 6 days before blood 
collection for the hSBA directed against MenC. 
 

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5.0  
STUDY PROCEDURES 
The sections that follow provide an overview of the procedures that are to be followed in 
enrolling, evaluating, and following subjects who participate in this clinical study. Visits 
can be either clinic visits or safety follow-up telephone calls, as specified in the Table 
below and in the Time and Events Tables 3 and 4 of the Study Synopsis. 
Table 5.0-1: Study procedures 
Visit Category 
Procedures 
Pre-vaccination Clinic Visit 
Section 5.1 describes procedures to be followed 
prior to subject enrollment, including: informed 
consent and screening procedures. 
Vaccination Clinic Visit 
Section 5.2 describes procedures to be followed 
during the vaccination clinic visit, including: 
prevaccination procedures, enrolment, 
randomization, vaccination and post-vaccination 
procedures. 
Post-vaccination Visits 
Section 5.3 describes follow-up clinic visits and 
safety follow-up calls. 
Unscheduled Visits 
Section 5.4 describes possible procedures to be 
followed at unscheduled clinic visit. 
Study Termination Visit 
Section 5.5 describes procedures to be followed at 
the last study visit for a subject (may include early 
termination visit). 
5.1 
Pre-vaccination Clinic Visit(s) 
The Pre-vaccination Clinic Visit must be performed in the period between Day -28 and 
Day -3. 
This section describes the procedures that must be performed for each potential subject 
prior to enrollment, including obtaining informed consent and screening. 
5.1.1  
Informed Consent 
"Informed consent" is the voluntary agreement of an individual or his/her legal 
guardian(s) to participate in research. Consent must be given with free will of choice, and 
without undue inducement. The individual must have sufficient knowledge and 
understanding of the nature of the proposed research, the anticipated risks and potential 
benefits, and the requirements of the research to be able to make an informed decision. 

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Informed consent following local IRB/EC guidance must be obtained before conducting 
any study-specific procedure (i.e., all of the procedures described in the protocol). Prior to 
any additional blood sample collection for exploratory objectives, a secondary informed 
consent must be signed by subjects. The process of obtaining informed consent should be 
documented in the subject source document in addition to maintaining a copy of the 
signed and dated informed consent. 
5.1.2  
Screening 
After an individual has consented to participate in the study and informed consent is 
signed, that individual will be given a unique Screening Number. The subject’s unique 
Screening Number will be documented in the Screening and Enrolment log. The 
eligibility of the subject will be determined based on the inclusion and exclusion criteria 
listed in section 4.0 and evaluated during this screening procedure. 
Screening procedures at the Pre-vaccination Clinical Visit (between Day -28 and Day -3) 
will include the following: 
▫ Review of demographic data, including age, gender, race, body weight and height. 
▫ Review of medical history, including but not limited to any medical history, ongoing 
illnesses or injuries that may be relevant to subject eligibility for study participation. 
Relevant medical history can also include any medical history that contributes to the 
understanding of an adverse event that occurs during study participation, if it 
represents an exacerbation of an underlying disease/pre-existing problem. 
▫ Perform physical examination, including but not limited to: 
- 
Assessment of general appearance 
- 
Collection of vital signs, including body temperature, blood pressure, heart rate 
and respiratory rate 
- 
Examination of head, ears, eyes, nose and throat (HEENT) 
- 
Examination of skin 
- 
Auscultation of heart and lungs 
▫ Collection and review of prior and concomitant medications or vaccinations taken 
prior to start of study (refer to section 6.5 for further details). 
▫ Collection of any unsolicited AEs occurring prior to administration of the study 
vaccine. 

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▫ Blood draw (approximately 10 ml) for Safety Laboratory assessments, measurement of 
Hepatitis B surface antigen, anti-Hepatitis C virus antibodies, anti-HIV 1 and 2 
antibodies and serum pregnancy test (all women). 
▫ Urine sample for Safety Laboratory assessments and drugs-of-abuse testing. 
NOTE: A general physical examination is to be performed by a qualified health care 
practitioner. “Qualified health care practitioner” refers to any licensed health care 
professional who is permitted by institutional policy to perform physical examinations 
and who is identified within the Study Staff Signature Log. 
Data collected during the Pre-vaccination Screening Clinic Visit must be written in the 
source document (see section 9.1) and will be captured in the screening CRF Forms. In 
the event that the individual is determined ineligible for study participation, he/she is 
considered a screen failure. The reason for screen failure must be documented in the 
Screening and Enrolment log. 
5.2  
Vaccination Clinic Visit(s) 
This section describes the procedures to be performed at the Vaccination Clinic Visit 
(Visit 1, Day 1), including: pre-vaccination procedures, enrolment, randomization, 
prevaccination blood draw, vaccination and post-vaccination procedures. 
5.2.1  
Pre-vaccination Procedures 
During pre-vaccination procedures at Visit 1 (Day 1), the eligibility of the subject will be 
confirmed based on the inclusion and exclusion criteria listed in section 4.0. 
Pre-vaccination procedures at Visit 1 (Day 1) will include the following: 
▫ Review of systems by means of a structured interview that queries the subject as to any 
complaints the subject has experienced across each organ system. 
▫ Perform physical examination, including but not limited to: 
- 
Assessment of general appearance 
- 
Assessment of body weight and collection of vital signs, including body 
temperature, blood pressure, heart rate, and respiratory rate 
- 
Examination of head, ears, eyes, nose and throat (HEENT) 
- 
Examination of skin 

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- 
Auscultation of heart and lungs 
▫ Collection and review of prior and concomitant medications or vaccinations taken, or 
recalled, since the last visit (refer to section 6.5 for further details). 
▫ Collection of any unsolicited AEs occurring prior to administration of the study 
vaccine. 
▫ One blood sample (approximately 10 ml) will be drawn from all subjects for serology 
testing. 
▫ One blood sample (approximately 10 ml) will be drawn from all subjects for baseline 
Safety Laboratory assessments. 
▫ Urine sample for baseline Safety Laboratory assessments, pregnancy testing (all 
women) and drugs-of-abuse testing. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of blood draws are provided in section 3.5. 
NOTE: A general physical examination is to be performed by a qualified health care 
practitioner. “Qualified health care practitioner” refers to any licensed health care 
professional who is permitted by institutional policy to perform physical examinations 
and who is identified within the Study Staff Signature Log. 
Data collected during pre-vaccination procedures at Visit 1 must be written in the source 
document (see section 9.1). In the event that the individual is determined ineligible for 
study participation, he/she is considered a screen failure. The reason for screen failure 
must be documented in the Screening and Enrolment log. If the individual is determined 
to be eligible for the study, he/she can be enrolled into the study. 
5.2.2 
Enrolment 
After an individual is determined to be eligible for study participation, the investigator 
will enroll the subject into the Electronic Data Capture (EDC) system where the 
randomization to the treatment group will occur. The Screening Number ceases to be used 
and remains in the Screening and Enrolment Log only. 
If for any reason, after signing the informed consent form (ICF), the subject who is 
eligible and enrolled fails to be randomized, this is called a randomization failure. In this 
case the early termination study procedures must be applied. The reason for all 
randomization failures should be recorded in the Screening and Enrolment Log and in the 

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source document as specified in the Source Data Agreement. The information on subjects 
who are randomization failures should be kept distinct from subjects who are screen 
failures, as described in section 5.1.2 and section 5.2.1. 
5.2.3 
Randomization 
Enrolled subjects will be randomized and automatically assigned a unique Subject ID. 
The Subject ID will be the subject’s unique identification number for all CRFs and 
associated study documentation that will be used for the duration of the study. 
If for any reason, after signing the informed consent form (ICF), the eligible subject is 
enrolled and randomized but fails to undergo treatment, this is an Early Termination and 
the reason should be recorded in source document as specified in the Source Data 
Agreement/Source Data Verification Form. The information on these Early Termination 
subjects should be kept distinct in the source documentation from randomization failures, 
which are described in section 5.2.2. 
5.2.4 
Vaccination 
After completing the pre-vaccination procedures at Visit 1 (Day 1), administer the 
vaccine to the subject according to the procedures described in section 6.3. Observe the 
blinding procedures described in section 3.3. 
5.2.5 
Post-vaccination Procedures 
The following post-vaccination procedures will be performed at Visit 1 (Day 1): 
▫ After vaccination, the subject will be observed for at least 30 minutes for any 
immediate solicited and unsolicited AEs and a body temperature measurement at 30 
min after vaccination. All safety and body temperature data collected during this time 
are to be recorded in the subject’s source document. 
▫ After vaccination, the subject will be observed for at least 24 hours at the clinic 
including observation for solicited and unsolicited AEs and body temperature 
measurements . Body temperature measurements must be performed at 2, 4, 6, 8, 10, 
12, 20 and 24 hours after vaccination. All safety and body temperature data collected 
during this time are to be recorded in the subject’s source.. 
▫ From those subjects that signed an additional Informed Consent for exploratory assays, 
additional blood samples will be drawn in the first 24 hours after vaccination. Details 
regarding the number and volume of post-vaccination blood draws are provided in 
section 3.5. 

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After the initial 24 hours inpatient observation period, a Subject Diary will be used in this 
study to document solicited and unsolicited AEs until Day 14. The Subject Diary is the 
only source for collection of solicited AEs after the initial 24 hours inpatient observation 
period. Therefore, it is critical that the subject completes the Subject Diary correctly. 
The following training regarding completion of the Subject Diary must be provided: 
▫ The subject should be trained on how and when to complete each field of the Subject 
Diary. 
▫ The subject should be trained on how to self-measure local solicited adverse events 
and body temperature. The measurement of solicited local adverse events is to be 
performed using the ruler provided by the site. 
▫ The subject should be instructed how to perform body temperature measurement using 
the thermometer provided by the site. If the subject feels unusually hot or cold during 
the day, the subject should check their body temperature. If the subject has fever, the 
highest body temperature observed that day should be recorded in the Subject Diary. 
Subject Diary training should be directed at the individual(s) who will perform the 
measurements of adverse events and who will enter the information into the Subject 
Diary. This individual may not be the subject, but if a person other than the subject enters 
information into the Subject Diary, this person’s identity must be documented in the 
Subject Diary. Any individual that writes in the Subject Diary must receive training on 
completion of the Diary Card at the time of the visit. This training must be documented in 
the subject’s source record. 
The site should schedule the next study activity (clinic visit) with the subject. 
The subject will receive a written reminder of the next planned study activity. The subject 
will be reminded to complete the Subject Diary and to contact the site if there are any 
questions, and to contact the site immediately (or as soon as the subject is medically 
stable) if the subject has a medical condition that leads to a hospitalization or an 
emergency room visit. 
5.3  
Post-vaccination Visit(s) 
5.3.1 Subject Diary Reminder, Safety Follow-up and/or Post-vaccination Blood 
Draw Clinic Visits 

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Subject Diary reminder, Safety follow-up and/or post-vaccination blood draw clinic visits 
will be performed on Day 4 (Visit 2), Day 8 (Visit 3), Day 15 (Visit 4), Day 29 (Visit 6), 
Day 85 (Visit 7), Day 113 (Visit 8) and Day 181 (Visit 9) 
At Day 4 (Visit 2) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. All unsolicited AEs, SAEs, AESIs, 
medically attended AEs, AEs leading to study withdrawal and NOCD must be 
recorded on source documents. Any concomitant medications or vaccinations 
associated with those events must also be recorded on the source documents. 
▫ All subjects will be reminded to complete the Subject Diary and to contact the site if 
there are any questions, and to contact the site immediately (or as soon as the subject 
is medically stable) if the subject has a medical condition that leads to a 
hospitalization or an emergency room visit. No changes to the Subject Diary should 
be done at the clinic visit. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of blood draws are provided in section 3.5. 
▫ The site should schedule the next study activity (clinic visit) with the subject and the 
subject will receive a written reminder of the next planned study activity. 
At Day 8 (Visit 3) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. All unsolicited AEs, SAEs, AESIs, 
medically attended AEs, AEs leading to study withdrawal and NOCD must be 
recorded on source documents. Any concomitant medications or vaccinations 
associated with those events must also be recorded on the source documents. 
▫ The subject will be reminded to complete the Subject Diary and to contact the site if 
there are any questions, and to contact the site immediately (or as soon as the subject 
is medically stable) if the subject has a medical condition that leads to hospitalization 

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or an emergency room visit. No changes to the Subject Diary should be done at the 
clinic visit. Blood draw (approximately 10 ml) from all subjects for Safety Laboratory 
assessments. 
▫ Urine sample from all subjects for Safety Laboratory assessments. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of blood draws are provided in section 3.5. 
▫ The site should schedule the next study activity (clinic visit) with the subject and the 
subject will receive a written reminder of the next planned study activity. 
At Day 15 (Visit 4) the following procedures will be performed: 
▫ The Subject Diary will be collected and reviewed. No changes to the Subject Diary 
should be done at the clinic visit. For details on the Subject Diary see sections 3.4.2, 
and 5.2.5. The healthcare professional reviewing these data will discuss the symptoms 
(if any) reported by the subject and will determine if any additional diagnoses and/or 
adverse events are present. All unsolicited AEs until Day 14, solicited local and 
systemic AEs persisting at Day 14, SAEs, AESIs, medically attended AEs, AEs 
leading to study withdrawal and NOCD must be recorded on source documents. All 
concomitant medications or vaccinations associated with those events must also be 
recorded on the source documents. 
▫ The site should schedule the next study activity (safety phone call) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 29 (Visit 6) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. Any solicited local and systemic AEs 
continuing beyond Day 14, SAEs, AESIs, medically attended AEs, AEs leading to 
study withdrawal and NOCD must be recorded on source documents. All concomitant 

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medications or vaccinations associated with those events must also be recorded on the 
source documents. 
▫ Blood draw (approximately 10 ml) from all subjects for Safety Laboratory 
assessments. 
▫ Urine sample from all subjects for Safety Laboratory assessments. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of post-vaccination blood draws are provided in section 3.5. 
▫ The site should schedule the next study activity (clinic visit) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact  
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 85 and Day 113 (Visit 7 and Visit 8), the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. Any solicited local and systemic AEs 
continuing beyond Day 14, SAEs, AESIs, medically attended AEs, AEs leading to 
study withdrawal and NOCD must be recorded on source documents. All concomitant 
medications or vaccinations associated with those events must also be recorded on the 
source documents. 
▫ The site should schedule the next study activity (clinic visit) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 181 (Visit 9), the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 

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the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. Any solicited local and systemic AEs 
continuing beyond Day 14, SAEs, AESIs, medically attended AEs, AEs leading to 
study withdrawal and NOCD must be recorded on source documents. All concomitant 
medications or vaccinations associated with those events must also be recorded on the 
source documents. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of post-vaccination blood draws are provided in section 3.5. 
▫ The site should schedule the next study activity (safety phone call) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
5.3.2  
Safety Follow-up Calls 
Safety follow-up calls will be performed on Day 22 (Visit 5), Day 209 (Visit 10) and Day 
271 (Visit 11) and include the following procedures: 
▫ Safety follow-up calls are calls made to the subject by a healthcare professional 
designated on the site log. These calls will follow a script which will facilitate the 
collection of relevant safety information. The subject will be interviewed according to 
the script, and information relating to solicited local and systemic AEs persisting 
beyond Day 14 and unsolicited adverse events including SAEs, AESIs, medically 
attended AEs, AEs leading to study withdrawal, and/or NOCD and concomitant 
medications or vaccinations associated with those events. All safety information 
described by the subject must be written down in a designated location within the 
source document and not written on the script used for the telephone call. 
▫ The site should schedule the next study activity (clinic visit or study termination visit) 
with the subject. 
▫ The subject will be reminded to contact the site if there are any questions and to 
contact the site immediately (or as soon as the subject is medically stable) if the 
subject has a medical condition that leads to a hospitalization or an emergency room 
visit. 

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5.4  
Unscheduled Visits  
An unscheduled visit describes a non-routine study visit triggered by a specific event. 
These could include anticipated or unanticipated adverse events or interventions. 
The following procedures should be carried out for all unscheduled visits: 
1. Evaluate the subject’s vital signs body temperature, heart rate, and blood pressure and 
perform a symptom-directed physical examination. 
2. Record any observed AEs in the source documents. 
3. Record any concomitant medications or vaccinations associated with AEs in the 
source documents. 
5.5  
Study Termination Visit 
The study termination visit is scheduled on Day 366 (Visit 12). The termination visit is a 
clinic visit. For visit procedures to be performed for a subject whose planned study 
participation ends prematurely, please see section 5.5.1. 
At the Study Termination clinic visit the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. 
▫ The healthcare professional reviewing these data will discuss the symptoms (if any) 
reported by the subject and will determine if any additional diagnoses and/or adverse 
events are present. 
▫ Medically attended AEs, SAEs, NOCDs, or AESIs will be recorded on source 
documents. 
▫ All medications taken or vaccines received will also be recorded on the source 
documents. 
▫ The site will review with the subject the plan of when information relating to the 
subject’s participation in the study may be available (e.g., study results, treatment 
assignments). It will also be discussed how information relating to the subject’s 
participation in the study will be shared with the subject’s healthcare provider, if the 
subject chooses to share this information. 
▫ The site will complete the termination CRF page and this will mark the completion of 
the subject’s participation in the study. 

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5.5.1  
Early Termination Visit 
The date of termination is the date of the last contact in which the subject’s health status 
was assessed or, in cases where the subject does not agree to any further safety follow-up, 
it is the date consent is withdrawn. This date should be recorded on the appropriate CRF 
page. 
When a subject is withdrawn from treatment or withdraws from the study, the investigator 
will notify the Sponsor and, when possible, will perform the procedures listed below. 
The reason(s) for the early termination must be included in the subject’s source 
documentation. If the Early Termination Visit is a telephone call, collect as much 
information as possible. Early Termination Visits include subjects who were randomized 
but not treated. 
At the clinic visit or during the telephone call, the following procedures should be 
performed, when possible: 
▫ Collection and review of Subject Diary (if not already collected). 
▫ Interview of subject to collect unsolicited adverse events, medically attended AEs, 
AEs leading to withdrawal, SAEs, AESIs, and NOCD. 
▫ Interview of subject to collect concomitant medications and/or vaccinations. 
▫ Symptom-directed physical assessment, at least including measurement of vital signs 
(body temperature, respiratory rate, blood pressure, heart rate) and a check of general 
appearance (in case of clinic early termination visit). 
▫ Draw a blood sample (approximately 10 ml) and a urine sample for Safety Laboratory 
assessment (in case of clinic early termination visit). 
▫ The site will review with the subject the plan of when information relating to the 
subject’s participation in the study may be available (e.g., study results, treatment 
assignments). It will also be discussed how information relating to the subject’s 
participation in the study will be shared with the subject’s healthcare provider, if the 
subject chooses to share this information. 
▫ The site will complete the appropriate CRF page and this will mark the completion of 
the subject’s participation in the study. 
 

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6.0  
TREATMENT OF SUBJECTS 
All vaccines associated with this study are to be stored separately from other vaccines and 
medications in a secure location under appropriate storage conditions with temperature 
monitoring. All vaccines associated with this study must be checked for expiration 
date prior to use. Expired vaccines must not be administered to subjects. 
6.1  
Study Vaccine(s) 
The term ‘study vaccine’ refers to those vaccines provided by the Sponsor, which will be 
evaluated as part of the study objectives. The study vaccines specific to this study are 
described in Table 6.1-1. 
Table 6.1-1: Study Vaccine Composition 
Group A (Control) Meningococcal C-CRM197 Conjugate Vaccine 
 
Vaccine Component 
Quantity per 0.5 ml dose 
 
 
Vial Containing Vaccine Conjugate 
 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
 
Aluminum Hydroxide Solvent Components (for 0.5 mL dose) 
 
Aluminum hydroxide 
1.0 mg 
Sodium Chloride 
3.5 mg 
Sterile water for injection, up to 
0.5 ml 
 
 
Group B (12.5µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
 

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Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
12.5 µg 
Sodium Chloride 
3.4 mg 
Histidine  
0.1 mg 
Tris 
30 µg 
Sterile water for injection, up to 
0.5 ml 
 
 
Group C (25 µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
25 µg 
Sodium Chloride 
3.4 mg  
Histidine 
0.2 mg 
Tris 
61 µg 
Sterile water for injection, up to 
0.5 ml 

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Group D (50µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
50 µg 
Sodium Chloride 
3.2 mg 
Histidine 
0.4 mg 
Tris 
121 µg 
Sterile water for injection, up to 
0.5 ml 
 
Group E (100µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 

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Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
100 µg 
Sodium Chloride 
2.9 mg 
Histidine 
0.8 mg 
Tris 
243 µg 
Sterile water for injection, up to 
0.5 ml 
6.2  
Non-Study Vaccines 
The term ‘non-study vaccine’ refers to those vaccines which will be intentionally given to 
study subjects but not formally included in the analysis of study objectives. 
No non-study vaccines are planned for this study. Any non-study vaccines administered 
during the study conduct will be captured in the CRF as concomitant medications and/or 
vaccinations. 
6.3  
Vaccine Preparation and Administration 
The investigator or designee will be responsible for oversight of the administration of 
vaccine to subjects enrolled in the study according to the procedures stipulated in this 
study protocol. All vaccines will be administered only by unblinded personnel who are 
qualified to perform that function under applicable local laws and regulations for the 
specific study site. 
The vaccine components will be provided in 5 separate kits (i.e. one for the control and 
one for each of the 4 dosage groups). The vaccine components must be mixed prior to 
vaccination taking into account the appropriate aseptic procedures. Detailed vaccine 
preparation and administration instructions, including the maximal administration period, 
will be provided to investigators prior to study start and must be filed in the Investigator 
Site File. 
PRECAUTIONS TO BE OBSERVED IN ADMINISTERING STUDY VACCINE: 
- 
Prior to vaccination, subjects must be determined to be eligible for study vaccination 
and it must be clinically appropriate in the judgment of the investigator to vaccinate. 
Eligibility for vaccination prior to first study vaccine administration is determined by 
evaluating the entry criteria outlined in protocol sections 4.0. 

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- 
Study vaccines must not be administered to individuals with known hypersensitivity 
to any component of the vaccines. 
- 
Standard immunization practices are to be observed and care should be taken to 
administer the injection intramuscularly. Before administering vaccine, the 
vaccination site is to be disinfected with a skin disinfectant (e.g., 70% alcohol). Allow 
the skin to dry. DO NOT inject intravascularly. 
- 
As with all injectable vaccines, trained medical personnel and appropriate medical 
treatment must be readily available in case of anaphylactic reactions following 
vaccine administration. For example, epinephrine 1:1000, diphenhydramine, and/or 
other medications for treating anaphylaxis should be available. 
6.4 
Vaccine Administration Error or Overdose of Vaccine 
Vaccine administration error is defined as receiving a dose of study vaccine that was not 
reconstituted as instructed or administered by a different route from the intended route of 
administration. An overdose of study vaccine (whether accidental or intentional) is 
defined when a dosage higher than the recommended dosage is administered in one dose 
of study vaccine. 
Any vaccine administration error or overdose of study vaccine detailed in this protocol 
must be reported as an adverse event, and if the vaccine administration error or overdose 
is associated with a serious adverse event, it must be reported as such within 24 hours to 
the Sponsor. 
6.5 
Prior and Concomitant Medications and Vaccines 
All medications, vaccines and blood products taken or received by the subject within 180 
days prior to the start of the study are to be recorded in the appropriate CRF. 
Medications taken for prophylaxis are those intended to prevent the onset of symptoms. 
Medications taken for treatment are intended to reduce or eliminate the presence of 
symptoms that are present. 
NOTE: Use of antipyretics/analgesics within 24 hours prior to vaccine administration is a 
reason to delay study vaccination (see section 4.3). 
Concomitant medications include all medications (including vaccines) taken 
by/administered to the subject at and after enrolment and must be documented in the 
appropriate CRF. 

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When recording concomitant medications/vaccines, they should be checked against the 
study entry criteria in section 4.0, to ensure that the subject should be enrolled in the 
study. 
6.6  
Vaccine Supply, Labeling, Storage and Tracking 
The Sponsor will ensure the following: 
▫ Supply the study vaccines. 
▫ Appropriate labeling of all study vaccines provided that complies with the legal 
requirements of each country where the study is to be performed. 
The investigator must ensure the following: 
▫ Acknowledge receipt of the study vaccines by a designated staff member at the site, 
including: 
- 
Confirmation that the vaccines were received in good condition 
- 
Confirmation to the Sponsor of the temperature range during shipment from the  
Sponsor to the investigator’s designated storage location 
- 
Confirmation by the Sponsor that the vaccines are authorized for use. 
▫ Proper storage of the study vaccines, including: 
- 
Storage in a secure, locked, temperature-controlled location. 
- 
Proper storage according to the instructions specified on the labels. 
- 
Appropriate record keeping and inventory of the study vaccines, including regular 
documentation of adequate storage temperature. 
▫ Appropriate use of the study vaccines, including: 
- 
No use of vaccines prior to receipt of authorization for use from the Sponsor. 
- 
Use only in accordance with the approved protocol. 
- 
Proper handling, including confirmation that the vaccine has not expired prior to 
administration. 
- 
Appropriate documentation of administration of vaccines to study subjects 
including: 
▪ 
Date, dosage, batch/lot numbers, expiration dates, unique identifying 
numbers assigned to subjects and study vaccines, and time of vaccine 

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administration. This information will be maintained in an accountability log 
that will be reviewed by the site monitor. 
▪ 
Reconciliation of all vaccines received from the Sponsor. Reconciliation is 
defined as maintaining records of which and how many vaccines were 
received, which vaccines were administered to subjects, which vaccines 
were destroyed at the site, and which vaccines were returned to the Sponsor, 
as applicable. 
▫ Proper adherence to the local institutional policy with respect to destruction of study 
vaccines. 
▫ Complete record keeping of vaccine use, wastage, return or destruction, including 
documentation of: 
- 
Copy of the site’s procedure for destruction of hazardous material. 
- 
Number of doses destroyed, date of destruction, destruction code (if available), 
method of destruction, and name of individual performing destruction. 
Vaccines that have been stored differently from the manufacturer’s indications must not 
be used unless the Sponsor provides written authorization for use. In the event that the use 
cannot be authorized, the Sponsor will make every effort to replace the vaccine supply. 
All vaccines used in conjunction with this protocol must be stored separately from normal 
hospital/practice stocks to prevent unintentional use of study vaccines outside of the 
clinical study setting. 
Monitoring of vaccine accountability will be performed by the study monitor during site 
visits and at the completion of the study. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator must ensure that all unused study vaccines, packaging and supplementary 
labels are destroyed locally (upon approval from Sponsor) or returned to the Sponsor. 

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7.0 
ASSESSMENTS 
7.1 
Safety Assessment 
The measures of safety used in this study are based on previous study data and based on 
comparable routine clinical/laboratory procedures. They include a close vigilance for, and 
stringent reporting of selected local and systemic adverse events routinely monitored in 
vaccine studies as indicators of reactogenicity. 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product at any dose that does 
not necessarily have to have a causal relationship with this treatment. Therefore, an AE 
can be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the investigational product. 
This definition includes intercurrent illnesses or injuries and exacerbation of pre-existing 
conditions. 
The period of observation for AEs extends from the time the subject signs informed 
consent until he or she completes the specified safety follow-up period (Day 366) or 
terminates the study early (whichever comes first). AEs occurring after the informed 
consent form is signed but prior to receiving study vaccine/product will be documented as 
an adverse event and recorded within the source documents. However, any AEs occurring 
prior to receipt of any study vaccine will be analyzed separately from “treatment 
emergent” AEs (AEs occurring after administration of the first study vaccine). 
Adverse events are collected as either solicited or unsolicited adverse events. Solicited 
events are derived from organized data collection systems, such as Subject Diaries or 
interview. 
7.1.1 
Solicited Adverse Events 
The term “reactogenicity” refers to solicited signs and symptoms (“solicited adverse 
events”) occurring in the hours and days following a vaccination, to be collected by the 
subject after the first 24 hours inpatient observation period at Day 1until Day 14, using a 
pre-defined Subject Diary. 
The following solicited adverse events are included in the Subject Diary. Each adverse 
event is to be assessed using the scoring system shown in Appendix A (Solicited Local 
AEs) and Appendix B (Solicited Systemic AE): 

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Solicited Local Adverse Events 
Solicited local AEs include: 
- 
injection site erythema 
- 
injection site induration 
- 
injection site pain 
- 
injection site swelling Solicited Systemic Adverse Events 
Solicited systemic AEs include: 
- 
body temperature ≥38.0°C (as measured orally) 
- 
loss of appetite 
- 
nausea 
- 
fatigue 
- 
generalized myalgia 
- 
generalized arthralgia 
- 
headache 
- 
chills 
- 
vomiting 
- 
diarrhea 
- 
generalized rash 
- 
urticaria 
Other Solicited Data 
Other solicited data collected per Subject Diary include: 
▫ Use of analgesics/antipyretics recorded as “absent” or “present” and summarized by 
“for treatment” or “for prophylaxis” 
▫ Body temperature as recorded daily, ideally at same time, by the oral route 
The study staff must review the data entered into the Subject Diary as described in 
sections 3.4.2 and 5.3.1. 

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NOTE: Any solicited adverse event that meets any of the following criteria must be 
entered into the subjects’ source documents (see section 9.1) and also as an adverse event 
in the appropriate CRF: 
▫ Solicited local or systemic adverse event that continues beyond Day 14 after 
vaccination. 
▫ Solicited local or systemic adverse event that leads to a visit to a healthcare provider 
(medically attended adverse event, see section 7.1.3). 
▫ Solicited local or systemic adverse event leading to the subject withdrawing from the 
study or the subject being withdrawn from the study by the investigator (adverse event 
leading to withdrawal, see section 7.1.3). 
▫ Solicited local or systemic adverse event that otherwise meets the definition of a 
serious adverse event (see section 7.1.4). 
7.1.2  
Unsolicited Adverse Events 
An unsolicited adverse event is an adverse event that was not solicited using a Subject 
Diary and that was spontaneously communicated by a subject who has signed the 
informed consent. 
7.1.3  
Evaluation of Adverse Events 
Every effort should be made by the investigator to evaluate safety information reported by 
a subject for an underlying diagnosis and to capture this diagnosis as the event in the AE 
page. In other words, the practice of reporting only symptoms (e.g., “cough” or “ear 
pain”) are better reported according to the underlying cause (e.g., “asthma exacerbation” 
or “otitis media”). 
The severity of events reported on the appropriate CRF page will be determined by the 
investigator as: 
Mild: 
transient with no limitation in normal daily activity. 
Moderate: 
some limitation in normal daily activity. 
Severe: unable to perform normal daily activity. 
The relationship of the study treatment to an AE will be determined by the investigator 
based on the following definitions: 

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1. Not Related 
The AE is not related to an investigational vaccine if there is evidence that clearly 
indicates an alternative explanation. If the subject has not received the vaccine, the timing 
of the exposure to the vaccine and the onset of the AE are not reasonably related in time, 
or other facts, evidence or arguments exist that reasonably suggest an alternative 
explanation, then the AE is not related. 
2. Possibly Related 
The administration of the investigational vaccine and AE are considered reasonably 
related in time and the AE could be explained by exposure to the investigational vaccine 
or by other causes. 
3. Probably Related 
Exposure to the investigational vaccine and AE are reasonably related in time and no 
alternative explanation has been identified. 
The relationship of the study treatment to an unsolicited AE will be determined by the 
investigator.  
Note: solicited AEs will not be evaluated for relationship to study treatment. Grading for 
severity of solicited local and systemic AEs is described in Appendix A and Appendix B. 
Adverse events will also be evaluated by the investigator for the co-existence of any of 
the other following conditions: 
▫ “Medically attended adverse event”: an adverse event that leads to a visit to a 
healthcare provider. 
▫ “New onset of chronic disease” (NOCD): an adverse event that represents a new 
diagnosis of a chronic medical condition that was not present or suspected in a subject 
prior to study enrolment. 
▫ AEs leading to withdrawal: adverse events leading to study or vaccine withdrawal. 
All AEs, regardless of severity, will be monitored until resolution or until the investigator 
assesses them as chronic or stable. All subjects experiencing AEs - whether considered 
associated with the use of the study vaccine or not - must be monitored until symptoms 
subside and any abnormal laboratory values have returned to baseline, or until there is a 
satisfactory explanation for the changes observed, or until death, in which case a full 
pathologist’s report should be supplied, if possible. 

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7.1.4  
Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose results in one or more of the following: 
▫ Death. 
▫ Is life-threatening (i.e., the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred); it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
▫ Required or prolonged hospitalization. 
▫ Persistent or significant disability/incapacity (i.e., the event causes a substantial 
disruption of a person’s ability to conduct normal life functions). 
▫ Congenital anomaly/or birth defect. 
▫ An important and significant medical event that may not be immediately life 
threatening or resulting in death or hospitalization but, based upon appropriate 
medical judgment, may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed above. 
Adverse events which do not fall into these categories are defined as non-serious. 
It should be noted that a severe adverse event need not be serious in nature and that a 
serious adverse event need not, by definition, be severe. 
Serious adverse events will be captured both on the Vaccines Serious Adverse Event 
(VSAE) form as well as on the appropriate CRF page. All SAEs will be evaluated by the 
investigator for relationship of the event to study vaccine. SAEs that are judged to be 
possibly or probably related to the study vaccine should be reported to the Sponsor as 
related/suspected events. 
The relationship of the study treatment to an SAE will be determined by the investigator 
based on the following definitions: 
1. Related/suspected 
The SAE is judged by the investigator to be possibly or probably related to the study 
vaccine on the appropriate CRF page (see section 7.1.3). 

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2. Not Related 
The SAE is not related if exposure to the study vaccine has not occurred, or the 
occurrence of the SAE is not reasonably related in time, or the SAE is considered 
unlikely to be related to use of the study vaccine, i.e., there are no facts (evidence) or 
arguments to suggest a causal relationship. 
The relationship of the study vaccine to an SAE will be determined by the investigator. 
In addition, SAEs will be evaluated by the Sponsor or designee for “expectedness.” An 
unexpected AE is one that is not listed in the current Summary of Product Characteristics 
or the Investigator’s Brochure or an event that is by nature more specific or more severe 
than a listed event. 
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded on the appropriate CRF. If the onset of an event occurred before the subject 
entered the study (e.g., any pre-planned hospitalization for conditions like cosmetic 
treatments or for non-emergency routine visits for a pre-existing condition), the 
hospitalization would not lead to an AE being classified as serious unless, in the view of 
the investigator, hospitalization was prolonged as a result of participation in the clinical 
study or was necessary due to a worsening of the pre-existing condition. 
7.1.4.1  
Adverse Events of Special Interest 
Certain adverse events of special interest (AESIs) are monitored after the administration 
of immunostimulatory agents. All subjects enrolled in this study will be monitored for 
AESIs for the entire follow-up period. The AESIs will be defined according to MedDRA 
preferred terms. The investigator will be provided with a list of AESIs prior to study start. 
Receipt of this list will be notified and stored, along with the list of AESIs, in the 
Investigator Site File. During the course of the trial the list of AESIs may change. If this 
occurs, the investigators will be advised of the change and confirmation of receipt will be 
documented. The updated list of AESIs and documentation of receipt are also stored in 
the Investigator Site File. The occurrence of any of these adverse events will be treated as 
a serious adverse event (SAE), meeting the criterion of a “medically important event.” 
Subjects will be assessed for diagnosis of an AESI at the following visits: 
- 
Pre-vaccination clinic visit (Day -28 to Day -3)  
- 
Visit 1 (Day 1, pre-vaccination) 
- 
Visit 2 (Day 4) 

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- 
Visit 3 (Day 8) 
- 
Visit 4 (Day 15) 
- 
Visit 5 (Day 22; Safety Follow-Up Call) 
- 
Visit 6 (Day 29) 
- 
Visit 7 (Day 85) 
- 
Visit 8 (Day 113) 
- 
Visit 9 (Day 181) 
- 
Visit 10 (Day 209; Safety Follow-Up Call) 
- 
Visit 11 (Day 271; Safety Follow-Up Call) 
- 
Visit 12 (Day 366; Study Termination Visit) 
At these visits a qualified health care practitioner listed on the site’s responsibilities and 
delegation logs will conduct a review of organ systems and a targeted physical exam and 
will evaluate subjects for any new signs or symptoms that could indicate one of the 
AESIs as specified in the list of AESIs stored in the Investigator Site File. They will also 
interview the subject about recent medical history and any new diagnosis that could 
indicate an AESI. Medical records related to any new medical event or diagnosis will be 
requested, reviewed by the site staff, and recorded in the subject’s source documents. 
A diagnosis of an AESI will be reported in the same manner and time frame as an SAE 
using the VSAE form. The investigator must notify Novartis within 24 hours. The AESI 
diagnosis, as well as any medications taken to treat the condition, will be recorded in the 
subject’s source documents and on the appropriate CRF. 
7.1.5  
Methods for Recording Adverse Events and Serious Adverse Events 
All findings regarding Adverse Events must be reported on the appropriate CRF page and 
on the VSAE form, if applicable, which is part of the Investigator Site File. All findings 
in subjects experiencing AEs must be reported also in the subject's source document. 
All SAEs which occur during the course of the study, whether considered to be associated 
with the study vaccination or not, must be reported within 24 hours of the site becoming 
aware of the event to Novartis or its designee. Specific instructions and contact details 
for collecting and reporting SAEs to Novartis will be provided to the investigator. 

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All SAEs are also to be documented on the appropriate CRF page. Any medication or 
other therapeutic measures used to treat the AE will be recorded on the appropriate 
CRF(s) in addition to the outcome of the AE. 
After receipt of the initial report, representatives of Novartis or its designee will contact 
the investigator if it is necessary to obtain further information for assessment of the event. 
All SAEs must be reported by the investigator to his/her corresponding EC and applicable 
regulatory authorities in accordance with institutional policy/regulatory requirements and 
adequate documentation of this notification must be provided to the Sponsor. 
Novartis or its designee must also comply with the applicable regulatory requirement(s) 
related to the reporting of suspected unexpected serious adverse vaccine reactions (also 
known as SUSARs) to the regulatory authority(ies) and the IRB/EC. If a SUSAR or other 
safety signal relating to use of one of the study vaccines is reported to Novartis or its 
designee, the Sponsor will communicate the information to the investigator and the 
investigator will be responsible for submitting this information to the EC and other 
relevant authorities. 
7.1.5.1 
Post-Study Events 
Any suspected SAE that occurs outside of the protocol-specified follow-up period or after 
the end of the study but considered to be caused by the study vaccine must be reported to 
Novartis or its designee. These SAEs will be processed by Novartis or its designee as 
during the course of the study, until 3 months after the last scheduled study visit. 
Instructions and contact details for collecting and reporting these suspected SAEs will be 
provided to the investigator. 
7.1.6  
Pregnancies 
To ensure subjects’ safety, each pregnancy in a subject after study vaccination must be 
reported to Novartis within 72 hours of the site learning of its occurrence. If the subject 
agrees to submit this information, the pregnancy must be followed to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. This follow-up should occur even if intended duration of safety follow-up 
for the study has ended. 
Pregnancy data must be recorded on a Pregnancy Report CRF (initial report) and 
Pregnancy Follow-Up CRF (outcome report). 

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Any pregnancy outcome meeting the definition of a SAE (see section 7.1.4) must also be 
reported on the VSAE Report Form. 
7.1.7  
Safety Laboratory Measurements 
Blood and urine samples will be collected from all subjects at the Pre-vaccination 
Screening, at Visit 1, at Visit 3 and at Visit 6 as outlined in Time and Events Table 3. The 
blood safety laboratory assessments will include sodium, potassium, chloride, 
bicarbonate, blood urea nitrogen, creatinine, liver function tests (ALT, AST), a complete 
blood count and C-reactive protein. The urine safety laboratory assessments will include 
protein, glucose and red blood cells. An additional blood and urine sample will be 
collected in case of a clinic Early Termination Visit as outlined in section 5.5.1. 
All testing will be conducted by qualified and certified laboratories. Abnormal laboratory 
values will be defined following the FDA CBER Guidance for Industry “Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials” dated September 2007, or the institution’s normal ranges if they 
differ from CBER guidance. Please see Appendix C, D and E for further details on the 
Toxicity Grading Scales according to CBER. 
Retesting may be performed in case of abnormal values per guidance of the investigator.  
Retest results will not be captured in the CRF. 
7.2  
Efficacy Assessment 
Efficacy measurement will not be performed as part of this study. 
7.3  
Immunogenicity Assessment 
The measures to assess the primary and secondary immunogenicity endpoints for this 
study are standard, i.e., widely used and generally recognized as reliable, accurate, and 
relevant (able to describe the quality and extent of the immune response). 
The assay’s used in this study to assess the primary and immunogenicity endpoints are 
human serum bactericidal assay (hSBA) and ELISA specific for MenC 
The hSBA is a functional measure of the ability of specific antibodies, in conjunction 
with human complement, to kill MenC indicator strains, and is widely used and generally 
recognized as the serological correlate of protection. The specific ELISA will be used to 
measure the induction of antibodies directed against MenC following vaccination with the 
study vaccines. 

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Blood samples (approximately 10 ml) to obtain serum for hSBA and ELISA assays will 
be collected at Day 1, Day 8, Day 29 and Day 181 (refer to section 3.5 for detailed 
specimen collection procedures). 
Testing will be conducted by a Novartis or designated laboratory in a blinded manner 
towards the treatment group. Laboratory contact details are listed in the Protocol 
Ancillary Document. 
All data will be captured at the laboratory and transferred via Electronic Data Transfer  
(EDT) 
Details on all blood sample handling steps are described in the Clinical Specimen Lab 
Manual provided to the study site. 
7.4 
Exploratory Measurements 
In those subjects who agree to a separate Informed Consent, additional blood samples will 
be collected at Day 1, Day 4, Day 8, Day 29 and Day 181 for exploratory measurements. 
The purpose of these exploratory measurements is to assess the systemic exposure of 
LHD153, to further delineate vaccine induced antigen specific immune responses and to 
evaluate  biomarkers that may be predictive for safety and/or innate immune activation. 
All exploratory measurements will be conducted by a Novartis or a designated laboratory. 
Laboratory contact details are listed in the Protocol Ancillary Document. 
Exploratory measurements may be performed after the Clinical Study Report (CSR) has 
been completed, in which case these data will be submitted as an addendum to the CSR. 
Systemic exposure of LHD153 
Systemic exposure of LHD153 will be assessed by analyzing LHD153 blood plasma 
levels at Day 1 (baseline, 1, 2, 4, 8 and 24h after vaccination) and Day 4 using 
LC/MS/MS. Time-points for assessment of clinical exposure of LHD153 have been 
selected based on non-clinical data in dogs and rats. 
Vaccine-induced antigen-specific immune responses 
The frequency of B cells specific for MenC polysaccharide and CRM197 will be 
determined by enzyme-linked immunosorbent spot (ELISPOT) at Day 1, Day 8, Day 29 
and Day 181 in order to evaluate the baseline specific B-cell frequency (Day 1), the peak 
of plasmablast responses (Day 8), the peak of B cell memory responses (Day 29), and the 
persistence of memory B cell responses (Day 181). 

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Subsequently, the diversity of the antigen specific B-cell repertoire as well as the specific 
antibody functionality will be analyzed in a selected subset of subjects. The selection of 
the subset will be based on the most pronounced response to the study vaccines when 
compared to baseline as determined by the primary and secondary immunogenicity 
assessment. 
The diversity of the elicited B-cell receptors will be assessed through sequence analysis of 
complementary DNA (cDNA) generated from immunoglobulin (Ig) messenger RNA 
(mRNA). The Ig cDNAs will be analyzed from antigen-specific B cells obtained at Day 
1, Day 29 and/or Day 181 and plasmablasts isolated at Day 8. The analysis of the B-cell 
receptor diversity does not have the intent nor the capability to identify or rule out any 
genetic modifications in the RNA or DNA that are presumably linked to disease or 
predisposition to disease. 
To evaluate the functionality specific antibodies induced by the study vaccines, 
biochemical and cell-based assays will be performed on a selected subset of serology 
samples collected for the assessment of the primary and secondary immunogenicity 
endpoints at Day 1, Day 8, Day 29 and Day 181. The evaluation of antigen specific 
antibody functionality includes determination of the antibody isotype and the antibody 
glycosylation state. Furthermore, the ability of the MenC-specific antibodies to fix 
complement, to promote antibody-dependent cell mediated cytoxicity (ADCC), to induce 
phagocytosis and to activate FcR+ cells in vitro will be assessed. If the quantity of serum 
available for this specific exploratory objective is limited, assessments of isotype and 
glycosylation state  will be prioritized over the other assessments. 
The frequency of T cells specific for the CRM197 protein at baseline (Day 1), at Day 8 and 
at Day 29 after vaccination with the study vaccines will be determined by FACS analysis 
using intracellular staining with a panel of cytokines and surface markers to identify cell 
populations. 
Early Markers for Safety and Innate immune activation 
The evaluation of potential biomarkers of safety and innate immune activation will be 
performed on blood specimens collected at Day 1 (baseline, 6h and 24h after vaccination) 
and Day 4. 
The vaccine-induced production of inflammatory cytokines and chemokines will be 
monitored on serum samples using a commercially available electrochemoluminescence 
assay for a panel of pro-inflammatory cytokines and chemokines, including Eotaxin, 
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IL15, IL-16, IL-17A, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IP-10, MCP-1, MCP-
4, MDC, MIP-1a, MIP-1b, TARC, TNF-a, TNF-b, VEGF. 
The vaccine-induced expression of genes and gene families will be monitored on whole 
blood samples using of RNA microarrays by existing technologies. The RNA micro array 
analysis does not have the intent nor the capability to identify or rule out any genetic 
modifications in the RNA or DNA that are presumably linked to disease or predisposition 
to disease. 
8.0  
STATISTICAL CONSIDERATIONS 
8.1  
Endpoints 
8.1.1 
Primary Endpoint(s) 
8.1.1.1  
Primary Safety Endpoint(s) 
The measures for assessing safety and tolerability (by vaccine group within each cohort 
and by LHD153R adjuvant dosage group overall) are as follows: 
▫ The frequency and percentage of subjects with solicited local and systemic  AEs 
through Day 14. Time intervals after vaccination that will be summarized are:30 
minutes post-vaccination, Days 1-4 (without 30 minutes), Days 5-8, Days 8-14, Days 
1-8 (without 30 minutes) and Days 1-14 (without 30 minutes). 
▫ The frequency and percentage of subjects with any unsolicited AEs from the day of 
vaccination (Day 1) to Day 14. 
▫ The frequency and percentage of subjects with SAEs, medically attended AEs,  AEs 
leading to study withdrawal, NOCDs, AESIs for the following time periods: day of 
signed informed consent until study completion (Day 366), day of vaccination (Day 1) 
to Day 29, and Day 29 to study completion (Day 366). 
▫ The absolute values and changes in hematology, chemistry, and urinalysis parameters 
(see section 7.1.7). 
▫ The frequency and percentage of subjects with abnormal laboratory parameter values 
as classified by investigator normal ranges (low, normal, high) and as classified by 
CBER toxicity grading scales, when available. 8.1.1.2  
Primary Efficacy 
Endpoint(s) 
Not applicable. 

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8.1.1.3  
Primary Immunogenicity Endpoint(s) 
The primary immunogenicity endpoints are the GMTs measured by hSBA directed 
against MenC from samples collected on Day 1 (baseline, before vaccination) and Day 29 
as well as the GMR of the titers (Day 29 / Day 1). 
8.1.2 
Secondary Endpoint(s) 8.1.2.1 
 Secondary Safety Endpoint(s) 
Not applicable. 
8.1.2.2  
Secondary Efficacy Endpoint(s) 
Not applicable. 
8.1.2.3  
Secondary Immunogenicity Endpoint(s) 
The secondary immunogenicity endpoints are: 
▫ GMTs and corresponding GMRs measured by hSBA directed against MenC for 
samples collected at Day 8 and Day181. 
▫ Percentage of subjects with hSBA seroresponse at Days 8, 29, and 181. Seroresponse 
is defined as a post vaccination hSBA ≥8 for subjects with a baseline hSBA <4 or 
have an increase of at least 4 times the baseline hSBA level for subjects with 
prevaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against MenC measured by ELISA 
for samples collected on Days 1 (baseline, prior to vaccination), 8, 29, and 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations to 
MenC as measured by ELISA on Day 8, 29, and 181 relative to baseline (Day 1). 
8.1.3  
Exploratory Endpoint(s) 
The exploratory  endpoints are based on results of testing which may not be performed 
until after the study report has been finalized and will be further refined prior to testing. 
They include the following: 
▫ Serum concentration of LHD153 at Day 1 baseline (prior to vaccination), Day 1 (1h , 
2h, 4h, 8h, and 24h after vaccination), Day 4 by LC-MS/MS. 

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▫ Frequency of MenC polysaccharide-specific and CRM197-specific B cells at Day 1 
(baseline), Day 8, Day 29, and Day 181 by ELISPOT. 
▫ Diversity of MenC polysaccharide-specific B-cell repertoire at Day 1 (baseline), Day 
8, Day 29, and Day 181 by immunoglobulin cDNA sequencing. 
▫ Functionality of antigen specific antibodies will be assessed at Day 1 (baseline), Day 
8, Day 29, and Day 181 by analysis of immunoglobulin isotype, glycosylation state 
and their ability to fix complement, to promote antibody-dependent cell mediated 
cytoxicity, to induce phagocytosis and to activate FcR+ cells. If the quantity of serum 
available for this specific exploratory objective is limited, assessments of 
immunoglobulin isotype and glycosylation state will be prioritized over the other 
assessments. 
▫ Frequency and quality of T cells specific for CRM197 at Day 1 (baseline), Day 8, and  
Day 29 by fluorescence activated cell sorting (FACS) analysis using intracellular  
staining with a wide panel of cytokines and surface markers to identify cell 
populations. 
▫ Serum concentrations of a panel of 30 chemokines and cytokines at Day 1 baseline 
(prior to vaccination), Day 1 (6h and 24h after vaccination), Day 4, and Day 8 by 
multiplex Electro-chemo-luminescence based assay. 
▫ Gene expression profile in whole blood at Day 1 baseline (prior to vaccination), Day 1 
(6h and 24h after vaccination), Day 4, and Day 8 by RNA micro array analysis. 
8.2  
Success Criteria 
The study has no formal statistical hypotheses and will not be declared positive or 
negative according to given rules. The selection of an appropriate LHD153R adjuvant 
dosage for future studies will be determined by the joint evaluation of the 
immunogenicity and safety profiles of each dosage group. 8.2.1  
Success Criteria 
for Primary Objective(s) Not applicable. 
8.2.2  
Success Criteria for Secondary Objective(s) 
Not applicable. 
8.3  
Analysis Sets 
8.3.1  
All Enrolled Set 

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All screened subjects who provide informed consent and provide demographic and/or 
baseline screening assessments, regardless of the subject’s randomization and treatment 
status in the study and received a Subject ID. 
8.3.2  
All Exposed Set 
All subjects in the enrolled set who receive a study vaccination. 
8.3.3  
Safety Set 
Safety Set (solicited adverse events and other solicited reactions) 
All subjects in the Exposed Set who: 
▫ Provide post vaccination reactogenicity data. 
Safety Set (unsolicited adverse events) 
All subjects in the Exposed Set who: 
▫ Have post-vaccination unsolicited adverse event records. 
Safety Set (overall) 
All subjects in the Exposed Set who: 
▫ Have either post-vaccination adverse event or reactogenicity records. 
Subjects will be analyzed as “treated” (i.e., according to the vaccine a subject received, 
rather than the vaccine to which the subject may have been randomized). 
8.3.4  
Full Analysis Set (FAS) Efficacy/Immunogenicity Set 
All subjects in the Enrolled Set who: 
▫ Receive a study vaccination AND provide efficacy/immunogenicity data at relevant 
time points. 
FAS sets will be analyzed “as randomized” (i.e., according to the vaccine a subject was 
designated to receive, which may be different from the vaccine the subject actually 
received). 
8.3.5  
Per Protocol (PP) Set Efficacy/Immunogenicity Set 

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All subjects in the FAS efficacy/immunogenicity set who: 
▫ Are not excluded due to reasons (see section 8.3.8) defined prior to unblinding or 
analysis. 
PPS are subsets of FAS and should always be defined even if the objectives do not 
require it. 
Examples for subjects excluded due to other reasons than protocol deviations are: 
- 
Subjects who withdrew informed consent. 
- 
Premature withdrawal due to an adverse event. 
Exclusions need to be considered by objective/time point, i.e., sometimes not all data of a 
subject but only part of the subject's data will be removed from the PPS analysis. 
8.3.6  
Other Analysis Sets  
All subjects in the Enrolled Set who consent to additional blood draws, receive a study 
vaccination AND provide exploratory assay data at relevant time points will be included 
in an exploratory assay subset. 
8.3.7  
Subgroups 
Selected immunogenicity analyses may be provided based on seropositivity status at 
baseline. 
8.3.8  
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. A protocol deviation may be a reason to remove data from 
an analysis set at the time of analysis. Reportable protocol deviations will be defined as 
exclusionary from the analysis according to protocol objectives and endpoints, which will 
be specified in the Statistical Analysis Plan. In some cases exclusion of data may be due 
to a reason other than a protocol deviation, e.g. early termination. 
8.4  
Statistical Analysis Plan 
This section provides a summary of the statistical methodology to be used. A more 
detailed description of analysis methods will be provided in a separate Statistical Analysis 
Plan which may also include additional exploratory analyses not explicitly mentioned in 
the following sections. 

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8.4.1  
Analysis of Demographic and Baseline Characteristics 
Descriptive statistics (number of non-missing observations, mean, standard deviation, 
median, minimum and maximum) for age, height and weight at enrolment will be 
calculated overall and by vaccine group and LHD153R adjuvant dosage. 
Distributions of subjects by sex and ethnic origin will be summarized overall and by 
vaccine group and LHD153R adjuvant dosage. 
8.4.2  
Analysis of Primary Objective(s) 
8.4.2.1  
Analysis of Primary Safety Objective(s) 
Safety of the study vaccines will be assessed in all subjects in terms of the frequency and 
percentage of reported AEs as well as by changes in clinical laboratory values.  
8.4.2.1.1  
Analysis of Extent of Exposure 
The frequency and percentage of subjects with vaccinations will be summarized by 
vaccine group and LHD153R adjuvant dosage, by cohort and overall, for the Enrolled 
Set. 
8.4.2.1.2  
Analysis of Solicited Local, Systemic and Other Adverse Events 
All solicited adverse events will be summarized according to defined severity grading 
scales. Use of medication to prevent/treat fever will be summarized according to 
frequencies and percentages reporting “Yes” and “No”. 
Frequencies and percentages of subjects experiencing each adverse event will be 
presented for each symptom severity. Summary tables showing the occurrence of any 
local or systemic adverse event overall and at each time point will also be presented. 
Post-vaccination solicited adverse events reported from Day 1 to Day 14 will be 
summarized for the intervals Day 1-4 (without 30 minutes), Day 5-8, Day 1-8 (without 30 
minutes), Day 8-14 and Day 1-14 (without 30 minutes) by maximal severity and by 
vaccine group and LHD153R adjuvant. The severity of solicited local adverse events, 
including injection-site erythema, swelling and induration will be summarized according 
to categories based on linear measurement: 25-50 mm, 51-100 mm, > 100 mm. 
Injection site pain and systemic reactions (except fever) occurring up to Day 14 will be 
summarized according to “mild”, “moderate” or “severe”. 

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Each solicited local and systemic adverse event will also be further summarized as “none” 
versus “any”. 
Implausible measurements (for further definition see Statistical Analysis Plan) will be left 
out of the analysis. 
Use of antipyretics and analgesics will be summarized by frequency by type of use 
(prophylactic versus treatment) and percentage of subjects reporting use. The influence of 
antipyretics and analgesics use on the occurrence of specific adverse events (e.g., fever, 
pain) will be assessed. 
Body temperature will be summarized by 0.5 °C and 1.0 °C increments from 36.0 °C up 
to ≥40 °C. 
8.4.2.1.3  
Analysis of Unsolicited Adverse Events 
This analysis applies to all adverse events occurring during the study, judged either as 
probably related, possibly related, or not related to vaccination by the investigator, 
recorded in the CRF, with a start date on or after the date of first vaccination. AE starting 
prior to the first vaccination will only be listed. The original verbatim terms used by 
investigators to identify adverse events in the CRFs will be mapped to preferred terms 
using the MedDRA dictionary. The adverse events will then be grouped by MedDRA 
preferred terms into frequency tables according to system organ class. 
All reported adverse events, as well as adverse events judged by the investigator as at 
least possibly related to study vaccine, will be summarized according to system organ 
class and preferred term within system organ class. These summaries will be presented by 
vaccination group and LHD153R adjuvant dosage for each cohort and by interval of 
study observation. When an adverse event occurs more than once for a subject, the 
maximal severity and strongest relationship to the vaccine group will be counted. 
Separate summaries will be produced for the following categories: 
▫ Serious adverse events. 
▫ Adverse events that are possibly or probably related to vaccine. 
▫ Adverse events of special interest. 
▫ New onset of chronic disease. 
▫ Adverse event leading to withdrawal. 
▫ Adverse events leading to a medically attended visit. 

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▫ Adverse event by data source. 
Data listings of all adverse events will be provided by subject. In addition, adverse events 
in the categories above will be provided as listed data. 
8.4.2.1.4  
Analysis of Safety Laboratory Values 
The investigator must review all safety laboratory results (see Section 7.1.7). Abnormal 
laboratory values and clinically significant changes in values from pre-vaccination 
(Screening Visit) will be assessed, using medical judgment, based on the FDA CBER  
Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” dated September 2007, or the 
institution’s normal ranges if they differ from CBER guidance. Please see Appendix C, D 
and E for further details. 
The following information will be provided: 
▫ Change in absolute laboratory value from pre-vaccination (Screening Visit) and Day 1 
(Visit 1) baseline to Day 8 (Visit 3) and Day 29 (Visit 6) after vaccination. 
▫ The classification of laboratory values and/or their changes from pre-vaccination 
according to the CBER toxicity grading scale. 
▫ 3 x 3 shift tables by visit using the categorization of laboratory values according to 
institutional normal reference ranges (below, within, above). 8.4.2.2  
Analysis 
of Primary Efficacy Objective(s) 
Not applicable. 
8.4.2.3  
Analysis of Primary Immunogenicity Objective(s) 
8.4.2.3.1  
Statistical Hypotheses 
There are no statistical hypotheses associated with the primary immunogenicity 
objectives. All analyses are descriptive. 
8.4.2.3.2  
Analysis Sets 
The primary immunogenicity analyses will be based on the per-protocol set (PPS) at Day 
29. The primary analyses will be repeated using the Full Analysis Set (FAS) as a measure 
of the sensitivity/robustness of the results (further details are given in section 8.3). 

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8.4.2.3.3  
Statistical Methods 
Before any statistical analysis that assumes normally distributed observations, antibody 
titers will be log10-transformed. Individual titers below the limit of quantitation (LLQ) 
will be set to half that limit. 
Geometric Mean Titers 
The logarithmically (base 10) transformed antibody titers will be modeled using an 
analysis of covariance (ANCOVA) model with a qualitative factor for LHD153R 
adjuvant dosage (0 [for unadjuvanted MenC], 12.5, 25, 50 or 100 µg) and log (base 10) 
pre-vaccination titer as a covariate. The adjusted GMT and the two-sided, 95%, 
confidence intervals (CIs) of the GMT will be calculated based on this model as will the 
ratio of GMTs and corresponding CIs. The adjusted GMT and two-sided 95% CIs will be 
constructed by exponentiation (base 10) of the least square means of the logarithmically 
transformed (base 10) antibody titer. The ratio of GMTs (LHD153R adjuvant dosage 
minus Men C), and corresponding two-sided 95% CIs, will be constructed by 
exponentiation (base 10) of the least square differences obtained from this model. The 
model can be written as:  
log10 (yik) = µ + αi + βxik + εik 
where µ represents a common overall mean, αi represents the adjuvant dose group i effect, 
β represents the common slope for the log10 pre-vaccination titer, xik for subject k in 
adjuvant dose group I, and εik represents random error for subject k in adjuvant dose 
group i. 
Geometric Mean Ratios 
The logarithmically (base 10) transformed within subject ratio of antibody titers (Day 29 / 
pre-vaccination) will be modeled using an analysis of variance model with a qualitative 
factor for LHD153R adjuvant dosage (0 [for non-LHD153R adjuvanted MenC], 12.5, 25, 
50 or 100 µg). The adjusted GMR and the two-sided, 95% CIs of the GMR will be 
calculated based on this model. The model can be written as: 
log10 (yik) = µ + αi + εik 
where µ represents a common overall mean, αi represents the adjuvant dose group i effect 
and εik represents random error for subject k in adjuvant dose group i. 
Handling of missing values 

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For immunogenicity data, it may be reasonable to consider missing immunogenicity 
values as missing completely at random (MCAR), i.e., not informative. Therefore, the 
primary analysis will comprise a complete case analysis only, without introducing any 
bias. Imputation methods will not be used. 
8.4.3  Analysis of Secondary Objective(s) 8.4.3.1 
 Analysis of Secondary Safety Objective(s) Not 
applicable. 
8.4.3.2  
Analysis of Secondary Efficacy Objective(s) 
Not applicable. 
8.4.3.3  
Analysis of Secondary Immunogenicity Objective(s) 
8.4.3.3.1  
Statistical Hypotheses 
There are no statistical hypotheses associated with the secondary immunogenicity 
objectives. All analyses are descriptive. 
8.4.3.3.2  
Analysis Sets 
The secondary immunogenicity analyses will be based on the PPS (further details are 
given in section 8.3) or the appropriate subset of subjects. 
8.4.3.3.3  
Statistical Methods 
The secondary immunogenicity endpoints are: 
▫ GMTs and corresponding GMRs measured by hSBA directed against MenC for 
samples collected at Day 8 and Day181. 
▫ Percentage of subjects with hSBA seroresponse at Days 8, 29, and 181. seroresponse is 
defined as a post vaccination hSBA ≥8 for subjects with a baseline hSBA <4 or have 
an increase of at least 4 times the baseline hSBA level for subjects with 
prevaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against MenC measured by ELISA 
for samples collected on Days 1 (baseline, prior to vaccination), 8, 29, and 181. 

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▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations to 
MenC as measured by ELISA on Day 8, 29, and 181 relative to baseline (Day 1). 
The GMTs for samples collected at Day 8 and Day 181 as well as the GMCs for samples 
collected at Day 1, Day 8, Day 29, and Day 181 will be analyzed using the same approach 
as for the primary immunogenicity endpoint. 
The remaining immunogenicity endpoints are based on subjects meeting criteria for 
seroconversion or achieving a certain threshold value. These endpoints will be 
summarized using frequencies and percentages by LHD153R adjuvant dosage (0 [for 
non-LHD153R adjuvanted MenC], 12.5, 25, 50 or 100 µg). Two-sided 95% 
ClopperPearson CIs will also be provided for percentages. For analyses of 
seroconversion, separate summaries may be provided based on seropositivity status at 
baseline. 
8.4.4  
Analysis of Exploratory Objectives 
Testing and analyses of exploratory endpoints may be performed after the Clinical Study 
Report (CSR) has been completed, in which case these data will be submitted as an 
addendum to the CSR. 
In general, concentration and titer results will be summarized for each LHD153R 
adjuvant dosage group using geometric means and associated 2-sided 95% confidence 
intervals; and, categorical data will be summarized using frequencies and percentages, 
with corresponding two-sided, 95% confidence intervals. 
8.5  
Sample Size and Power Considerations of Primary Objectives 
Sample size is not driven by statistical assumptions for formal hypothesis testing, but was 
based on the safety objective for the study. The table below provides the probability for 
various combinations of sample size (N) and presumed true frequency of a given event 
within an individual vaccine group  
Frequency 
of Event 
Probability to Observe at Least 1 Subject with a Given Event For  
Various Choices of N 
4 
8 
12 
16 
0.05 
0.1855 
0.3366 
0.4596 
0.5599 
0.10 
0.3439 
0.5695 
0.7176 
0.8147 
0.15 
0.4780 
0.7275 
0.8577 
0.9257 

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0.20 
0.5904 
0.8322 
0.9313 
0.9718 
0.30 
0.8250 
0.9423 
0.9862 
0.9967 
0.40 
0.8704 
0.9832 
0.9978 
0.9997 
The proposed combinations of sample sizes within each cohort are 4 aluminium 
hydroxide adjuvanted MenC-CRM197 and 16 MenC-CRM197 plus an assigned-level of 
LHD153R adsorbed to aluminium hydroxide. If all four cohorts are fully enrolled, there 
will be 16 subjects receiving aluminium hydroxide adjuvanted MenC-CRM197. 
With 16 subjects, events which occur at a frequency of 15% or more will be detected with 
at least 90% probability; and, events which occur at a frequency of 10% or more will be 
detected with 81% probability. With 4 subjects, events which occur at a frequency of 30% 
or more will be detected with at least 80% probability. Intermediate values of 8 and 12 
are provided to correspond to sample sizes in the MenC- CRM197 after cohort 2 and 
cohort 3 are fully enrolled. 
8.6  
Interim Analysis 
The DMC will be reviewing the accumulating safety data from the study in order to 
continue enrollment of subjects within a cohort and whether to enroll subjects into the 
next cohort. 
In addition to these periodic reviews, there will be a safety and immunogenicity interim 
analysis for the selection of an LHD153R adjuvant dosage based on the data collected 
through Day 29 from subjects enrolled in all cohorts. This analysis will be performed by 
personnel not involved in study decisions. The results will be unblinded at the group level 
thereby preserving the blind for individual subjects. No adjustment to the overall alpha 
will be performed as the data collected subsequent to this analysis involve secondary and 
exploratory endpoints. 
 

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9.0  
SOURCE DOCUMENTATION, STUDY MONITORING AND 
AUDITING 
Study monitoring and auditing will be standardized and performed in accordance with the 
Sponsor’s or delegated contract research organization’s (CRO) standard operating 
procedures and applicable regulatory requirements (e.g., FDA, EMA, and ICH 
guidelines). 
Prior to enrolment of the first study subject, Novartis or delegate will train investigators 
and/or their study staff on the study protocol, all applicable study procedures, 
documentation practices and all electronic systems. CRFs must be completed for each 
enrolled subject (see section 8.3.1 for definition of enrolled subject). Documentation of 
screened but not enrolled subjects must be maintained at the site and made available for 
review by the site monitor. 
9.1  
Source Documentation 
Prior to the start of the study, the site staff participating in the study conduct will be 
instructed on what documents will be required for review as source documents. The kinds 
of documents that will serve as source documents will be agreed between Sponsor or 
delegate and investigator and designees and specified in the SDA/Source Data 
Verification Form prior to subject enrolment. 
In addition, source documentation must include all of the following: subject identification 
(on each page), eligibility and participation, proper informed consent procedures, dates of 
visits, adherence to protocol procedures, adequate reporting and follow-up of adverse 
events, documentation of prior/concomitant medication/vaccines, study vaccine 
receipt/dispensing/return records, study vaccine administration information, any data 
collected by a telephone conversation with the subject and date of completion and reason. 
The subject must also allow access to the subject’s medical records. Each subject must be 
informed of this prior to the start of the study and consent for access to medical records 
may be required in accordance with local regulations. 
All safety data reported by subjects must be written down in source documents. If there 
are multiple sources of information (e.g., Subject Diary, verbal report of the subject, 
telephone contact details, medical chart) supporting the diagnosis of an adverse event, 
these sources must be identified in the source documents, discrepancies between sources 
clarified, the ultimate diagnosis must be justified and written in the source documents, 
and this diagnosis must be captured in the appropriate CRF page. The CRF must also 

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capture which source(s) of information were used to determine the adverse event (e.g., 
subject recall, medical chart, Subject Diary). 
9.2  
Study Monitoring, Auditing and Source Data Verification 
Prior to enrolment of the first study subject, Novartis or its designee (e.g., a CRO) will 
develop a Monitoring Plan to specify how centralized and/or on-site monitoring, 
including clinical specimens reconciliation, will be performed for the study. Study 
progress will be monitored as frequently as necessary to ensure: 
▫ that the rights and well-being of human subjects are protected, 
▫ the reported study data are accurate, complete, and verifiable from the source 
documents and 
▫ the conduct of the study is in compliance with the current approved 
protocol/amendment(s), GCP and applicable regulatory requirements. 
Contact details for the team involved in study monitoring will be provided to the 
investigator. Study data recorded on CRFs will be verified by checking the CRF entries 
against source documents in order to ensure data completeness and accuracy as required 
by study protocol. 
Additional documents such as the investigator site file, pharmacy records, and informed 
consent documentation must also be available for review if requested. Arrangements for 
monitoring visits will be made in advance in accordance with the monitoring plan, except 
in case of emergency. 
The investigator and/or site staff must make source documents of subjects enrolled in this 
study available for inspection at the time of each monitoring visit and Sponsor audits, 
when applicable. These documents must also be available for inspection, verification and 
copying, as required by regulations, by officials of the regulatory health authorities (e.g., 
FDA, EMA and others) and/or ECs/IRBs. The investigator and study site staff must 
comply with applicable privacy, data protection and medical confidentiality laws for use 
and disclosure of information related to the study and enrolled subjects. 
10.0  
DATA MANAGEMENT 
10.1 
Data Entry and Management 
In this study, all clinical data (including, but not limited to, AE/SAEs, concomitant 
medications, medical history, and physical assessments), safety data, and immunogenicity 
data will be entered into an EDC system, which is compliant with Title 21 Part 11 

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policies of the Code of Federal Regulations (FDA, 1997). The data system includes 
password protection and internal quality checks. The EDC system will be designed and 
validated by the Sponsor prior to activation for data entry by sites. The investigator or 
designated delegate must review data entered and electronically sign the CRFs to verify 
their accuracy. 
Access to the EDC system for data entry or review will require training and distinct 
individual access code assignments to those site staff members who will be entering study 
data and those involved in study oversight who may review study data. Data are collected 
within the EDC system, to which the Sponsor and site monitors have exclusively “read 
only” access. 
Paper CRFs will be provided for each pregnant subject by the Sponsor. All appropriate 
pregnant subject data collected will be recorded on this form. One copy must be retained 
by the investigator, and all other copies (including the original copy) will be returned as 
directed by the Sponsor. Instructions on how to complete this form will be provided to the 
investigator. 
10.2  
Data Clarification 
As part of the conduct of the trial, the Sponsor may have questions about the data entered 
by the site, referred to as queries. The monitors and the Sponsor are the only parties that 
can generate a query. All corrections and clarifications will be entered into the EDC 
system and will be identified by the person entering the information, the reason for the 
change, as well as the time of the changes made. If changes are made to a previously and 
electronically signed CRF, the investigator must confirm and endorse the changes 
10.3  
Data Protection 
Novartis respects the subjects’ rights to privacy and will ensure the confidentiality of their 
medical information in accordance with all applicable laws and regulations. 
The Sponsor as Data Controller according to the European Directive on the protection of 
individuals with regard to the processing of personal data and on the free movement of 
such data (95/46/EC) confirms herewith compliance to Directive 95/46/EC in all stages of 
Data Management. 
 

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11.0  
RECORD RETENTION 
Investigators must retain all study records required by Novartis and by the applicable 
regulations in a secure and safe facility. The investigator must consult a Novartis 
representative before disposal of any study records, and must notify the Sponsor of any 
change in the location, disposition, or custody of the study files. Essential documents 
must be retained for 15 years. “Essential documents” are defined as documents that 
individually and collectively permit evaluation of the conduct of a study and the quality 
of the data produced. These documents should be retained for a longer period, however, if 
required by the applicable national regulatory or institutional requirements.  
These principles of record retention will also be applied to the storage of laboratory 
samples, provided that the integrity of the stored sample permits testing. 
 

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12.0  
USE OF INFORMATION AND PUBLICATION 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov, and in compliance with current regulations. 
Novartis also assures that key results of this clinical study will be posted in a publicly 
accessible database within the required time-frame from the End of Study as defined in 
section 3.9. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
Novartis must be notified of any intent to publish data collected from the study and prior 
approval from Novartis must be obtained prior to submission for publication. 

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13.0  
ETHICS 
13.1  
Regulatory and Ethical Compliance 
The study will be conducted in compliance with the protocol, GCP and applicable 
regulatory requirement(s). 
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, European 
Directive 2001/20/EC, Novartis codes on protection of human rights, and with the ethical 
principles laid down in the Declaration of Helsinki (European Council 2001, US Code of 
Federal Regulations, ICH 1997). 
13.2  
Informed Consent Procedures 
Eligible subjects may only be included in the study after providing written informed 
consent or assent, as described in section 5.1.1. Before the start of the study, the 
investigator will have the informed consent and any other materials that will be provided 
to the subjects reviewed and approved by the IRB/EC. This review and approval will be 
documented and stored with other study documents. The investigator or designee must 
fully inform the subject or legal guardian of all pertinent aspects of the study. A copy of 
the written informed consent will be given to the subject or the designee. The 
subject/designee must be allowed ample time to ask about the details of the study and to 
make a decision as to whether or not to participate in the study. The subject and/or legal 
guardian(s) must sign the consent form indicating their agreement to participate in the 
study before any study-related procedures are conducted. The informed consent process 
may be conducted up to 23 days prior to vaccination on Day 1. If the subject is unable to 
read and write, a witness must be present during the informed consent discussion and at 
the time of informed consent signature. 
Prior to the start of the study, Novartis will provide to investigators a proposed informed 
consent form that complies with the ICH GCP guideline and regulatory requirements and 
is considered appropriate for this study. Any changes to the proposed consent form 
suggested by the investigator must be agreed to by Novartis before submission to the 
IRB/EC and a copy of the approved version must be provided to Novartis after IRB/EC 
approval. 
Women of childbearing potential should be informed that taking the study medication 
may involve unknown risks to the fetus if pregnancy were to occur during the study and 
agree that in order to participate in the study they must adhere to the contraception 

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requirements indicated in the protocol for the duration of the study. In case of doubt on 
the ability of a subject to adhere to these requirements, that subject should not be allowed 
in the study 
13.3  
Responsibilities of the Investigator and IRB/EC 
The protocol and the proposed informed consent form must be reviewed and approved by 
a properly constituted IRB/EC before study start. Properly constituted IRB/EC is defined 
in ICH Guideline for Good Clinical Practice E6 (R1), Section 3 (ICH, 1997). A signed 
and dated statement that the protocol and informed consent have been approved by the 
IRB/EC must be given to Novartis before study initiation. Prior to study start and at any 
time the protocol is amended during study conduct, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance 
with these documents and all of the instructions and procedures found in this protocol and 
to give access to all relevant data and records to Novartis monitors, auditors, Novartis 
Clinical Quality Assurance representatives, designated agents of Novartis, IRBs/ECs, and 
regulatory authorities as required. If an inspection of the clinical site is requested by a 
regulatory authority, the investigator must inform Novartis immediately that this request 
has been made. 
The investigator also responsible for the following: 
▫ Maintaining a list of appropriately qualified persons to whom the investigator has 
delegated significant study-related duties. 
▫ Demonstrating the capability of recruiting the required number of suitable subjects 
within the recruitment period. 
▫ Demonstrating sufficient time and staffing to properly conduct and complete the study 
within the agreed study period. 
▫ Ensuring that all persons assisting with the study are adequately informed about the 
protocol, the investigational product(s), and their study-related duties and functions 
▫ Ensuring that appropriately trained health care professionals are responsible for all 
study-related medical decisions and for ensuring appropriate medical care of subjects 
experiencing any adverse event related to the study. 
▫ If permission to do so is given by the subject, ensuring that the subject’s primary 
healthcare provider is informed of the subject’s participation in the study. 
The investigator should not implement any deviation from, or changes of the protocol 
without agreement by the Sponsor and prior review and documented approval/favourable 

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opinion from the IRB/IEC of an amendment, except where necessary to eliminate an 
immediate hazard(s) to study subjects, or when the change(s) involves only logistical or 
administrative aspects of the study (e.g., change in monitor(s), change of telephone 
number(s)). In addition, the investigator, or person designated by the investigator, should 
document and explain any deviation from the approved protocol. 
The investigator may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior IRB/IEC 
approval/favourable opinion. As soon as possible, the implemented deviation or change, 
the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be 
submitted: 
(a) to the IRB/IEC for review and approval/favourable opinion, 
(b) to the Sponsor for agreement and, if required, 
(c) to the regulatory authority(ies). 
13.4  
Protocol Amendments 
An amendment is a written description of change(s) to or formal clarification of a study 
protocol which may impact on the conduct of the clinical study, potential benefit of the 
clinical study, or may affect subject safety, including changes of study objectives, study 
design, subject population, sample sizes, study procedures, or significant administrative 
aspects. An administrative change of a study protocol is a minor correction or 
clarification that has no significant impact on the way the clinical study is to be conducted 
and no effect on subject safety (e.g., change of telephone number(s), logistical changes). 
Protocol amendments must be approved by Novartis, health authorities where required, 
and the IRB/EC. In cases when the amendment is required in order to protect the subject 
safety, the amendment can be implemented prior to IRB/EC approval. Notwithstanding, 
the need for formal approval of a protocol amendment, the investigator is expected to take 
any immediate action required for the safety of any subject included in this study, even if 
this action represents a deviation from the protocol. In such cases, Novartis should be 
notified of this action, the IRB/EC at the study site, and, if required by local regulations, 
the relevant health authority should be informed within 10 working days. 
14.0  
REFERENCE LIST 
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Bissett SL, Draper E, Myers RE, Godi A, Beddows S. Cross-neutralizing antibodies 
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Campanelli, A et al., Topical application of imiquimod and associated fever in children. J 
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Code of Federal Regulations (1997): Food and Drug Administration, U.S. Department of 
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Connolly M and Noah N, Is group C meningococcal disease increasing in Europe? A 
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Del Giudice G, Fragapane E, Della Cioppa G, et al. Aflunov®: a vaccine tailored for 
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European Centre for Disease Prevention and Control. Surveillance of invasive bacterial 
diseases in Europe 2008/2009. Stockholm: ECDC 2011 
European Parliament (1995): Directive 95/46/EC of the European Parliament and of the 
Council of 4 April 2001. Official Journal of the European Communities. L 281/31-39 
European Parliament (2001): Directive 2001/20/EC of the European Parliament and of the 
Council of 4 April 2001. Official Journal of the European Communities. L 121/34-44 
Hellenbrand W, Elias J, Wichmann O et al. Epidemiology of invasive meningococcal 
disease in Germany, 2002-2010, and impact of vaccination with meningococcal C 
conjugate vaccine. Journal of Infection 2013; 66: 48-56. 
ICH (1997) ICH Harmonised Tripartite ICH Guideline for Good Clinical Practices E6  
(R1). Federal Register, 62 (90): 25691-25709 
ICH (1998) ICH Harmonised Tripartite ICH Guideline for Statistical Principles for 
Clinical Trials E9. Federal Register, 63 (179): 49583 

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Ilyinskii, PO, et al., Adjuvant-carrying synthetic vaccine particles augment the immune 
response to encapsulated antigen and exhibit strong local immune activation without 
inducing systemic cytokine release. Vaccine, available online 1 March 2014. 
Khurana, S., W. Chearwae, F. Castellino, J. Manischewitz, L.R. King, A. Honorkiewicz, 
M.T. Rock, K.M. Edwards, G. Del Giudice, R. Rappuoli, and H. Golding. 2010. 
MF59adjuvanted vaccines expand antibody repertoires targeting protective sites of 
pandemic H5N1 influenza virus. Science Transl. Med. 2: 15ra5: 1-8. 
Khurana, S., N. Verma, J.W. Yewdell, A.K. Hilbert, F. Castellino, M. Lattanzi, G. Del 
Giudice, R. Rappuoli, and H. Golding. 2011. MF59 adjuvant affects human epitope 
repertoire, augments affinity maturation, and neutralization titers to pandemic influenza in 
all age groups. Science Transl. Med. 3: 85ra48. 
Levine RJ. (1988) Ethics and Regulations of Clinical Research. New Haven: Yale 
University Press. 
Meyer, T et al., Clinical investigations of Toll-like receptor agonists. Expert Opin Investig 
Drugs 2008, 17:1051-1065. 
Recommendations of the Standing Committee on Vaccination (STIKO) at the Robert  
Koch Institute / Effective: August 2013; Robert Koch Institut Epidemiologisches Bulletin 
34, 26 August 2013 
Reed SG, Orr MT, Fox CB. Key roles of adjuvants in modern vaccines. Nat Med. 
2013;19 :1597-608. 
Regules JA, Cummings, JF and Ockenhouse CF. The RTS, S vaccine candidate for 
malaria. Expert Rev Vaccines 2011; 10:589-599. 
Rosenstein N, Perkins B, Stephens DS, et al. N. Engl. J. Med. 2001; 344: 1378-1388. 
Tacken, PJ et al., Targeted delivery of TLR ligands to human and mouse dendritic cells 
strongly enhances adjuvanticity. Blood 2011, 118:6836-6844. 
Takeda K, Kaisho T, Akira S Toll-like receptors. Annu.Rev.Immunol. 2003; 21: 335-76. 
U.S. Department of Health and Human Services, Food and Drug Administration, CBER  
(2009): Guidance for Industry Patient-Reported Outcome Measures: Use in Medical  
Product Development to Support Labeling Claims 

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Vasilakos JP, and Tomai MA. The use of Toll-like receptor 7/8 agonists as vaccine 
adjuvants." Expert Rev Vaccines 2013; 12: 809-819. 
64th World Medical Association General Assembly (October 2013) Declaration of  
Helsinki - Ethical Principles for Medical Research Involving Human Subjects. Fortaleza, 
Brazil 
 

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APPENDIX A: GRADING SCALES FOR SOLICITED LOCAL ADVERSE  
EVENTS* 
(Adapted from CBER 2007b) 
Adverse event Following  
Administration of  
Injectable Product  
Mild (Grade 
1)  
Moderate 
(Grade 2)  
Severe 
(Grade 3)  
Pain 
present but does not 
interfere with activity 
interferes with activity 
prevents daily activity 
Induration / Swelling /  
Erythema 
25 – 50 mm 
51 – 100 mm  
> 100 mm  
*This toxicity grading scale is adapted from CBER 2007 to enable ease of reporting by Subjects in the 
source documents for ‘patient reported’ solicited adverse events. This toxicity grading scale is a Novartis 
standard that is used for patient reporting. ‘Grade 4’ is not listed here but will be defined in the Statistical 
Analysis Plan as necessary. 
 

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APPENDIX B: GRADING SCALES FOR SOLICITED SYSTEMIC ADVERSE  
EVENTS* 
(Adapted from CBER 2007b) 
Systemic  
Adverse event 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Fever 
°C 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 - 102 
39.0 – 40 
102.1 - 104 
°F 
Chills 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Loss of Appetite 
Loss of appetite without 
decreased oral intake  
decreased oral intake  
without weight loss 
decreased oral intake with 
weight loss 
Nausea 
Nausea present but not 
interfering with oral intake 
Nausea leading to decreased 
oral intake 
Nausea leading to minimal to 
no oral intake 
Vomiting 
1-2 episodes/24 hours 
>2 episodes/24 hours 
requires outpatient 
hydratation 
Diarrhea 
2-3 loose stools /24 hours 
4-5 loose stools /24 hours 
6 or more watery stools /24 
hours or requires outpatient 
IV hydration 
Generalized  
Myalgia 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Generalized  
Arthralgia 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Headache 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Fatigue 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Generalized  
Rash 
localized area of the skin (1 
extremity only) 
moderate area of the skin 
(2 or more body regions 
without whole body 
involvement) 
most of the skin 
Urticaria 
localized area of the skin (1 
extremity only) 
moderate area of the skin 
(2 or more body regions 
without whole body 
involvement) 
most of the skin 
*This toxicity grading scale is adapted from CBER 2007b to enable ease of reporting by Subjects in the 
source documents for ‘patient reported’ solicited adverse events. This toxicity grading scale is a Novartis 

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standard that is used for patient reporting. ‘Grade 4’ is not listed here but will be defined in the statistical 
analysis plan as necessary 
APPENDIX C: TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(SERUM CLINICAL CHEMISTRY)  
Serum*,** 
Mild (Grade 1)  
Moderate 
(Grade 2)  
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)*** 
Sodium – Hyponatremia 
mEq/L  
132 – 134  
130 – 131  
125 – 129  
< 125  
Sodium – Hypernatremia 
mEq/L  
144 – 145  
146 – 147  
148 – 150  
> 150  
Potassium – Hypokalemia 
mEq/L  
3.5 – 3.6  
3.3 – 3.4  
3.1 – 3.2  
< 3.1  
Potassium – Hyperkalemia 
mEq/L  
5.1 – 5.2  
5.3 – 5.4  
5.5 – 5.6  
> 5.6  
Blood Urea Nitrogen  
BUN mg/dL  
23 – 26  
27 – 31  
> 31  
Requires dialysis  
Creatinine – mg/dL  
1.5 – 1.7  
1.8 – 2.0  
2.1 – 2.5  
> 2.5 or requires 
dialysis  
Liver Function Tests –ALT,  
AST  
increase by factor  
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN  
5.1 – 10 x ULN  
> 10 x ULN  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 
**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 
***The clinical signs or symptoms associated with laboratory abnormalities might result in characterization 
of the laboratory abnormalities as Potentially Life Threatening (Grade 4). For example. a low sodium value 
that falls within a grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia event if 
the subject had a new seizure associated with the low sodium value. “ULN” = the upper limit of the normal 
range. 
APPENDIX D: TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(HEMATOLOGY) 
Hematology*,** 
Mild (Grade 
1)  
Moderate  
(Grade 2)  
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)  
Hemoglobin (Female) 
gm/dL  
11.0 – 12.0  
9.5 – 10.9  
8.0 – 9.4  
< 8.0  

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Hemoglobin (Female) 
change from baseline 
value - gm/dL  
Any decrease – 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
Hemoglobin (Male) 
gm/dL  
12.5 – 13.5  
10.5 – 12.4  
8.5 – 10.4  
< 8.5  
Hemoglobin (Male) 
change from baseline 
value – gm/dL  
Any decrease – 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
WBC Increase - cell/mm3 
10,800 – 15,000  
15,001 – 20,000  
20,001 – 25, 000  
> 25,000  
WBC Decrease cell/mm3 
2,500 – 3,500  
1,500 – 2,499  
1,000 – 1,499  
< 1,000  
Platelets Decreased 
cell/mm3 
125,000 – 140,000 
100,000 – 124,000 
25,000 – 99,000  
< 25,000  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate.  
**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 
APPENDIX E: TOXICITY SCALES FOR LABORATORY ABNORMALITIES 
(URINE) 
Urine*,** 
Mild (Grade 
1)  
Moderate  
(Grade 2)  
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)  
Protein  
Trace  
1+  
2+  
Hospitalization or 
dialysis  
Glucose  
Trace  
1+  
2+  
Hospitalization for 
hyperglycemia  
Blood (microscopic) – 
red blood cells per high 
power field (rbc/hpf)  
1 - 10  
11 – 50  
> 50 and/or gross 
blood  
Hospitalization or 
packed red blood 
cells (PRBC) 
transfusion  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 
**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 

 
 
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GSK  
Clinical Study Protocol V132_01EXP Amendment 3 
 
JUN 15 
Confidential 
Page 1 of 3 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 
18 
CLINICAL STUDY PROTOCOL AMENDMENT 
Study Number: V132_01EXP 
Protocol Title:  A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study 
to Evaluate the Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R 
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium  
Hydroxide Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy 
Adults (18-45 years of age) 
Amendment Number 3 
Revised Protocol version 4.0 issued on 18 JUN 2015 
The present amendment reflects changes to the Protocol version 3.0 issued on 
17DEC14   
Property of GlaxoSmithKline Biologicals S.A. 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of GSK 
GSK  
18 
Confidential 
 

Clinical Study Protocol V132_01EXP Amendment 3 
JUN 15 
Page 2 of 3 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 
DESCRIPTION OF CHANGE(S) AND RATIONALE: 
CHANGE 
LOCATION(S) OF  
CHANGE 
RATIONALE FOR  
CHANGE 
Change in Sponsor name      Throughout the entire 
document     
Company transition from  
Novartis Vaccines to GSK  
Vaccines 
Addition of one Blood Draw 
and one Urine sample for 
Safety Laboratory 
assessment at 24 h after 
vaccination. 
Synopsis (Page 12) 
Times and Events Table 3 
(Page 19) 
Section 3.1 ‘Overview of 
Study Design’ (Page 31) 
Section 3.5 ‘Collection of  
Clinical Specimens’ (Pages 
35 and 36)   
Section 5.2.5 
‘PostVaccination 
Procedures’ (Page 48)  
Section 7.1.7 ‘Safety  
Laboratory Measurements’  
(Page 70 and 71) 
Alignment with Early  
Clinical Research  
Experience with legacy 
GSK Adjuvant System (AS) 
platform. Transient 
CRPlevel increase has been 
observed at 24h with 
TLR4L (MPL) containing 
AS.    
18 

GSK  
Clinical Study Protocol V132_01EXP Amendment 3 
 
JUN 15 
Confidential 
Page 3 of 3 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 
CHANGE 
LOCATION(S) OF  
CHANGE 
RATIONALE FOR  
CHANGE 
Addition of Exploratory 
Endpoint #8 ‘Number and 
Activation Status of 
myeloid and lymphoid cell 
populations at Day 1, Day 4 
and Day 8’ 
Synopsis (Page 16) 
Times and Events Table 3 
(Page 20) 
Section 3.5 ‘Collection of  
Clinical Specimens’ (Pages 
34-36) 
Section 7.4 ‘Exploratory  
Measurements’ (Page 73)   
Section 8.1.3 ‘Exploratory  
Endpoints’ (Page 76) 
Alignment with Early  
Clinical Research  
Experience with legacy 
GSK AS platform. Vaccine 
adjuvant-induced changes in 
innate immune cell 
populations/activation state   
have been observed at 24h  
and 72h post vaccination 
with TLR4L (MPL) 
containing AS. 
Changed one of the 
timepoints (i.e. 18h instead 
of  
20h post-vaccination) for 
Body 
Temperature 
assessments in first 24h 
after vaccination  
Times and Events Table 3 
(Page 20) 
Section 5.2.5 
‘PostVaccination 
Procedures’  
(Page 48) 
Alignment with Early  
Clinical Research  
Experience with legacy 
GSK AS platform.  
Transient rise in 
bodytemperature has been 
observed with TLR4L 
(MPL) containing AS that 
peaked at 18h. 

Clinical Study Protocol V132_01EXP Amendment 3 
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Page 4 of 3 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 
Increased blood volume for 
LHD153 systemic exposure  
assay (PK analysis) from 2 
mL to 3 mL 
Times and Events Table 3 
(Page 20) 
Section 3.5 ‘Collection of  
Clinical Specimens’ (Pages  
34-36) 
Ensure sufficient plasma 
can be recovered for 
preparing 4 aliquots: 1 
aliquot for the assay, 2 
aliquots for potential retests 
and 1 back-up aliquot. 

 
 
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GSK  
Protocol V132_01EXP 
18 JUN 15 Version 4 
Confidential 
Page 1 of 103 
PRO-01 TEMP 06 / Atlas No. 293620 
Version No. 2 / Version Date: December 2, 2013 
CLINICAL STUDY PROTOCOL V132_01EXP Version 4 
A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study to Evaluate the 
Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R Adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium Hydroxide  
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy Adults (18-45 
years of age) 
EUDRACT No. 2014-002430-31 
Property of GlaxoSmithKline Biologicals S.A. (hereafter referred to as GSK) 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of GSK. 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................ 2 
PROTOCOL SYNOPSIS V132_01EXP.......................................................................... 7 
LIST OF ABBREVIATIONS........................................................................................ 23 
1.0  
BACKGROUND AND RATIONALE............................................................... 25 

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1.1  
Background.................................................................................................... 25 
 
1.2  
Rationale........................................................................................................ 28 
2.0  
OBJECTIVES.................................................................................................... 29 
 
2.1  
Primary Objectives......................................................................................... 29 
 
2.2  
Secondary Objectives..................................................................................... 29 
 
2.3  
Exploratory Objectives................................................................................... 29 
3.0  
STUDY DESIGN .............................................................................................. 31 
 
3.1  
Overview of Study Design............................................................................. 31 
 
3.2  
Study Period .................................................................................................. 32 
 
3.3  
Blinding Procedures....................................................................................... 33 
 
3.4  
Data Collection.............................................................................................. 33 
 
3.4.1  
Data Collected from Subjects ................................................................. 33 
 
3.4.2  
Tools Used for Data Collection .............................................................. 34 
 
3.5  
Collection of Clinical Specimens ................................................................... 35 
 
3.6  
Stopping/Pausing Guidelines.......................................................................... 37 
 
3.7  
Data Monitoring Committee........................................................................... 38 
 
3.8  
Premature Withdrawal from Study................................................................. 39 
 
3.9  
End of Study.................................................................................................. 41 
4.0  
SELECTION OF STUDY POPULATION......................................................... 42 
 
4.1  
Inclusion Criteria ........................................................................................... 42 
 
4.2  
Exclusion Criteria .......................................................................................... 42 
 
4.3  
Criteria for Delay of Vaccination or Blood Draw........................................... 44 
5.0  
STUDY PROCEDURES ................................................................................... 45 
 
5.1  
Pre-vaccination Clinic Visit(s) ....................................................................... 45 
 
5.1.1  
Informed Consent................................................................................... 45 
 
5.1.2  
Screening ............................................................................................... 46 
 
5.2  
Vaccination Clinic Visit(s)............................................................................. 47 

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5.2.1 
Pre-vaccination Procedures..................................................................... 47 
 
5.2.2  
Enrolment .............................................................................................. 48 
 
5.2.3  
Randomization ....................................................................................... 48 
 
5.2.4  
Vaccination............................................................................................ 49 
 
5.2.5  
Post-vaccination Procedures................................................................... 49 
 
5.3  
Post-vaccination Visit(s) ................................................................................ 50 
 
5.3.1  
Subject Diary Reminder, Safety Follow-up and/or Post-vaccination Blood  
Draw Clinic Visits.................................................................................. 50 
 
5.3.2  
Safety Follow-up Calls........................................................................... 54 
 
5.4  
Unscheduled Visits ........................................................................................ 54 
 
5.5  
Study Termination Visit................................................................................. 55 
 
5.5.1  
Early Termination Visit.......................................................................... 55 
6.0  
TREATMENT OF SUBJECTS.......................................................................... 57 
 
6.1  
Study Vaccine(s)............................................................................................ 57 
 
6.2  
Non-Study Vaccines ...................................................................................... 60 
 
6.3  
Vaccine Preparation and Administration ........................................................ 60 
 
6.4  
Vaccine Administration Error or Overdose of Vaccine................................... 61 
 
6.5  
Prior and Concomitant Medications and Vaccines.......................................... 61 
 
6.6  
Vaccine Supply, Labeling, Storage and Tracking ........................................... 61 
7.0  
ASSESSMENTS................................................................................................ 64 
 
7.1  
Safety Assessment ......................................................................................... 64 
 
7.1.1  
Solicited Adverse Events........................................................................ 64 
 
7.1.2  
Unsolicited Adverse Events.................................................................... 66 
 
7.1.3  
Evaluation of Adverse Events................................................................. 66 
 
7.1.4  
Serious Adverse Events.......................................................................... 67 
 
7.1.4.1  
Adverse Events of Special Interest...................................................... 69 
 
7.1.5  
Methods for Recording Adverse Events and Serious Adverse Events ..... 70 

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7.1.5.1  
Post-Study Events .............................................................................. 71 
 
7.1.6  
Pregnancies............................................................................................ 71 
 
7.1.7  
Safety Laboratory Measurements ........................................................... 71 
 
7.2  
Efficacy Assessment ...................................................................................... 72 
 
7.3  
Immunogenicity Assessment.......................................................................... 72 
 
7.4  
Exploratory Measurements............................................................................. 73 
8.0  
STATISTICAL CONSIDERATIONS................................................................ 75 
 
8.1  
Endpoints....................................................................................................... 75 
 
8.1.1  
Primary Endpoint(s)............................................................................... 75 
 
8.1.1.1  
Primary Safety Endpoint(s) ................................................................ 75 
 
8.1.1.2  
Primary Efficacy Endpoint(s) ............................................................. 75 
 
8.1.1.3  
Primary Immunogenicity Endpoint(s)................................................. 75 
 
8.1.2  
Secondary Endpoint(s) ........................................................................... 75 
 
8.1.2.1  
Secondary Safety Endpoint(s)............................................................. 75 
 
8.1.2.2  
Secondary Efficacy Endpoint(s) ......................................................... 76 
 
8.1.2.3  
Secondary Immunogenicity Endpoint(s)............................................. 76 
 
8.1.3  
Exploratory Endpoint(s)......................................................................... 76 
 
8.2  
Success Criteria ............................................................................................. 77 
 
8.2.1  
Success Criteria for Primary Objective(s)............................................... 77 
 
8.2.2  
Success Criteria for Secondary Objective(s) ........................................... 77 
 
8.3  
Analysis Sets ................................................................................................. 77 
 
8.3.1  
All Enrolled Set...................................................................................... 77 
 
8.3.2  
All Exposed Set...................................................................................... 77 
 
8.3.3  
Safety Set............................................................................................... 78 
 
8.3.4  
Full Analysis Set (FAS) Efficacy/Immunogenicity Set ........................... 78 
 
8.3.5  
Per Protocol (PP) Set Efficacy/Immunogenicity Set................................ 78 
 
8.3.6  
Other Analysis Sets................................................................................ 79 

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8.3.7  
Subgroups.............................................................................................. 79 
 
8.3.8  
Protocol Deviations................................................................................ 79 
 
8.4  
Statistical Analysis Plan................................................................................. 79 
 
8.4.1  
Analysis of Demographic and Baseline Characteristics........................... 79 
 
8.4.2  
Analysis of Primary Objective(s)............................................................ 80 
 
8.4.2.1  
Analysis of Primary Safety Objective(s)............................................. 80 
 
8.4.2.1.1  
Analysis of Extent of Exposure.................................................... 80 
 
8.4.2.1.2  Analysis of Solicited Local, Systemic and Other Adverse Events. 80 
 
8.4.2.1.3  
Analysis of Unsolicited Adverse Events....................................... 81 
 
8.4.2.1.4  
Analysis of Safety Laboratory Values .......................................... 81 
 
8.4.2.2  
Analysis of Primary Efficacy Objective(s).......................................... 82 
 
8.4.2.3  
Analysis of Primary Immunogenicity Objective(s) ............................. 82 
 
8.4.2.3.1  
Statistical Hypotheses .................................................................. 82 
 
8.4.2.3.2  
Analysis Sets................................................................................ 82 
 
8.4.2.3.3  
Statistical Methods....................................................................... 82 
 
8.4.3  
Analysis of Secondary Objective(s)........................................................ 83 
 
8.4.3.1  
Analysis of Secondary Safety Objective(s) ......................................... 83 
 
8.4.3.2  
Analysis of Secondary Efficacy Objective(s)...................................... 83 
 
8.4.3.3  
Analysis of Secondary Immunogenicity Objective(s).......................... 84 
 
8.4.3.3.1  
Statistical Hypotheses .................................................................. 84 
 
8.4.3.3.2  
Analysis Sets................................................................................ 84 
 
8.4.3.3.3  
Statistical Methods....................................................................... 84 
 
8.4.4  
Analysis of Exploratory Objectives ........................................................ 85 
 
8.5  
Sample Size and Power Considerations of Primary Objectives....................... 85 
 
8.6  
Interim Analysis............................................................................................. 86 
9.0  
SOURCE DOCUMENTATION, STUDY MONITORING AND AUDITING... 87 
 
9.1  
Source Documentation................................................................................... 87 

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9.2  
Study Monitoring, Auditing and Source Data Verification ............................. 88 
10.0  
DATA MANAGEMENT................................................................................... 89 
 
10.1  
Data Entry and Management.......................................................................... 89 
 
10.2  
Data Clarification........................................................................................... 89 
 
10.3  
Data Protection .............................................................................................. 89 
11.0  
RECORD RETENTION.................................................................................... 91 
12.0  
USE OF INFORMATION AND PUBLICATION ............................................. 92 
13.0  
ETHICS............................................................................................................. 93 
 
13.1  
Regulatory and Ethical Compliance ............................................................... 93 
 
13.2  
Informed Consent Procedures ........................................................................ 93 
 
13.3  
Responsibilities of the Investigator and IRB/EC............................................. 94 
 
13.4  
Protocol Amendments.................................................................................... 95 
14.0  
REFERENCE LIST........................................................................................... 96 
APPENDIX A:  
GRADING SCALES FOR SOLICITED LOCAL ADVERSE  
EVENTS ........................................................................................ 99 
APPENDIX B:  
GRADING SCALES FOR SOLICITED SYSTEMIC ADVERSE  
EVENTS ...................................................................................... 100 
APPENDIX C:  
TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(SERUM CLINICAL CHEMISTRY)........................................... 101 
APPENDIX D:  
TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(HEMATOLOGY) ....................................................................... 102 
APPENDIX E:  
TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(URINE)....................................................................................... 103 
PROTOCOL SYNOPSIS V132_01EXP 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Title of Study: A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study to  
Evaluate the Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R 
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium  
Hydroxide Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy Adults 
(18-45 years of age) 
Study Period: Approximately 12 months for 
each subject 
Clinical Phase: Phase 1 
Background and Rationale: 
Neisseria meningitidis (N. meningitides)serogroup C (MenC) is one of the major 
serogroups causing invasive meningocococcal disease. Case fatality in Germany has 
ranged between 6% and 8% between 1999 and 2006, and has remained generally 
consistent across the different European countries, varying between 6-11%, with the case 
fatality rate being notably higher for serogroup C disease than for serogroup B. The 
safety and immunogenicity of the GSK Meningococcal C-CRM197 Conjugate Vaccine 
(Menjugate®) has been confirmed through years of commercial use. For children over 
the age of 12 months, for adolescents and for adults a single dose is recommended. For 
infants between 2 and 12 months of age, the recommended schedule for primary 
immunization with the Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) is 
two doses given with an interval of at least 2 months A more potent Meningococcal 
CCRM197 Conjugate Vaccine formulation might enable a reduction of the antigen dosage 
and/or a reduction in the number of doses needed in infants. One approach to achieve 
more potent well-characterized sub-unit vaccines - like the Meningococcal C-CRM197 
Conjugate Vaccine - is the use of new adjuvants that activate the Toll-like receptor 
(TLR) pathway. 
GSK is developing a small molecule immune potentiator (SMIP) LHD153 that is an 
agonist for TLR7. The objective driving the development of LHD153 is to achieve a 
vaccine adjuvant with strong immunopotentiating properties and minimal side effects. In 
line with this objective, it has been postulated that the ideal SMIP should remain local 

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and target innate immune cells at the injection site. To this end, LHD153 contains a 
functional phosphonate group to allow for adsorption to aluminium hydroxide. The  
 
Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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arginine salt derivative of this compound is LHD153R. Preclinical results from animal 
models for bacterial and viral antigens, including MenC, MenB, rabies, HIV and 
respiratory syncytial virus (RSV) showed increased functional antibodies and 
antigenspecific T-cells with LHD153R adsorbed to aluminium hydroxide (Aluminium  
Hydroxide/LHD153R) when compared to aluminium hydroxide adjuvanted controls. In 
vitro toxicity screens confirmed that LHD153R is not phototoxic, genotoxic or 
mutagenic. Furthermore, toxicology studies in dog and rats showed that intramuscular 
(IM) injection of Aluminium Hydroxide/LHD153R was well tolerated. Importantly, in 
contrast to free LHD153R, toxicokinetic analysis in rats and dogs confirmed very 
limited exposure of LHD153 when LHD153R was adsorbed to aluminium hydroxide 
after IM injection. 
The aim of this Phase 1 clinical study is to assess the safety of Aluminium  
Hydroxide/LHD153R adjuvanted MenC-CRM197 conjugate vaccine 
(MenCCRM197/Aluminium Hydroxide/LHD153R) and to compare the antibody-
mediated immune response elicited by MenC-CRM197/Aluminium Hydroxide/LHD153R 
with the licensed aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate 
Vaccine (Menjugate®). Furthermore, a comprehensive set of exploratory objectives has 
been selected to assess the systemic exposure of LHD153 after intramuscular injection of 
MenC-CRM197/Aluminium Hydroxide/LHD153R, to evaluate the quality of the specific 
immune response against MenC-CRM197 in detail and to evaluate biomarkers that may 
be predictive of safety and/or innate immune activation. 
The licensed Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) has been 
selected as the primary vaccine candidate to assess the safety and immunopotentiating 
properties of Aluminium Hydroxide/LHD153R for several reasons. Firstly, the safety 
and immunogenicity profiles of the Meningococcal C-CRM197 Conjugate Vaccine 
(Menjugate®) have been well established through years of commercial use. Secondly, a 
more potent MenC-CRM197 conjugate vaccine might enable a reduction of the antigen 
dosage or the number of doses needed in infants. Finally, MenC-CRM197  is a 
wellcharacterized, single conjugate antigen preparation which provides an ideal setting 
to evaluate the potential of this new Aluminium Hydroxide/LHD153R adjuvant. 
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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Study Objectives: 
Primary Safety Objective: 
To assess the safety of MenC-CRM197/Aluminium Hydroxide/LHD153R as compared to 
that of aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
Primary Immunogenicity Objective: 
To compare the antibody responses of MenC-CRM197/Aluminium Hydroxide/LHD153R 
and aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at 
Day 29, as measured by human complement serum bactericidal assay (hSBA) directed 
against MenC. 
Secondary Immunogenicity Objectives: 
1. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine, at Day 8 and Day 181 after vaccination, as measured 
by hSBA directed against MenC. Baseline antibody titers will also be measured by 
hSBA. 
2. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine at Day 8, Day 29 and Day 181 after vaccination, as 
measured by an enzyme-linked immunosorbent assay (ELISA) to MenC. Baseline 
antibody concentrations will also be measured by ELISA. 
Exploratory Objectives: 
1. To evaluate the systemic exposure of LHD153 at several early time-points after IM 
injection of MenC-CRM197/Aluminium Hydroxide/LHD153R or aluminium 
hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
2. To explore the frequency of B cells specific for MenC polysaccharide and CRM197 
protein at baseline (Day 1) and at Day 8, Day 29 and Day 181 after vaccination with  
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
MenC-CRM197/Aluminium Hydroxide/LHD153R or the aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. Subsequently, the B cell 
repertoire of the antigen specific B cells and the specific antibody functionality will 
be analyzed in a selected subset of subjects. 
3. To explore the baseline T cell mediated immunity to CRM197 and to evaluate the 
frequency and quality of CRM197 specific T cells induced by MenC- 
CRM197/Aluminium Hydroxide/ LHD153R compared to aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at Day 8 and Day 29. 
4. To evaluate biomarkers that may be predictive for safety and/or innate immune 
activation. 

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Study Design: 
This Phase 1, randomized, observer-blind, dosage-escalation study will be performed at 
a single center. In total, approximately 80 healthy male and healthy non-pregnant female 
adults (18-45 years of age) will be enrolled in the study. Subjects will be randomized to 
receive a single IM vaccination of either the licensed aluminium hydroxide adjuvanted 
Meningococcal C-CRM197 Conjugate Vaccine (i.e. 10 µg MenC conjugated to CRM197,  
adjuvanted with 1 mg aluminium hydroxide) or one of four dosages of the 
investigational vaccine, MenC-CRM197/Aluminium Hydroxide/LHD153R (i.e. 10 µg 
MenC conjugated to CRM197, adjuvanted with 1 mg aluminium hydroxide and one of 
four dosages [12.5, 25, 50 or 100 µg] of LHD153R). 
For the dosage-escalation of LHD153R, the subjects will be enrolled into 1 of 4 cohorts, 
in a stepwise manner with 20 subjects per cohort. Subjects in all cohorts will be 
randomized in a 1:4 ratio, to receive either aluminium hydroxide adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine (control) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R with increasing doses of LHD153R.Cohort 1 will receive 12.5 μg 
of LHD153R; Cohort 2 will receive 25 μg of LHD153R; Cohort 3 will receive 50 μg of 
LHD 153; and Cohort 4 will receive 100 μg of LHD153R (Table 1). 
 
Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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Table 1. Subjects Randomized per Cohort and Treatment Dosage Group 
Cohort 
Group 
Subjects/ 
Group 
MenC  
Dosage*  
(µg) 
Adjuvant Dosages  
Total 
Volume/Dose 
Total 
Subjects/Cohort 
Aluminium  
Hydroxide  
(mg) 
LHD153R  
(µg) 
1 
A 
4 
10 
1 
0 
0.5 mL 
20 
 
 
 
 
 
 
 
B 
16 
10 
1 
12.5 
0.5 mL 
 
2 
A 
4 
10 
1 
0 
0.5 mL 
20 
C 
16 
10 
1 
25 
0.5 mL 
3 
A 
4 
10 
1 
0 
0.5 mL 
20 
D 
16 
10 
1 
50 
0.5 mL 
4 
A 
4 
10 
1 
0 
0.5 mL 
20 
E 
16 
10 
1 
100 
0.5 mL 
*Conjugated to 12.5-25 µg CRM197 
After vaccination, all subjects will be confined to the clinical site for 24 hours for 
clinical observation, including but not limited to observations for solicited and 
unsolicited adverse events, body temperature measurements and blood sampling for 
exploratory endpoint measurements. 
Importantly, all cohorts will have a staggered entry based on Data Monitoring 
Committee (DMC) reviews. 
▫ For each cohort, the first 5 subjects (i.e. the first 1:4 randomization block) to receive 
either aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate 
Vaccine (n=1) or MenC-CRM197/Aluminium Hydroxide/LHD153R (n=4) will be 
treated at a vaccination rate of 1 subject each day. 
▫ After entry of the first 5 subjects in each cohort, the enrollment will be paused. The 
remaining 15 subjects for each cohort will be enrolled only after DMC review of the 
safety results obtained through Day 14 has been finalized (Table 2). 
▫ In addition, enrollment of the first 5 subjects in the next cohort will only proceed after 
the Day 14 safety results of the first 5 subjects of the previous cohort have been 
reviewed by the DMC (Table 2). 
▫ Furthermore, all available Day 14 and Day 29 safety results will be included in DMC 
reviews between the different enrollment stages. 
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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Table 2. Overview of staggered entry of subjects based on DMC reviews 
Stage 
Dosage Cohort 
MenC-CRM197/ 
Aluminium Hydroxide (n) 
MenC-CRM197/ 
Aluminium Hydroxide 
/LHD153R (n) 
1   
1  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 14 Safety Results 
2 
1  
3 
12 
2  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 29 and Stage 2 Day 14 Safety Results 
3 
2  
3 
12 
3  
1 
4 
Enrollment pause until DMC review of Stage 2 Day 29 and Stage 3 Day 14 Safety Results 
4 
3  
3 
12 
4  
1 
4 
Enrollment pause until DMC review of Stage 3 Day 29 and Stage 4 Day 14 Safety Results 
5 
4  
3 
12 
The DMC review will be performed according to predefined stopping/pausing guidelines 
used to ensure the safety of study subjects. These stopping/pausing guidelines are based 
on FDA guidance and with grading scales from the CBER Guidance for Industry 
“Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials”. See protocol section 3.6 for further details. 
Safety Measurements 
Schedule of safety data collection: 
▫ Solicited local and systemic adverse events (AEs), body temperature and all 
unsolicited AEs will be collected until Day 14. 
▫ All serious adverse events (SAEs), medically attended AEs, AEs leading to study 
withdrawal, new onset of chronic disease (NOCDs), and adverse events of special 
interest (AESIs) will be collected from the date of signed informed consent to study 
completion at Day 366. 
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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▫ All concomitant medications administered in relation to the reported AEs will be 
collected from vaccination to study completion at Day 366. 
Solicited local AEs include injection site erythema, injection site induration, injection 
site pain and injection site swelling. Solicited systemic AEs include body temperature ≥ 
38.0°C (as measured orally), loss of appetite, nausea, fatigue, generalized myalgia, 
generalized arthralgia, headache, chills, vomiting, diarrhea, generalized rash and 
urticaria. 
All AESIs will be reported in the same manner as SAEs. All AEs will be monitored until 
resolution or, if the AE becomes chronic, a cause is identified. If an AE is unresolved at 
the conclusion of the study, a clinical assessment will be made by the investigator and 
the medical monitor to determine whether or not continued follow-up of the AE is 
warranted. 
The relationship of the study treatment to any AE will be determined by the investigator 
as probably related, possibly related, or not related; the relationship of the study 
treatment to any SAE will be determined by the investigator as probably 
related/suspected, or not related. 
Safety Laboratory Parameters 
To assess laboratory AEs, blood and urine samples will be collected from each subject as 
outlined in Table 3 to perform blood chemistry, hematology, and urine analyses. 
Safety laboratory samples will be drawn from all subjects at pre-vaccination screening 
(between Day -28 and Day -3) at Day 1 (pre-vaccination and 24h after vaccination), at 
Day 8 and at Day 29. Safety laboratory assessments will include sodium, potassium, 
chloride, bicarbonate, blood urea nitrogen, creatinine, liver function tests (ALT, AST), a 
complete blood count and C-reactive protein. A urine sample will be collected at the 
same time-points and will be assessed for the presence of protein, glucose and red blood 
cells. 
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Primary and Secondary Immunogenicity Measurements 
Four blood samples per subject (i.e. at Day 1, Day 8, Day 29 and Day 181) will be 
collected for serum preparation and determination of antibody-mediated immune 
responses to MenC-CRM197 as outlined in Table 3 and Table 4. See section 7.3 for 
further details. 
Exploratory Measurements 
In all subjects who agree by signing a separate Informed Consent, additional blood 
samples will be collected at Day 1, Day 4, Day 8, Day 29 and Day 181 for exploratory 
assays as outlined in Table 3 and Table 4. The purpose of these assays is to assess the 
systemic exposure of LHD153, to determine the frequency and quality of B- and T-cells 
specific for MenC polysaccharide and/or CRM197 and to evaluate biomarkers that may 
be predictive of safety and/or innate immune activation. Subsequently, MenC-CRM197 
specific B-cell repertoires as well as the MenC-CRM197 specific antibody functionalities 
will be analyzed in a selected subset of subjects, dependent on the results from primary 
and secondary immunogenicity measurements and the volume of whole blood (specific 
B cell repertoire) and serum (specific antibody functionality) remaining for additional 
testing. See section 7.4 for further details. All exploratory analyses may be performed 
after the Clinical Study Report (CSR) has been completed, in which case these data will 
be submitted as an addendum to the CSR. 
Number of Subjects planned: 
Approximately 80 adult subjects will be randomized, with anticipated dropout rates of 
5% by Day 181 (last serology time point), and 10%, by Day 366 (last safety time point). 
Sample size is not driven by statistical assumptions for formal hypothesis testing, but the 
proposed number of subjects will be sufficient to provide a descriptive summary of the 
safety and immunogenicity of the study vaccine. 

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Study Population and Subject Characteristics: 
Healthy adult male and female volunteers between 18-45 years of age, inclusive. 
The list of inclusion and exclusion criteria is included in protocol section 4.0. 
 
Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Study Vaccines: 
The MenC-CRM197 conjugate is a lyophilized powder consisting of 10 µg of MenC 
polysaccharide conjugated to 12.5-25 µg CRM197 carrier protein. The MenC-CRM197 
lyophilized powder will be reconstituted with adjuvant by the unblinded designated site 
staff member who is to follow the procedure as described in the vaccine preparation 
instructions in the Investigator Site File (i.e. the vaccine will be prepared in the clinic 
prior to administration). 
The lyophilized MenC-CRM197 powder will be reconstituted with either: 
(a) aluminium hydroxide adjuvant 
(b) Aluminium Hydroxide/LHD153R adjuvant with specified dosages of LHD153R 
(12.5, 25, 50 or 100 µg) 
The components for each formulation of MenC-CRM197 will be provided in a separate 
kit. 
Aluminium Hydroxide/LHD153R with specified dosages of LHD153R will be prepared  
by dilution of the highest Aluminium Hydroxide/LHD153R dosage (100 µg of 
LHD153R) with aluminium hydroxide. 
In each cohort, subjects will be randomized to receive one injection of MenC- 
CRM197/Aluminium Hydroxide/LHD153R adjuvant or aluminium hydroxide adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine. The 0.5 mL of vaccine will be injected 
IM in the deltoid muscle, with preference that the injection is administered in the 
nondominant arm. 

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Primary Safety Endpoint: 
Safety will be assessed by measuring the frequency of local and systemic solicited AEs, 
unsolicited AEs, SAEs, AESIs, NOCDs, and safety laboratory data for all subjects.  
Specifically, 
▫ The frequency and percentage of subjects with solicited local and systemic AEs 
through Day 14. Time intervals after vaccination that will be summarized are: 30 
min post-vaccination, Days 1-4 (without 30 min), Days 5-8, Days 8-14, Days 1-8 
 
Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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(without 30 min) and Days 1-14 (without 30 min). 
▫ The frequency and percentage of subjects with any unsolicited AEs from the day of 
vaccination (Day 1) to Day 14. 
▫ The frequency and percentage of subjects with SAEs, medically attended AEs,  AEs 
leading to study withdrawal, NOCDs, AESIs for the following time periods: day of 
signed informed consent until study completion (Day 366), day of vaccination (Day 
1) to Day 29 and Day 29 to study completion (Day 366). 
▫ The absolute values and changes in hematology, chemistry, and urinalysis parameters. 
▫ The frequency and percentage of subjects with abnormal laboratory parameter values 
as classified by investigator normal ranges (low, normal, high) and as classified by 
CBER toxicity grading scales, when available. 
Primary Immunogenicity Endpoint: 
Geometric mean titers (GMTs) measured by hSBA directed against MenC from samples 
collected on Day 1 (baseline, before vaccination) and Day 29 as well as the GMR of the 
titers (Day 29 / Day 1). 
Secondary Immunogenicity Endpoints: 
▫ GMTs and corresponding GMRs measured by hSBA directed against MenC for samples 
collected at Day 8 and Day181. 
▫ Percentage of subjects with hSBA seroresponse at Day 8, Day 29, and Day 181. 
seroresponse is defined as a post vaccination hSBA ≥8 for subjects with a baseline 
hSBA <4 or have an increase of at least 4 times the baseline hSBA level for subjects 
with pre-vaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against MenC measured by ELISA 
for samples collected on Day 1 (baseline, prior to vaccination), Day 8, Day 29, and 
Day 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations 
to MenC measured by ELISA on Day 8, Day 29, and Day 181 relative to baseline 
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
(Day 1). 
Exploratory Endpoints: 
Testing and analyses of exploratory endpoints may be performed after the Clinical Study 
Report (CSR) has been completed, in which case these data will be submitted as an 
addendum to the CSR. 
1. Serum concentration of LHD153 at Day 1 baseline (prior to vaccination), Day 1 (1h , 
2h, 4h, 8h, and 24h after vaccination) and Day 4 by LC-MS/MS. 
2. Frequency of MenC polysaccharide-specific and CRM197-specific B cells at Day 1 
(baseline), Day 8, Day 29, and Day 181 by ELISPOT. 
3. Diversity of the MenC polysaccharide-specific B-cell repertoire at Day 1 (baseline), 
Day 8, Day 29, and Day 181 by immunoglobulin cDNA sequencing. 
4. Functionality of antigen specific antibodies will be assessed at Day 1 (baseline), Day 
8, Day 29, and Day 181 by analysis of immunoglobulin isotype, glycosylation state 
and their ability to fix complement, to promote antibody-dependent cell mediated 
cytoxicity, to induce phagocytosis and to activate FcR+ cells. If the quantity of serum 
available for this specific exploratory objective is limited, assessments of 
immunoglobulin isotype and glycosylation state will be prioritized over the other 
assessments. 
5. Frequency and quality of T cells specific for CRM197 at Day 1 (baseline), Day 8, and 
Day 29 by flow cytometry using intracellular staining with a panel of cytokines and 
staining of surface markers to identify cell populations. 
6. Serum concentrations of a panel of 30 chemokines and cytokines at Day 1 baseline 
(prior to vaccination), Day 1 (6h and 24h after vaccination), Day 4, and Day 8 by 
electrochemo-luminescence based assay. 
7. Gene expression profile in whole blood at Day 1 baseline (prior to vaccination), Day 
1 (6h and 24h after vaccination), Day 4, and Day 8 by RNA micro array analysis. 

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8. Number and activation status of myeloid and lymphoid cell populations at Day 1 
baseline (prior to vaccination), Day 1 (24h after vaccination), Day 4 and Day 8 by  
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
flow cytometry. 
Statistical Analyses: 
The study is exploratory in nature, thus analyses will be descriptive and no formal 
hypothesis testing will be performed. 
Primary Safety Analyses 
The primary safety analyses will be based on the safety set for solicited and unsolicited 
adverse events. There is no statistical null hypothesis associated with the safety 
objective, which will be analyzed descriptively. 
Immunogenicity Analyses 
The primary immunogenicity analyses will be based on the per-protocol set (PPS) on 
Day 29. The primary analyses will also be performed using the Full Analysis Set (FAS) 
as a measure of the sensitivity/robustness of the results. All other immunogenicity 
assessments will be performed using the PPS or the appropriate subset of subjects. The 
antibody concentrations/titers will be summarized using GMC/GMTs and two-sided 
95% confidence intervals (CIs) constructed by exponentiation (base 10) of the least 
square means of the logarithmically transformed (base 10) antibody titer. The 95% CIs 
will be obtained from an analysis of covariance (ANCOVA) with baseline 
concentration/titer as a covariate. Additional details will be further described in the 
Statistical Analysis Plan. 
The immunogenicity endpoints based on subjects meeting criteria for seroconversion or 
achieving a certain threshold value will be summarized using frequencies and 
percentages and associated two-sided 95% Clopper-Pearson CIs. For analyses of 
seroconversion, separate summaries may be provided based on seropositivity status at 
baseline. 

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Interim Analysis: 
An Interim Analysis will be performed on the immunogenicity and safety data collected 
from all subjects until Day 29, after all cohorts have been enrolled. Further details  
 
Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
regarding the interim analysis are contained in section 8.6. 
Data Monitoring Committee: 
A DMC will be implemented to review safety data during scheduled periodic reviews. 
The DMC will review safety data collected until Day 14, as described in the DMC 
charter and in the Statistical Analysis Plan, after enrollment of the first 5 subjects in each 
cohort, before proceeding with enrollment of the remaining 15 subjects in each cohort. In 
addition, enrollment of the first 5 subjects of the next cohort will only proceed after the 
Day 14 safety results of the first 5 subjects of the previous cohort have been reviewed. 
Furthermore, all available Day 14 and Day 29 safety results will be included in DMC 
reviews between the different enrollment stages. Further information regarding the DMC 
is discussed in more detail in the protocol, section 3.7. 

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Table 3: 
Time and Events Table – Treatment Period (until Day 29) 
 
Visit Type 
Clinic Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
 
Study Day 
-28 to -3 
1 
4 
8 
15 
22 
29 
 
Visit Window (Days) 
n/a 
n/a 
n/a 
-1/+1 
+1 
n/a 
-2/+2 
 
Visit Number 
Screening  
1 
2 
3 
4 
5 
6 
Study Event 
References 
 
 
 
 
 
 
 
Study Treatment 
 
 
 
 
 
 
 
 
Vaccination 
Section 5.2 
 
X 
 
 
 
 
 
Screening and Safety 
 
 
 
 
 
 
 
 
Informed Consent  
Section 5.1.1 
X 
 
 
 
 
 
 
Demographic Data & Medical History 
Sections 5.1.2 
X 
 
 
 
 
 
 
Physical Exam 
Sections 5.1.2 and 5.2.1 
X 
Xa 
 
 
 
 
 
Safety Laboratory blood draw (10 ml) 
Section 7.1.7 
X 
Xb 
 
X 
 
 
X 
Urinalysis 
Sections 7.1.7 
X 
Xb 
 
X 
 
 
X 
Pregnancy Test 
Sections 5.1.2 and 5.2.1 
X 
Xa 
 
 
 
 
 
Exclusion/Inclusion Criteria 
Section 4.0 
X 
Xa 
 
 
 
 
 
Randomization 
Section 5.2.3 
 
Xa 
 
 
 
 
 
30 min and 24 hr Post Injection Assessment 
Section 5.2.5 
 
Xc 
 
 
 
 
 
Subject Diary Dispensed with Training 
Section 5.2.5 
 
X 
 
 
 
 
 
Subject Diary Reminder 
Section 5.2.5 
 
 
X 
X 
 
 
 

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Subject Diary Reviewed and Collected 
Section 5.3.1 
 
 
 
 
X 
 
 
Assess all solicited AEs 
Section 7.1.1 and 7.1.3 
 
 
 
 
X 
 
 
Assess all unsolicited AEs 
Sections 7.1.2 and 7.1.3 
X 
X 
X 
X 
X 
 
 
PRO-01 TEMP 06 / Atlas No. 293620 
Visit Type 
Clinic Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Study Day 
-28 to -3 
1 
4 
8 
15 
22 
29 
Visit Window (Days) 
n/a 
n/a 
n/a 
-1/+1 
+1 
n/a 
-2/+2 
Visit Number 
Screening  
1 
2 
3 
4 
5 
6 
Study Event 
References 
Assess SAEs 
Section 7.1.4 
X 
X 
X 
X 
X 
X 
X 
Assess AESIs 
Section 7.1.4.1 
X 
X 
X 
X 
X 
X 
X 
Assess NOCDs, medically attended AEs, AEs 
leading to withdrawal  
Sections 7.1.3 
X 
X 
X 
X 
X 
X 
X 
Assess relevant medications 
Sections 5.1.2 and 6.5 
X 
X 
X 
X 
X 
X 
X 
Blood draws for Immunogenicity and Exploratory Objectives 
Serum Blood Draws (Primary/Secondary Objectives; 10 mL)  
Section 3.5 
Xa 
X 
X 
Serum Blood Draws (Exploratory Objectives; 5 mL)  
Section 3.5 
Xd 
X 
X 
Whole Blood Draws (Exploratory Objectives; 3 mL) 
Section 3.5 
Xe 
X 
Whole Blood Draws (Exploratory Objectives; 5 mL) 
Section 3.5 
Xf 
X 
X 
Whole Blood Draws (Exploratory Objectives; 20 mL) 
Section 3.5 
Xg 
X 
Whole Blood Draws (Exploratory Objectives; 50 mL) 
Section 3.5 
X 

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Whole Blood Draws (Exploratory Objectives; 70 mL) 
Section 3.5 
Xa 
X 
Notes: 
a. 
Procedure must be performed prior to vaccination. 
b. 
Two blood draws (2 x 10 ml) and two urine samples must be taken at Study Day 1, i.e. at baseline (prior to vaccination) and at 24h after 
vaccinati 
c. 
Body temperature measurement must be performed at 30 min, 2, 4, 6, 8, 10, 12, 18 and 24h after vaccination. 
d. 
Three Serum Blood Draws (3 x 5ml) must be taken at Study Day 1, i.e. at baseline (prior to vaccination), at 6h and at 24h after vaccination. 
e. 
Six Whole Blood Draws (6 x 3 mL) must be taken at Study Day 1, i.e. at baseline (prior to vaccination) and at 1, 2, 4, 8 and 24h after 
vaccination. 
f. 
Three Whole Blood Draws (3 x 5 mL) must be taken at Study Day 1, i.e. at baseline (prior to vaccination), at 6h and at 24h after vaccination. 
g. Whole Blood Draw (20 mL) at Study Day 1 must be taken at 24h after vaccination. 
on. 
PRO-01 TEMP 06 / Atlas No. 293620 
Table 4: 
Time and Events Table – Follow-up Period (until Day 366) 
Visit Type 
Clinic Visit 
Clinic Visit 
Clinic Visit 
Phone Call 
Phone Call 
Clinic Visit 
Study Day 
85 
113 
181 
209 
271 
366 
Visit Window (Days) 
-7 to +7 
-7 to +7 
-7 to +7 
-14 to +14 
-14 to +14 
-14 to +14 
Visit Number 
7 
8 
9 
10 
11 
12 
Study Event 
References 
 
 
Safety 
 
Assess SAEs 
Section 7.1.4 
X 
X 
X 
X 
X 
X 
Assess AESI 
Section 7.1.4.1 
X 
X 
X 
X 
X 
X 
Assess NOCDs, medically attended 
AEs, AEs leading to withdrawal 
Sections 7.1.3 
X 
X 
X 
X 
X 
X 
Assess relevant medications 
Sections 5.1.2 and 6.5 
X 
X 
X 
X 
X 
X 
Blood draws for Immunogenicity and Exploratory Objectives 
 

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Serum Blood Draw (Secondary 
Objective; 10 mL) 
Section 3.5 
 
 
X 
 
 
 
Whole Blood Draw  
(Exploratory Objectives; 50 mL) 
Section 3.5 
 
 
X 
 
 
 
Study Completion Procedures 
 
Study Terminationa 
Section 5.5 
 
 
 
 
 
X 
Notes: 
a. Subjects who terminate the study early are recommended to complete certain study-related procedures. See section 5.5 for further details. 
 
PRO-01 TEMP 06 / Atlas No. 293620 

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LIST OF ABBREVIATIONS 
ADCC 
Antibody-dependent cell mediated cytotoxicity 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BZN 
Benzonaphthyridines 
CBER 
Center for Biologics Evaluation and Research 
cDNA 
Complementary deoxyribonucleic acid 
CI 
Confidence interval 
CRF 
Case report form 
CRM197 
Cross Reacting Material 197 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
EC 
Ethics committee 
EDC 
Electronic data capture 
ELISA 
Enzyme-linked immunosorbent assay 
ELISPOT 
Enzyme-Linked ImmunoSpot 
EMA 
European Medicines Agency 
FACS 
Fluorescence-activated cell sorting 
FAS 
Full analysis set 
FDA 
Federal Drug Agency 
GCP 
Good clinical practice 
GMC 
Geometric mean concentration 
GMP 
Good manufacturing practice 

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GMT 
Geometric mean titer 
GMR 
Geometric mean ratio 
HEENT  
Head, ears, eyes, nose and throat 
HIV 
Human immunodeficiency virus 
 
HPV 
Human papillomavirus 
hSBA 
Human complement serum bactericidal assay 
ICF 
Informed consent form 
ICH 
International Committee for Harmonization 
IM 
Intramuscular 
IRB 
Institutional review board 
IV 
Intravenous 
LLQ 
Lower limit of quantification 
MenC 
Meningococcal type C 
MPL 
Monophosphoryl lipid A 
NCR 
No carbon required 
NOCD 
New Onset of Chronic Disease 
PEG 
Polyethylene glycol 
PO 
Per oral 
PP 
Per protocol 
RNA 
Ribonucleic acid (RNA 
SAE 
Serious Adverse Event 
SMIP 
Small molecule immune potentiator 
TLR 
Toll-like receptor 
VSAE 
Vaccine serious adverse event 
1.0  
BACKGROUND AND RATIONALE 
1.1  
Background 

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MenC-CRM197 Conjugate Vaccine 
Meningococcal disease worldwide is predominantly a disease of infants and young 
children. N. meningitidis serogroup B and C remain the most prevalent strains in North 
America and Europe, (Rosenstein, N. et al., 2001) and together cause more than 95% of 
reported cases of meningococcal disease in Europe (Connolly, M, et al., 1999). In Europe, 
N. meningitidis serogroup C (MenC) is one of the major serogroups causing invasive 
disease. Case fatality in Germany has ranged between 6% and 8% between 1999 and 
2006, and has remained generally consistent across the different European countries, 
varying between 6-11%, with the case fatality rate being notably higher for serogroup C 
disease than for serogroup B (European Centre for Disease Prevention and Control, 
2011). Since MenC vaccination was added to Germany’s routine schedule for children in 
2006, there has been a reported decline in MenC incidence. However, the decline was not 
as rapid when compared to other European countries (Hellenbrand, W. et al., 2013). 
The GSK Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) comprises MenC 
oligosaccharides conjugated to the protein carrier, CRM197, a nontoxic mutant of 
diphtheria toxin. The vaccine has been shown to be safe and immunogenic and able to 
prime infants, toddlers and young children for immunological memory (see 
Meningococcal C-CRM197 Conjugate Vaccine Summary of Product Characteristics).  
In Germany, the Standing Committee on Vaccination (STIKO) of the Robert Koch  
Institute recommends a single dose of MenC conjugate vaccine in children over the age of  
12 months as part of the routine vaccination campaign (Robert Koch Institute 
Epidemiologisches Bulletin, August 2013). For specific indications, e.g. in case of 
postexposure prophylaxis, the recommended schedule for primary immunization of 
infants between 2 to 12 months of age with a MenC conjugate vaccine is two dosages 
given with an interval of at least 2 months. 
Although the Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) represents an 
example of how vaccination with a well characterized, purified polysaccharide antigen 
can yield pivotal public health triumphs, there remains a need for further improvement of 
the MenC vaccine. A more potent MenC vaccine formulation might yield an increase in 
the magnitude of the antigen-specific immune response enabling a reduction of the 
antigen dosage. Furthermore, induction of a more rapid antigen-specific immune response 
may enable a reduction in the number of doses needed for post-exposure prophylaxis in 
infants. 

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Vaccine Adjuvants 
Immunization with purified protein or polysaccharide antigens typically results in the 
induction of a modest antibody response with little or no T cell response when compared 
to vaccines comprised of whole or killed bacteria or viruses that have inherent 
immunepotentiating activity. The need to increase the immunogenic response of 
wellcharacterized and purified antigens that display suboptimal immunogenicity when 
used alone affirms the essential role for the use of adjuvants. Vaccine adjuvants may 
significantly reduce the amount of antigen needed (Del Giudice, G, et al., 2013) and may 
induce a more rapid immune response enabling a reduction in the number of doses in a 
regimen. 
Besides reducing the antigen dosage or number of doses in the vaccine regimen, there is 
now an increased appreciation of the capacity of adjuvants to increase not just overall 
antibody titer but also to increase the number of functional antibodies and/or antibodies 
with higher affinity for vaccine antigens. Many pathogens, such as influenza viruses, 
HIV, human papilloma virus (HPV) and the malaria parasite, display substantial antigenic 
drift, subtype and/or strain variations. Therefore, the ability of adjuvants to broaden an 
immune response profile could be crucial to the success of vaccines against such targets. 
Previous studies have shown that the broadening effect of adjuvants may be mediated via 
expansion of B cell diversity, not merely through increased titers (Khurana, et al., 2010, 
2011). Clinically, antibody response broadening by adjuvants such as AS04 or oil-inwater 
emulsions has been demonstrated in HPV vaccines and influenza, respectively (Bissett, 
SL et al., 2014; Del Giudice, G et al., 2013). 
One unmet need is the development of vaccines for effective T cell responses. Several 
vaccines in development are aimed at eliciting T cell responses, which historically have 
not been induced by the most commonly used adjuvants in vaccines for human use, such 
as aluminium hydroxide. Therefore, an objective of many adjuvant discovery and 
development programs is to elicit more effective engagement of T-helper cells for 
optimizing the quality, breadth and durability of antibody responses, or, to induce effector 
CD4+ or CD8+ T cells to kill intracellular pathogens. One approach for new generation 
vaccines is the use of agonists for Toll-like receptors (TLRs) that activate innate immune 
receptors, mainly on antigen presenting cells, and facilitate the generation of T helper cell 
responses. 
Adjuvants that are currently employed in human vaccines licensed for use in the USA 
and/or Europe include aluminium salts, oil-in-water emulsions (MF59, AS03 and AF03), 
virosomes, and AS04 (Alving, CR, et al., 2012). Among the most advanced adjuvants 
systems is AS04 which is used in the Cervarix® HPV vaccine and consist of the TLR4 
ligand monophosphoryl lipid A (MPL) combined with aluminium salt. MPL, along with 

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QS21, is also part of the adjuvant system (AS01) in the RTS, S malaria vaccine which has 
been evaluated in a Phase 3 clinical trial (Regules, JA, et al., 2011). Another clinically 
advanced adjuvant is CpG oligodeoxynucleotide (ODN), a TLR9 ligand contained in the 
Heplisav® vaccine candidate for hepatitis B from Dynavax, that has completed a Phase 3 
clinical trial (Reed, SG, et al., 2013). 
Small molecule immune potentiators as a new class of vaccine adjuvants 
A new class of adjuvants, small molecule immune potentiators (SMIPs), has been 
identified that activate immune cells by targeting TLR7 and TLR8. Imiquimod and 
Resiquimod (R848) are clinically advanced TLR7 and/or TLR8 SMIPs that are used as 
immunotherapeutics. Although Imiquimod and Resiquimod have been studied 
extensively as vaccine adjuvants in preclinical models (Vasilakos et al. 2013), they were 
never optimized for this use and, in general, compare poorly to other pre-clinical and 
clinical adjuvant candidates. Furthermore, when Imiquimod is applied topically (it is a 
licensed topical treatment for viral and malignant skin lesions) it induces strong local and 
systemic inflammatory reactions, and is poorly tolerated (Bauza, et al. 2009; Campanelli, 
et al. 2005; Meyer, et al. 2008). 
Unlike traditional drugs, TLR7 SMIPs activate innate immunity and initiate a cascade of 
immune responses that can have systemic impact and endure after the compound has been 
cleared from the organism. For SMIPs as vaccine adjuvants this difference is highlighted 
further by the fact that 2-3 local IM injections drive antigen-specific B and T cell 
responses at distal sites and these can provide protection in the form of immunologic 
memory (Tacken,  et al. 2011; Ilyinskii, et al., 2014). Therefore, limiting the systemic 
exposure of the SMIP adjuvants has been postulated as an approach to both increase 
vaccine efficacy and minimize side effects associated with systemic and generalized 
inflammation. GSK is currently developing a novel adjuvant, containing a SMIP from the 
benzonaphthryridines (BZN) series, LHD153, which targets TLR7. The objective driving 
the discovery of this new TLR7 ligand was to develop a vaccine adjuvant with high 
efficacy in increasing the vaccine specific immune response and with minimal side 
effects. To obtain this objective it was postulated that the ideal compound would remain 
localized at the site of injection to help trigger the immune reaction to vaccine antigens, 
yet maintain a low systemic distribution. At the same time this compound had to be 
soluble to make industrial scale-up and manufacturing feasible. Soluble BZN were 
engineered so that they could be formulated with aluminium salts with the aim of limiting 
their systemic exposure and keeping them localized in the muscle for short time after 
immunization. The strongest adsorption to aluminium hydroxide particles is obtained 
through ligand exchange of hydroxyl and/or phosphate groups on the surface of 
aluminium hydroxide or phosphate with soft anionic moieties such as phosphates, 
phosphonates, phosphites, sulfates and carboxylates. To drive the adsorption to 

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aluminium hydroxide through ligand exchange, LHD153 was functionalized with a 
polyethylene glycol (PEG) linker and a terminal phosphonate. Furthermore, LHD153 was 
stabilized with arginine salt to allow scale up for GMP manufacturing, yielding 
LHD153R. As predicted, unformulated LHD153R exhibited high levels of systemic 
exposure when injected IM in mice, rats and dogs, whereas the serum concentrations of 
LHD153R adsorbed to aluminium hydroxide (Aluminium Hydroxide/LHD153R) was 
dramatically reduced. Moreover, Aluminium Hydroxide/LHD153R remained localized to 
the injection site. 
Preclinical studies using Aluminium Hydroxide/LHD153R to date confirm the activation 
of the TLR7 pathway and subsequent boost of both the humoral and cellular immune 
response. Moreover, Aluminium Hydroxide/LHD153R displays a unique 
pharmacokinetic profile as demonstrated by its minimal systemic exposure, potentially 
minimizing any systemic inflammatory response associated with tolerability issues. 
Aluminium hydroxide/LHD153R has achieved proof of concept in animal models using 
several vaccine antigens including MenC, MenB, rabies, HIV and respiratory syncytial 
virus (RSV). In vitro toxicity of LDH153R has been assessed, and in vivo nonclinical 
tolerability and safety of LHD153R and Aluminium Hydroxide/LHD153R have been 
evaluated in rats, dogs and non-human primates. LHD153R was not phototoxic, 
genotoxic or mutagenic (Ames and chromosomal aberration tests), and did not cause local 
or systemic toxicity in dogs or rats. Furthermore, Aluminium Hydroxide/LHD153R was 
well tolerated in rhesus monkeys. 
1.2  
Rationale 
The aim of this study is to assess the safety of Aluminium Hydroxide/LHD153R 
adjuvanted MenC-CRM197 conjugate vaccine (MenC-CRM197/Aluminium  
Hydroxide/LHD153R) and to compare the antibody-mediated immune response elicited 
by MenC-CRM197/Aluminium Hydroxide/LHD153R with the licensed aluminium 
hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®). 
Furthermore, a comprehensive set of exploratory objectives has been selected to assess 
the systemic exposure of LHD153 after intramuscular injection and to evaluate the quality 
of the specific immune response against MenC-CRM197 in detail and to evaluate  
biomarkers that may be predictive of safety and/or innate immune activation. 
The licensed Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) has been 
chosen as the primary vaccine candidate to assess the safety and immunopotentiating 
properties of Aluminium Hydroxide/LHD153R for several reasons. Firstly, the safety and 
immunogenicity profiles of the Meningococcal C-CRM197 Conjugate Vaccine have been 
well established through years of commercial use. Secondly, a more potent 

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Meningococcal C-CRM197 Conjugate Vaccine might enable a reduction of the antigen 
dosage or the number of doses needed in infants between 2 and 12 months of age. Finally, 
Meningococcal C-CRM197 is a well-characterized, single conjugate antigen preparation 
which provides an ideal setting to explore the potential of this new Aluminium 
Hydroxide/LHD153R adjuvant. 
2.0  
OBJECTIVES 
2.1  
Primary Objectives 
Primary Safety Objective 
To assess the safety of MenC-CRM197/Aluminium Hydroxide/LHD153R as compared to 
that of aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
Primary Immunogenicity Objective 
To compare the antibody responses of MenC-CRM197/Aluminium Hydroxide/LHD153R 
and aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at 
Day 29, as measured by human complement serum bactericidal assay (hSBA) directed 
against MenC. 
2.2  
Secondary Objectives 
Secondary Immunogenicity Objective(s) 
1. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine at Day 8 and Day 181 after vaccination, as measured by 
hSBA directed against MenC. Baseline antibody titers will also be measured by 
hSBA. 
2. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine, at Day 8, Day 29 and Day 181 after vaccination, as 
measured by an enzyme-linked immunosorbent assay (ELISA) to MenC. Baseline 
antibody concentrations will also be measured by ELISA. 
2.3  
Exploratory Objectives 

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1. To evaluate the systemic exposure of LHD153 at several early time-points after IM 
injection of MenC-CRM197/Aluminium Hydroxide/LHD153R or Meningococcal 
CCRM197 Conjugate Vaccine. 
2. To explore the frequency of B cells specific for MenC polysaccharide and CRM197 
protein at baseline (Day 1) and at Day 8, Day 29 and Day 181 after vaccination with 
MenC-CRM197/Aluminium Hydroxide/LHD153R or the aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. Subsequently, the B cell 
repertoire of the antigen specific B cells and the specific antibody functionality will 
be analyzed in a selected subset of subjects. 
3. To explore the baseline T cell mediated immunity to CRM197 and to evaluate the 
frequency and quality of CRM197 specific T cells induced by 
MenCCRM197/Aluminium Hydroxide/ LHD153R compared to aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at Day 8 and Day 29. 
4. To evaluate biomarkers that may be predictive for safety and/or innate immune 
activation. 
 

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3.0 
STUDY DESIGN 
3.1 
Overview of Study Design 
This is a Phase 1, randomized, observer blind, adjuvant dosage-escalation study. It will be 
performed at a single center. In total, approximately 80 healthy male and healthy 
nonpregnant female adults (18-45 years of age) will be enrolled in the study. 
Subjects will be randomized to receive a single IM vaccination of either the licensed 
aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine 
(Menjugate®) or the investigational vaccine, MenC-CRM197/Aluminium 
Hydroxide/LHD153R. 
The dosage of LHD153R will be escalated from 12.5 µg to 100 µg.  For the 
dosageescalation of LHD153R, the subjects will be enrolled into 1 of 4 cohorts, in a 
stepwise manner with 20 subjects per cohort. Subjects in all cohorts will be randomized 
in a 1:4 ratio, to receive either aluminium hydroxide adjuvanted Meningococcal C-
CRM197 Conjugate Vaccine (control) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R with increasing doses of LHD153R. Subjects assigned to MenC-
CRM197/Aluminium Hydroxide/LHD153R in Cohort 1 will receive 12.5 μg of LHD153R; 
Subjects in Cohort 2 will receive 25 μg of LHD153R; Subjects in Cohort 3 will receive 
50 μg of LHD153R; Subjects in Cohort 4 will receive 100 μg of LHD153R (Table 3.1-1). 
Table 3.1-1: Subjects Randomized per Cohort and Treatment Dosage Group 
Cohort 
Group 
Subjects/ 
Group 
MenC 
Dosage* 
(µg) 
Adjuvant Dosages 
Total 
Volume/Dose 
Total 
Subjects/Cohort 
Aluminium  
Hydroxide  
(mg) 
LHD153R  
(µg) 
1 
A 
4 
10 
1 
0 
0.5 mL 
20 
 
 
 
 
 
 
 
B 
16 
10 
1 
12.5 
0.5 mL 
 
2 
A 
4 
10 
1 
0 
0.5 mL 
20 
C 
16 
10 
1 
25 
0.5 mL 
3 
A 
4 
10 
1 
0 
0.5 mL 
20 
D 
16 
10 
1 
50 
0.5 mL 
4 
A 
4 
10 
1 
0 
0.5 mL 
20 
E 
16 
10 
1 
100 
0.5 mL 
*Conjugated to 12.5-25 µg CRM197 
All cohorts will have a staggered entry. For each cohort, the first 5 subjects (i.e. the first  
1:4 randomization block) to receive either aluminium hydroxide adjuvanted  

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Meningococcal C-CRM197 Conjugate Vaccine (n=1) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R (n=4) will be vaccinated at rate of 1 subject each day. 
After entry of the first 5 subjects in each cohort, the enrollment will be paused. The 
remaining 15 subjects for each cohort will be enrolled only after DMC review of the 
safety results obtained through Day 14 has been finalized (Table 3.1-2). In addition, 
enrollment of the first 5 subjects of the next cohort will only proceed after the Day 14 
safety results of the first 5 subjects of the previous cohort have been reviewed by the 
DMC. Furthermore, all available Day 14 and Day 29 safety results will be included in 
DMC review between the different enrollment stages. 
Table 3.1-2: Overview of staggered entry of subjects based on DMC reviews 
Stage 
Dosage Cohort 
MenC-CRM197/ 
Aluminium Hydroxide (n) 
MenC-CRM197/ 
Aluminium Hydroxide 
/LHD153R (n) 
1   
1  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 14 Safety Results 
2 
1  
3 
12 
2  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 29 and Stage 2 Day 14 Safety Results 
3 
2  
3 
12 
3  
1 
4 
Enrollment pause until DMC review of Stage 2 Day 29 and Stage 3 Day 14 Safety Results 
4 
3  
3 
12 
4  
1 
4 
Enrollment pause until DMC review of Stage 3 Day 29 and Stage 4 Day 14 Safety Results 
5 
4  
3 
12 
Post-vaccination procedures include collection of urine specimens at Day 1, Day 8 and 
Day 29 for safety assessment and blood specimens at Day 1, Day 8, Day 29 and Day 181 
for safety assessment and evaluation of the primary and secondary immunogenicity 
endpoints. Furthermore, additional blood specimens will be collected for assessment of 
exploratory endpoints at Day 1, Day 4, Day 8, Day 29 and Day 181 from those subjects 
that signed an additional informed consent concerning blood collection for exploratory 
assessment. 
3.2  
Study Period 
Each subject should expect to participate in the study for approximately 12 months, from 
the time of enrolment through the last study visit. 

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3.3  
Blinding Procedures 
This study is designed as an observer-blind study. For each dosage cohort, subjects, 
investigators, laboratories and the sponsor will be blinded to vaccine assignments. 
To maintain the blindness within each cohort, designated nurse(s) or physician(s) will be 
responsible for administering the study vaccines to the subjects, and will be instructed not 
to reveal the identity of the study vaccines neither to the subject nor to the investigative 
site personnel (investigator, study nurse, monitor) involved in the conduct or monitoring 
of the trial. This (these) designated individual(s) will have no contact with the subjects 
after the administration of the study vaccine. Furthermore, unblinded monitors are 
assigned to reconcile actual vaccine treatment. 
Study unblinding, at the group level, is planned for an Interim Analysis of the safety and 
immunogenicity data obtained up to Day 29 after all cohorts are enrolled and for full 
unblinding at the End of Study. 
Except in the case of medical necessity, a subject’s treatment should not be unblinded 
without the approval of the Sponsor. In such instance of medical emergency, every effort 
should be made to contact the Sponsor prior to unblinding. If unblinding should occur (by 
either accidental unblinding or emergency unblinding for a serious adverse event) prior to 
completion of the study, the investigator must promptly contact the Sponsor and 
document the circumstances on the appropriate forms. Instructions regarding emergency 
unblinding will be provided to the investigator. 
3.4  
Data Collection 
3.4.1  
Data Collected from Subjects 
The following data will be collected from each subject over the duration of their study 
participation: 
▫ Demographic Information 
▫ Adverse Events 
▫ Medical History 
▫ Concomitant Medications 
▫ Vital signs 

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All data collected must only be identified using the Subject ID, as described in section 
5.2.3. 
3.4.2  
Tools Used for Data Collection 
Data will be recorded in the Subject Diary and collected on Case Report Forms (CRFs). 
Subject Diary 
Subject Diaries will be the only source document allowed for solicited local and systemic 
adverse events (including body temperature measurements), starting after the initial 24 
hours post-vaccination observation period at the clinic. The following additional rules 
apply to documentation of safety information collected in the Subject Diary: 
1. No corrections or additions to the Subject Diary will be allowed after it is delivered to 
the site. 
2. Any blank or illegible fields on the Subject Diary must be described as missing in the 
CRF. 
3. Any corrections to the Subject Diary must be performed by the person completing the 
Subject Diary and should include a single strike through line through the incorrect 
value or text with a brief explanation for each change, the initials of that person, and 
date of correction. 
Case Report Forms 
This study utilizes CRFs to collect study-related data from each subject. A qualified site 
staff member(s) is required to enter subject data in the CRFs based on the medical 
information available in each subject’s record. The following additional rules apply to 
documentation of Subject Diary information collected in the CRFs: 
1. The site must enter all readable entries in the Subject Diary into the CRF, including 
those values that may be biologically implausible (e.g. body temperature: 400°C). 
2. Any illegible or implausible data should be reviewed with the subject. If an 
underlying solicited or unsolicited adverse event is described on review with the 
subject, this should be described in the source document and reported as an 
unsolicited adverse event in the appropriate CRF (e.g., if the subject above confirms 
body temperature of 40°C on the day in which body temperature: 400°C was written 
into his/her Subject Diary, this fever of 40°C should be recorded in the appropriate 
CRF). 

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3. Any newly described safety information (including a solicited adverse event) must not 
be written into the Subject Diary and must be described in the study file as a verbally 
reported adverse event. Any adverse event reported in this fashion must be described 
as an unsolicited adverse event and therefore, entered in the appropriate CRF. 
Data should be entered into the CRF in a timely fashion following each subject’s clinic 
visit, study procedure, or phone call. Each subject’s CRF casebook will be compared with 
the subject’s source records by a GSK-approved study monitor (or designee) over the 
duration of the study in order to ensure data collection accuracy. 
3.5  
Collection of Clinical Specimens 
The following clinical specimens are required to be collected from each subject in this 
study: 
▫ Blood 
▫ Urine 
Processing of each specimen should be completed by a qualified site member. Testing of 
clinical specimens will be performed by a GSK or designated laboratory. 
Blood Specimens 
Before Vaccination 
▫ At the Pre-vaccination Screening Visit (between Day -28 to -3) one sample of 
approximately 10 ml blood will be drawn from all subjects. 
▫ At Visit 1 (Day 1) - prior to vaccination – two samples of approximately 10 ml blood 
will be drawn from all subjects. 
▫ At Visit 1 (Day 1) - prior to vaccination - the following blood samples will be drawn 
from subjects that gave additional informed consent for blood collection for 
exploratory assays: 
- 
One sample of approximately 3 ml 
- 
Two samples of approximately 5 ml 
- 
One sample of approximately 70 ml 

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After Vaccination 
▫ At Visit 1 (Day 1) - 1 hour after vaccination - one sample of approximately 3 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 2 hours after vaccination - one sample of approximately 3 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 4 hours after vaccination - one sample of approximately 3 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 6 hours after vaccination – two samples of approximately 5 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 8 hours after vaccination - one sample of approximately 3 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 24 hours after vaccination - one sample of approximately 10 ml 
blood will be drawn from all subjects. 
▫ At Visit 1 (Day 1) - 24 hours after vaccination - the following blood samples will be 
drawn from subjects that gave additional informed consent for blood collection for 
exploratory assays: 
- 
One sample of approximately 3 ml 
- 
Two samples of  approximately 5 ml 
- 
One sample of approximately 20 ml 
▫ At Visit 2 (Day 4) the following blood samples will be drawn from subjects that gave 
additional informed consent for blood collection for exploratory assays: 
- 
One sample of  approximately 3 ml 
- 
Two samples of  approximately 5 ml 
- 
One sample of approximately 20 ml 
▫ At Visit 3 (Day 8) two samples of approximately 10 ml blood will be drawn from all 
subjects. 

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▫ At Visit 3 (Day 8) the following blood samples will be drawn from subjects that gave 
additional informed consent for blood collection for exploratory assays 
- 
Two samples of approximately 5 ml 
- 
One sample of approximately 70 ml 
▫ At Visit 6 (Day 29) two samples of approximately 10 ml blood will be drawn from all 
subjects. 
▫ At Visit 6 (Day 29) one sample of approximately 50 ml blood will be drawn from 
subjects that gave additional informed consent for blood collection for exploratory 
assays. 
▫ At Visit 9 (Day 181) one sample of approximately 10 ml blood will be drawn from all 
subjects. 
▫ At Visit 9 (Day 181) one sample of approximately 50 ml blood will be drawn from 
subjects that gave additional informed consent for blood collection for exploratory 
assays. 
The blood will be used for screening and safety laboratory assessments, immunological 
serology assays, pharmacokinetic analysis, cell mediated immunity assays and gene 
expression and protein production assays. See section 5.1.2, section 5.2.1 and section 7.0 
for additional details. 
Processing of each blood specimen should be completed in accordance with the study 
specific Clinical Specimen Laboratory Manual. 
The total amount of blood collected over the study period for all subjects will be 
approximately 90 ml. 
For subjects that signed an additional informed consent for blood collection for 
exploratory assays the total amount of blood collected over the study period will be 
approximately 441 ml. 
Urine Specimens 
Urine will be collected at the Pre-vaccination Screening Visit (between Day -28- to -3), at 
Visit 1 (Day 1; before vaccination and 24 hours after vaccination), at Visit 3 (Day 8) and 
at Visit 6 (Day 29). Results will be recorded in the source document and CRF. 

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Urine will be collected from all subjects for safety laboratory assessments and drugs-
ofabuse testing. Furthermore, urine will be collected for pregnancy testing in all females. 
3.6  
Stopping/Pausing Guidelines 
Stopping/pausing guidelines are predefined criteria that halt the conduct of a study (either 
a vaccine group or the entire study). These guidelines are used to ensure the safety of study 
subjects.  
The following criteria, based on FDA guidance and with grading scales adapted from the 
CBER Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive vaccine Clinical Trials”, will be used for this study: 
1. The study will be halted (no new enrollments and no further investigational product 
administered until a full safety review by the DMC and consultation with the IRB/EC 
and the health authorities is completed) if one of the following occurs 
a. One subject experiences a serious adverse event (SAE) assessed as possibly or 
probably related to investigational product or, 
b. There is a subject death assessed as possibly or probably related to the 
investigational product. 
2. If one or more subjects experience a Grade 4 AE (see Appendix C, D, and E), vital 
sign or clinically significant laboratory abnormality that cannot be clearly attributed to 
another cause, vaccination will be suspended until a full safety review by the DMC is 
performed. 
3. If six or more subjects experience a Grade 3 AE (see Appendix A, B, C, D, and E), 
vital sign or clinically significant laboratory abnormality, dosage escalation will be 
suspended for that vaccine until a full safety review by the DMC is performed.  
The sponsor or the investigator (following consultation with the sponsor) has the right to 
discontinue the study at any time. If the clinical study is prematurely terminated, the 
investigator must promptly inform the study subjects and must assure appropriate therapy 
and follow-up for the subjects.  All procedures and requirements pertaining to the 
archiving of the documents must be followed.  All other study materials (such as study 
vaccines) must be returned to the sponsor or destroyed after sponsor approval. 
3.7  
Data Monitoring Committee 
A DMC will be formed to review safety data during scheduled periodic reviews. The 
DMC may also perform reviews on an ad hoc basis as needed. DMC membership will 

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consist of at least 3 individuals who are external to the site and sponsor, and will include 
1 statistician who is independent from the study team.  
Subjects will be enrolled in a stepwise manner in each of the four vaccine dosage cohorts  
(Cohort 1: 12.5 μg LHD153R, Cohort 2: 25 μg of LHD153R, Cohort 3: 50 μg of  
LHD153R and Cohort 4: 100 μg of LHD153R). The DMC will review all safety data, as 
described in the DMC charter and in the Statistical Analysis Plan, after the first 5 subjects 
in each cohort have completed Visit 4 and their data are available for analysis, and before 
enrollment of the remaining subjects in the respective cohort and before enrollment of the 
first 5 subjects in the subsequent cohort. In addition, in between the different enrollment 
stages, the DMC will review all available safety data of subjects that have completed 
Visit 4 and all available safety data of subjects that have completed Visit 6. 
The specific roles and responsibilities of the DMC members and other personnel involved 
will be documented in the DMC charter. The DMC charter will be finalized before the 
start of the study and will outline in detail all pausing and stopping rules according to the 
Clinical Study Protocol. 
3.8  
Premature Withdrawal from Study 
Subjects may withdraw at any time, or be dropped from the study at the discretion of the 
investigator should any untoward effects occur and/or for safety reasons. In addition, a 
subject may be withdrawn by the investigator or the Sponsor if he/she violates the study 
plan or for administrative reasons. The investigator or study coordinator must notify the 
Sponsor immediately when a subject has been withdrawn due to an adverse event. 
The circumstances above are referred to as premature withdrawal from the study, and the 
reason for premature withdrawal should be clearly documented and detailed in the source 
documentation. The investigator should make every attempt to evaluate the subject’s 
safety, including resolution of ongoing AEs, at the time of premature withdrawal. If a 
subject wants to withdraw from the study prior to the last planned study visit, the subject 
will be asked to be followed for safety for the duration of the study. When a subject 
withdraws, or is withdrawn, from the study, the procedures described in section 5.5.1 
should be completed if possible. 
The reasons for premature withdrawal from the study include: Adverse event, death, 
withdrawal of consent, lost to follow-up, administrative reason, and protocol deviation. 
These reasons are described in greater detail below. 
Adverse Event 

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For any subject withdrawn from study participation prior to the planned Study  
Termination Visit, it is important to determine if an AE was associated with the reason for 
discontinuing the study. This AE must be identified on the appropriate CRF page by 
indicating “Withdrawn from study due to AE”. Any ongoing AEs at the time of study 
withdrawal must be followed until resolution or stabilization. 
Death 
For any subject withdrawn from study participation due to death, this should be noted on 
the appropriate CRF page and the associated SAE that led to the death must be reported. 
Withdrawal of consent 
The subject can withdraw consent for participation in the study at any time without 
penalty or loss of benefit to which the subject is otherwise entitled. Reason for early 
termination should be deemed as “withdrawal of consent” if the subject withdraws from 
participation due to a non-medical reason (i.e., reason other than AE). If the subject 
intends to withdraw consent from the study, the investigator should clarify if the subject 
will withdraw completely from the study or if the subject will continue study participation 
for safety, or a subset of other study procedures. If the subject requests complete 
withdrawal from the study, no further study interventions will be performed with the 
subject. 
Lost to Follow-Up 
For subjects who fail to show up for study visits (clinic or telephone contacts), study staff 
is encouraged to make at least three documented attempts to contact the subject by 
telephone and at least one documented written attempt to contact the subject to encourage 
the completion of study termination procedures. These efforts to contact the subject must 
be recorded in the source document. The termination date for the subject to be captured 
on the appropriate CRF page is the date of the last contact (clinic visit or telephone) with 
the subject. 
Administrative Reason 
Examples for subjects withdrawn from the study due to administrative reason can include: 
Sponsor decision to terminate the study, subject meeting a pre-specified withdrawal 
criterion, subject discontinuation for insurance issues, moving, no time, etc. This reason 
should be noted in the appropriate CRF page and any ongoing AEs at the time of study 
withdrawal must be followed until resolution/stabilization. 

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If the clinical study is prematurely terminated by the Sponsor, the investigator is to 
promptly inform the study subjects and local EC/IRB and should assure appropriate 
therapy and follow up for the subjects. All procedures and requirements pertaining to the 
archiving of study documents should be followed. All other study materials (study 
medication/vaccines, etc.) must be returned to the Sponsor. 
For subjects who are withdrawn from the study due to receipt of an excluded 
medication/vaccination or due to significant protocol non-compliance, this reason should 
be noted in the appropriate CRF page. 
Protocol Deviation 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. In general, subjects associated with protocol deviations 
may remain in the study unless continuation in the study jeopardizes the subject’s health, 
safety, or rights. 
Investigators will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact GSK or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are 
permitted. If the investigator feels a change to the protocol would improve the conduct of 
the study this must be considered a protocol amendment, and unless such an amendment 
is agreed upon by GSK and approved by the IRB/EC and health authorities it cannot be 
implemented. 
Any subject who becomes pregnant during the study should be encouraged to continue 
participating in the study for safety follow-up. The site must complete a Pregnancy 
Report CRF (initial report) as soon as possible after learning of pregnancy occurrence 
(see section 7.1.6 for further details). If the subject withdraws from the study for any of 
the above categories except death, the site will obtain permission from the subject to 
continue to remain in contact with her until the outcome of the pregnancy is known, even 
if the outcome is not known until after the subject reaches the end of the routine study 
period. 
3.9  
End of Study 
Most clinical trials intended to support the efficacy/immunogenicity and safety of an 
Investigational Product proceed to full completion of planned sample size accrual. 

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A subject is considered to have completed this study when he/she has: (1) received the 
intended dose of study vaccine and (2) completed 365 days (Visit 12) of safety follow-up 
after receiving the study vaccine. 
Evaluation of the primary and secondary immunogenicity objectives requires the testing 
of biological samples from all study subjects, which can only be completed after all 
samples are collected. The last samples for the analysis of the primary and/or secondary 
objectives will be taken at Visit 9 (Day 181). For the purpose of this protocol, End of 
Study is defined as the completion of the testing of such biological samples, to be 
achieved no later than 8 months after collection of the last biological sample at Visit 9. 
4.0  
SELECTION OF STUDY POPULATION 
4.1  
Inclusion Criteria 
In order to participate in this study, all subjects must meet all of the inclusion criteria 
described. 
1. Male or female individuals of 18 through 45 years of age on the day of informed 
consent. 
2. Healthy volunteers with good physical and mental health status, determined on the 
basis of the medical history, a physical examination and the results of the screening 
tests as judged by the investigator. 
3. Individuals who have voluntarily given written informed consent after the nature of 
the study has been explained according to local regulatory requirements, prior to 
study entry. 
4. Individuals who can comply with study procedures including follow-up1. 
5. Individuals that are able to understand, read and write German language. 
6. Females of childbearing potential who are using an effective birth control method2 
which they intend to use for at least 30 days after the study vaccination. 
4.2  
Exclusion Criteria 
Each subject must not have or must not be: 
1. Progressive, unstable or uncontrolled clinical conditions. 
2. Hypersensitivity, including allergy, to any component of vaccines, medicinal products 
or medical equipment whose use is foreseen in this study. 

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1 A subject is considered to be compliant if the Investigator judges that the subject will complete the Subject 
Diary, return for all the follow-up visits and be available for telephone calls as scheduled in the study. 
2 The following birth control methods are considered effective: 
- 
Hormonal contraceptive (such as oral, injection, transdermal patch, implant) if used for at least 30 
days prior to informed consent 
- 
Diaphragm with spermicide, tubal occlusion device 
- 
Intrauterine device (IUD) 
- 
Tubal ligation 
- 
Male partner using condom with spermicide 
- 
Male partner having been vasectomized at least six months prior to informed consent 
3. Clinical conditions representing a contraindication to intramuscular vaccination and 
blood draws. 
4. Abnormal function of the immune system resulting from: 
a. Clinical conditions. 
b. Systemic administration of corticosteroids (PO/IV/IM) for more than 14 
consecutive days within 90 days prior to informed consent. 
c. Administration of antineoplastic and prescription immunomodulating agents or 
radiotherapy within 90 days prior to informed consent. 
5. Received immunoglobulins or any blood products within 180 days prior to informed 
consent. 
6. Received an investigational or non-registered medicinal product within 30 days prior 
to informed consent or intend to participate in another clinical study at any time 
during the conduct of this study. 
7. Vulnerable subjects (e.g. persons kept in detention), study personnel or an immediate 
family or household member of study personnel, subjects with legal incapacity or 
limited legal capacity 
8. Any relevant deviation from the laboratory parameters at screening as judged by the 
investigator. 
9. Previously received any vaccine that included a MenC antigen. 
10. Previously suspected or confirmed disease caused by N. meningitides. 
11. Had household contact with and/or intimate exposure to an individual with culture 
proven MenC. 

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12. A positive serum or urine pregnancy test prior to the study vaccine administration or 
are currently lactating. 
13. A positive drugs-of-abuse test prior to the study vaccine administration 
14. Received any other vaccines within 30 days prior to enrolment in this study or who 
are planning to receive any vaccine within 30 days from the administration of study 
vaccines. 
15. Any other condition that, in the opinion of the investigator, might interfere with the 
results of the study or pose additional risk to the subject due to participation in the 
study. 
4.3  
Criteria for Delay of Vaccination or Blood Draw 
There may be instances when individuals meet all eligibility criteria for vaccination or 
blood draw yet have a transient clinical circumstance which may warrant delay of 
vaccination or blood draw. Under such circumstances, a subject may be considered 
eligible for study enrolment after the appropriate window for delay has passed and 
inclusion/exclusion criteria have been rechecked, and if the subject is confirmed to be 
eligible. 
Reasons for delay of vaccination include: 
▫ Body temperature elevation ≥38.0°C (measured orally) within 3 days prior to intended 
study vaccination. 
▫ Use of antipyretics and/or analgesic medications within 24 hours prior to vaccination. 
Reasons for delay of blood draw include: 
▫ Subject has received a dose of systemic antibiotics less than 6 days before blood 
collection for the hSBA directed against MenC. 
 

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5.0  
STUDY PROCEDURES 
The sections that follow provide an overview of the procedures that are to be followed in 
enrolling, evaluating, and following subjects who participate in this clinical study. Visits 
can be either clinic visits or safety follow-up telephone calls, as specified in the Table 
below and in the Time and Events Tables 3 and 4 of the Study Synopsis. 
Table 5.0-1: Study procedures 
Visit Category 
Procedures 
Pre-vaccination Clinic Visit 
Section 5.1 describes procedures to be followed 
prior to subject enrollment, including: informed 
consent and screening procedures. 
Vaccination Clinic Visit 
Section 5.2 describes procedures to be followed 
during the vaccination clinic visit, including: 
prevaccination procedures, enrolment, 
randomization, vaccination and post-vaccination 
procedures. 
Post-vaccination Visits 
Section 5.3 describes follow-up clinic visits and 
safety follow-up calls. 
Unscheduled Visits 
Section 5.4 describes possible procedures to be 
followed at unscheduled clinic visit. 
Study Termination Visit 
Section 5.5 describes procedures to be followed at 
the last study visit for a subject (may include early 
termination visit). 
5.1 
Pre-vaccination Clinic Visit(s) 
The Pre-vaccination Clinic Visit must be performed in the period between Day -28 and 
Day -3. 
This section describes the procedures that must be performed for each potential subject 
prior to enrollment, including obtaining informed consent and screening. 
5.1.1  
Informed Consent 
"Informed consent" is the voluntary agreement of an individual or his/her legal 
guardian(s) to participate in research. Consent must be given with free will of choice, and 
without undue inducement. The individual must have sufficient knowledge and 
understanding of the nature of the proposed research, the anticipated risks and potential 
benefits, and the requirements of the research to be able to make an informed decision. 

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Informed consent following local IRB/EC guidance must be obtained before conducting 
any study-specific procedure (i.e., all of the procedures described in the protocol). Prior to 
any additional blood sample collection for exploratory objectives, a secondary informed 
consent must be signed by subjects. The process of obtaining informed consent should be 
documented in the subject source document in addition to maintaining a copy of the 
signed and dated informed consent. 
5.1.2  
Screening 
After an individual has consented to participate in the study and informed consent is 
signed, that individual will be given a unique Screening Number. The subject’s unique 
Screening Number will be documented in the Screening and Enrolment log. The 
eligibility of the subject will be determined based on the inclusion and exclusion criteria 
listed in section 4.0 and evaluated during this screening procedure. 
Screening procedures at the Pre-vaccination Clinical Visit (between Day -28 and Day -3) 
will include the following: 
▫ Review of demographic data, including age, gender, race, body weight and height. 
▫ Review of medical history, including but not limited to any medical history, ongoing 
illnesses or injuries that may be relevant to subject eligibility for study participation. 
Relevant medical history can also include any medical history that contributes to the 
understanding of an adverse event that occurs during study participation, if it 
represents an exacerbation of an underlying disease/pre-existing problem. 
▫ Perform physical examination, including but not limited to: 
- 
Assessment of general appearance 
- 
Collection of vital signs, including body temperature, blood pressure, heart rate 
and respiratory rate 
- 
Examination of head, ears, eyes, nose and throat (HEENT) 
- 
Examination of skin 
- 
Auscultation of heart and lungs 
▫ Collection and review of prior and concomitant medications or vaccinations taken 
prior to start of study (refer to section 6.5 for further details). 
▫ Collection of any unsolicited AEs occurring prior to administration of the study 
vaccine. 

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▫ Blood draw (approximately 10 ml) for Safety Laboratory assessments, measurement of 
Hepatitis B surface antigen, anti-Hepatitis C virus antibodies, anti-HIV 1 and 2 
antibodies and serum pregnancy test (all women). 
▫ Urine sample for Safety Laboratory assessments and drugs-of-abuse testing. 
NOTE: A general physical examination is to be performed by a qualified health care 
practitioner. “Qualified health care practitioner” refers to any licensed health care 
professional who is permitted by institutional policy to perform physical examinations 
and who is identified within the Study Staff Signature Log. 
Data collected during the Pre-vaccination Screening Clinic Visit must be written in the 
source document (see section 9.1) and will be captured in the screening CRF Forms. In 
the event that the individual is determined ineligible for study participation, he/she is 
considered a screen failure. The reason for screen failure must be documented in the 
Screening and Enrolment log. 
5.2  
Vaccination Clinic Visit(s) 
This section describes the procedures to be performed at the Vaccination Clinic Visit 
(Visit 1, Day 1), including: pre-vaccination procedures, enrolment, randomization, 
prevaccination blood draw, vaccination and post-vaccination procedures. 
5.2.1  
Pre-vaccination Procedures 
During pre-vaccination procedures at Visit 1 (Day 1), the eligibility of the subject will be 
confirmed based on the inclusion and exclusion criteria listed in section 4.0. 
Pre-vaccination procedures at Visit 1 (Day 1) will include the following: 
▫ Review of systems by means of a structured interview that queries the subject as to any 
complaints the subject has experienced across each organ system. 
▫ Perform physical examination, including but not limited to: 
- 
Assessment of general appearance 
- 
Assessment of body weight and collection of vital signs, including body 
temperature, blood pressure, heart rate, and respiratory rate 
- 
Examination of head, ears, eyes, nose and throat (HEENT) 
- 
Examination of skin 
- 
Auscultation of heart and lungs 

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▫ Collection and review of prior and concomitant medications or vaccinations taken, or 
recalled, since the last visit (refer to section 6.5 for further details). 
▫ Collection of any unsolicited AEs occurring prior to administration of the study 
vaccine. 
▫ One blood sample (approximately 10 ml) will be drawn from all subjects for serology 
testing. 
▫ One blood sample (approximately 10 ml) will be drawn from all subjects for baseline 
Safety Laboratory assessments. 
▫ One urine sample for baseline Safety Laboratory assessments, pregnancy testing (all 
women) and drugs-of-abuse testing. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of blood draws are provided in section 3.5. 
NOTE: A general physical examination is to be performed by a qualified health care 
practitioner. “Qualified health care practitioner” refers to any licensed health care 
professional who is permitted by institutional policy to perform physical examinations 
and who is identified within the Study Staff Signature Log. 
Data collected during pre-vaccination procedures at Visit 1 must be written in the source 
document (see section 9.1). In the event that the individual is determined ineligible for 
study participation, he/she is considered a screen failure. The reason for screen failure 
must be documented in the Screening and Enrolment log. If the individual is determined 
to be eligible for the study, he/she can be enrolled into the study. 
5.2.2 
Enrolment 
After an individual is determined to be eligible for study participation, the investigator 
will enroll the subject into an Electronic Data Capture (EDC) system where the 
randomization to the treatment group will occur. The Screening Number ceases to be used 
and remains in the Screening and Enrolment Log only. 
If for any reason, after signing the informed consent form (ICF), the subject who is 
eligible and enrolled fails to be randomized, this is called a randomization failure. In this 
case the early termination study procedures must be applied. The reason for all 
randomization failures should be recorded in the Screening and Enrolment Log and in the 
source document as specified in the Source Data Agreement. The information on subjects 

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who are randomization failures should be kept distinct from subjects who are screen 
failures, as described in section 5.1.2 and section 5.2.1. 
5.2.3 
Randomization 
Enrolled subjects will be randomized and automatically assigned a unique Subject ID. 
The Subject ID will be the subject’s unique identification number for all CRFs and 
associated study documentation that will be used for the duration of the study. 
If for any reason, after signing the informed consent form (ICF), the eligible subject is 
enrolled and randomized but fails to undergo treatment, this is an Early Termination and 
the reason should be recorded in source document as specified in the Source Data 
Agreement/Source Data Verification Form. The information on these Early Termination 
subjects should be kept distinct in the source documentation from randomization failures, 
which are described in section 5.2.2. 
5.2.4 
Vaccination 
After completing the pre-vaccination procedures at Visit 1 (Day 1), administer the 
vaccine to the subject according to the procedures described in section 6.3. Observe the 
blinding procedures described in section 3.3. 
5.2.5 
Post-vaccination Procedures 
The following post-vaccination procedures will be performed at Visit 1 (Day 1): 
▫ After vaccination, the subject will be observed for at least 30 minutes for any 
immediate solicited and unsolicited AEs and a body temperature measurement at 30 
min after vaccination. All safety and body temperature data collected during this time 
are to be recorded in the subject’s source document. 
▫ After vaccination, the subject will be observed for at least 24 hours at the clinic 
including observation for solicited and unsolicited AEs and body temperature 
measurements. Body temperature measurements must be performed at 2, 4, 6, 8, 10, 
12, 18 and 24 hours after vaccination. All safety and body temperature data collected 
during this time are to be recorded in the subject’s source. 
▫ One blood sample (approximately 10 ml) will be drawn from all subjects at 24 hours 
after vaccination for Safety Laboratory assessments. 
▫ One urine sample will be collected from all subjects at 24 hours after vaccination for 
Safety Laboratory assessments. 

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▫ From those subjects that signed an additional Informed Consent for exploratory assays, 
additional blood samples will be drawn in the first 24 hours after vaccination. Details 
regarding the number and volume of post-vaccination blood draws are provided in 
section 3.5. 
After the initial 24 hours inpatient observation period, a Subject Diary will be used in this 
study to document solicited and unsolicited AEs until Day 14. The Subject Diary is the 
only source for collection of solicited AEs after the initial 24 hours inpatient observation 
period. Therefore, it is critical that the subject completes the Subject Diary correctly. 
The following training regarding completion of the Subject Diary must be provided: 
▫ The subject should be trained on how and when to complete each field of the Subject 
Diary. 
▫ The subject should be trained on how to self-measure local solicited adverse events 
and body temperature. The measurement of solicited local adverse events is to be 
performed using the ruler provided by the site. 
▫ The subject should be instructed how to perform body temperature measurement using 
the thermometer provided by the site. If the subject feels unusually hot or cold during 
the day, the subject should check their body temperature. If the subject has fever, the 
highest body temperature observed that day should be recorded in the Subject Diary. 
Subject Diary training should be directed at the individual(s) who will perform the 
measurements of adverse events and who will enter the information into the Subject 
Diary. This individual may not be the subject, but if a person other than the subject enters 
information into the Subject Diary, this person’s identity must be documented in the 
Subject Diary. Any individual that writes in the Subject Diary must receive training on 
completion of the Diary Card at the time of the visit. This training must be documented in 
the subject’s source record. 
The site should schedule the next study activity (clinic visit) with the subject. 
The subject will receive a written reminder of the next planned study activity. The subject 
will be reminded to complete the Subject Diary and to contact the site if there are any 
questions, and to contact the site immediately (or as soon as the subject is medically 
stable) if the subject has a medical condition that leads to a hospitalization or an 
emergency room visit. 
5.3  
Post-vaccination Visit(s) 

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5.3.1 Subject Diary Reminder, Safety Follow-up and/or Post-vaccination Blood 
Draw Clinic Visits 
Subject Diary reminder, Safety follow-up and/or post-vaccination blood draw clinic visits 
will be performed on Day 4 (Visit 2), Day 8 (Visit 3), Day 15 (Visit 4), Day 29 (Visit 6), 
Day 85 (Visit 7), Day 113 (Visit 8) and Day 181 (Visit 9) 
At Day 4 (Visit 2) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. All unsolicited AEs, SAEs, AESIs, 
medically attended AEs, AEs leading to study withdrawal and NOCD must be 
recorded on source documents. Any concomitant medications or vaccinations 
associated with those events must also be recorded on the source documents. 
▫ All subjects will be reminded to complete the Subject Diary and to contact the site if 
there are any questions, and to contact the site immediately (or as soon as the subject 
is medically stable) if the subject has a medical condition that leads to a 
hospitalization or an emergency room visit. No changes to the Subject Diary should 
be done at the clinic visit. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of blood draws are provided in section 3.5. 
▫ The site should schedule the next study activity (clinic visit) with the subject and the 
subject will receive a written reminder of the next planned study activity. 
At Day 8 (Visit 3) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. All unsolicited AEs, SAEs, AESIs, 
medically attended AEs, AEs leading to study withdrawal and NOCD must be 
recorded on source documents. Any concomitant medications or vaccinations 
associated with those events must also be recorded on the source documents. 

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▫ The subject will be reminded to complete the Subject Diary and to contact the site if 
there are any questions, and to contact the site immediately (or as soon as the subject 
is medically stable) if the subject has a medical condition that leads to hospitalization 
or an emergency room visit. No changes to the Subject Diary should be done at the 
clinic visit. 
▫ Blood draw (approximately 10 ml) from all subjects for Safety Laboratory 
assessments. 
▫ Urine sample from all subjects for Safety Laboratory assessments. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 

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volume of blood draws are provided in section 3.5. 
The site should schedule the next study activity (clinic visit) with the subject and the 
subject will receive a written reminder of the next planned study activity. 
At Day 15 (Visit 4) the following procedures will be performed: 
▫ The Subject Diary will be collected and reviewed. No changes to the Subject Diary 
should be done at the clinic visit. For details on the Subject Diary see sections 3.4.2, 
and 5.2.5. The healthcare professional reviewing these data will discuss the symptoms 
(if any) reported by the subject and will determine if any additional diagnoses and/or 
adverse events are present. All unsolicited AEs until Day 14, solicited local and 
systemic AEs persisting at Day 14, SAEs, AESIs, medically attended AEs, AEs 
leading to study withdrawal and NOCD must be recorded on source documents. All 
concomitant medications or vaccinations associated with those events must also be 
recorded on the source documents. 
▫ The site should schedule the next study activity (safety phone call) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 29 (Visit 6) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events 
occurred and if any concomitant medications or vaccines were taken / received in the 
time since the last clinic visit. The healthcare professional reviewing these data will 
discuss the symptoms (if any) reported by the subject and will determine if any 
additional diagnoses and/or adverse events are present. Any solicited local and 
systemic AEs continuing beyond Day 14, SAEs, AESIs, medically attended AEs, 
AEs leading to study withdrawal and NOCD must be recorded on source documents. 
All concomitant medications or vaccinations associated with those events must also 
be recorded on the source documents. 

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▫ Blood draw (approximately 10 ml) from all subjects for Safety Laboratory 
assessments. 
▫ Urine sample from all subjects for Safety Laboratory assessments. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 
volume of post-vaccination blood draws are provided in section 3.5. 
The site should schedule the next study activity (clinic visit) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 85 and Day 113 (Visit 7 and Visit 8), the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events 
occurred and if any concomitant medications or vaccines were taken / received in the 
time since the last clinic visit. The healthcare professional reviewing these data will 
discuss the symptoms (if any) reported by the subject and will determine if any 
additional diagnoses and/or adverse events are present. Any solicited local and 
systemic AEs continuing beyond Day 14, SAEs, AESIs, medically attended AEs, 
AEs leading to study withdrawal and NOCD must be recorded on source documents. 
All concomitant medications or vaccinations associated with those events must also 
be recorded on the source documents. 
▫ The site should schedule the next study activity (clinic visit) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 181 (Visit 9), the following procedures will be performed: 

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▫ The subject will be interviewed to determine if any unsolicited adverse events 
occurred and if any concomitant medications or vaccines were taken / received in the 
time since the last clinic visit. The healthcare professional reviewing these data will 
discuss the symptoms (if any) reported by the subject and will determine if any 
additional diagnoses and/or adverse events are present. Any solicited local and 
systemic AEs continuing beyond Day 14, SAEs, AESIs, medically attended AEs, 
AEs leading to study withdrawal and NOCD must be recorded on source documents. 
All concomitant medications or vaccinations associated with those events must also 
be recorded on the source documents. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 
volume of post-vaccination blood draws are provided in section 3.5. 
The site should schedule the next study activity (safety phone call) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
5.3.2  
Safety Follow-up Calls 
Safety follow-up calls will be performed on Day 22 (Visit 5), Day 209 (Visit 10) and Day 
271 (Visit 11) and include the following procedures: 
▫ Safety follow-up calls are calls made to the subject by a healthcare professional 
designated on the site log. These calls will follow a script which will facilitate the 
collection of relevant safety information. The subject will be interviewed according to 
the script, and information relating to solicited local and systemic AEs persisting 
beyond Day 14 and unsolicited adverse events including SAEs, AESIs, medically 
attended AEs, AEs leading to study withdrawal, and/or NOCD and concomitant 
medications or vaccinations associated with those events. All safety information 
described by the subject must be written down in a designated location within the 
source document and not written on the script used for the telephone call. 

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▫ The site should schedule the next study activity (clinic visit or study termination visit) 
with the subject. 
▫ The subject will be reminded to contact the site if there are any questions and to 
contact the site immediately (or as soon as the subject is medically stable) if the 
subject has a medical condition that leads to a hospitalization or an emergency room 
visit. 
5.4  
Unscheduled Visits  
An unscheduled visit describes a non-routine study visit triggered by a specific event. 
These could include anticipated or unanticipated adverse events or interventions. 
The following procedures should be carried out for all unscheduled visits: 
1. Evaluate the subject’s vital signs body temperature, heart rate, and blood pressure and 
perform a symptom-directed physical examination. 
2. Record any observed AEs in the source documents. 

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3. Record any concomitant medications or vaccinations associated with AEs in the 
source documents. 
5.5  
Study Termination Visit 
The study termination visit is scheduled on Day 366 (Visit 12). The termination visit is a 
clinic visit. For visit procedures to be performed for a subject whose planned study 
participation ends prematurely, please see section 5.5.1. 
At the Study Termination clinic visit the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. 
▫ The healthcare professional reviewing these data will discuss the symptoms (if any) 
reported by the subject and will determine if any additional diagnoses and/or adverse 
events are present. 
▫ Medically attended AEs, SAEs, NOCDs, or AESIs will be recorded on source 
documents. 
▫ All medications taken or vaccines received will also be recorded on the source 
documents. 
▫ The site will review with the subject the plan of when information relating to the 
subject’s participation in the study may be available (e.g., study results, treatment 
assignments). It will also be discussed how information relating to the subject’s 
participation in the study will be shared with the subject’s healthcare provider, if the 
subject chooses to share this information. 
▫ The site will complete the termination CRF page and this will mark the completion of 
the subject’s participation in the study. 
5.5.1  
Early Termination Visit 
The date of termination is the date of the last contact in which the subject’s health status 
was assessed or, in cases where the subject does not agree to any further safety follow-up, 
it is the date consent is withdrawn. This date should be recorded on the appropriate CRF 
page. 
When a subject is withdrawn from treatment or withdraws from the study, the investigator 
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The reason(s) for the early termination must be included in the subject’s source 
documentation. If the Early Termination Visit is a telephone call, collect as much 
information as possible. Early Termination Visits include subjects who were randomized 
but not treated. 
At the clinic visit or during the telephone call, the following procedures should be 
performed, when possible: 
▫ Collection and review of Subject Diary (if not already collected). 
▫ Interview of subject to collect unsolicited adverse events, medically attended AEs, 
AEs leading to withdrawal, SAEs, AESIs, and NOCD. 
▫ Interview of subject to collect concomitant medications and/or vaccinations. 
▫ Symptom-directed physical assessment, at least including measurement of vital signs 
(body temperature, respiratory rate, blood pressure, heart rate) and a check of general 
appearance (in case of clinic early termination visit). 
▫ Draw a blood sample (approximately 10 ml) and a urine sample for Safety Laboratory 
assessment (in case of clinic early termination visit). 
▫ The site will review with the subject the plan of when information relating to the 
subject’s participation in the study may be available (e.g., study results, treatment 
assignments). It will also be discussed how information relating to the subject’s 
participation in the study will be shared with the subject’s healthcare provider, if the 
subject chooses to share this information. 
▫ The site will complete the appropriate CRF page and this will mark the completion of 
the subject’s participation in the study. 
6.0  
TREATMENT OF SUBJECTS 
All vaccines associated with this study are to be stored separately from other vaccines and 
medications in a secure location under appropriate storage conditions with temperature 
monitoring. All vaccines associated with this study must be checked for expiration 
date prior to use. Expired vaccines must not be administered to subjects. 
6.1  
Study Vaccine(s) 
The term ‘study vaccine’ refers to those vaccines provided by the Sponsor, which will be 
evaluated as part of the study objectives. The study vaccines specific to this study are 
described in Table 6.1-1. 

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Table 6.1-1: Study Vaccine Composition 
Group A (Control) Meningococcal C-CRM197 Conjugate Vaccine 
 
Vaccine Component 
Quantity per 0.5 ml dose 
 
 
Vial Containing Vaccine Conjugate 
 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
 
Aluminum Hydroxide Solvent Components (for 0.5 mL dose) 
 
Aluminum hydroxide 
1.0 mg 
Sodium Chloride 
3.5 mg 
Sterile water for injection, up to 
0.5 ml 
 
 
Group B (12.5µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
12.5 µg 
Sodium Chloride 
3.4 mg 

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Histidine  
0.1 mg 
Tris 
30 µg 
Sterile water for injection, up to 
0.5 ml 
 
 
Group C (25 µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
25 µg 
Sodium Chloride 
3.4 mg  
Histidine 
0.2 mg 
Tris 
61 µg 
Sterile water for injection, up to 
0.5 ml 
 
 
Group D (50µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 

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Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
50 µg 
Sodium Chloride 
3.2 mg 
Histidine 
0.4 mg 
Tris 
121 µg 
Sterile water for injection, up to 
0.5 ml 
 
Group E (100µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
100 µg 
Sodium Chloride 
2.9 mg 
Histidine 
0.8 mg 
Tris 
243 µg 
Sterile water for injection, up to 
0.5 ml 
6.2  
Non-Study Vaccines 

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The term ‘non-study vaccine’ refers to those vaccines which will be intentionally given to 
study subjects but not formally included in the analysis of study objectives. 
No non-study vaccines are planned for this study. Any non-study vaccines administered 
during the study conduct will be captured in the CRF as concomitant medications and/or 
vaccinations. 
6.3  
Vaccine Preparation and Administration 
The investigator or designee will be responsible for oversight of the administration of 
vaccine to subjects enrolled in the study according to the procedures stipulated in this 
study protocol. All vaccines will be administered only by unblinded personnel who are 
qualified to perform that function under applicable local laws and regulations for the 
specific study site. 
The vaccine components will be provided in 5 separate kits (i.e. one for the control and 
one for each of the 4 dosage groups). The vaccine components must be mixed prior to 
vaccination taking into account the appropriate aseptic procedures. Detailed vaccine 
preparation and administration instructions, including the maximal administration period, 
will be provided to investigators prior to study start and must be filed in the Investigator 
Site File. 
PRECAUTIONS TO BE OBSERVED IN ADMINISTERING STUDY VACCINE: 
- 
Prior to vaccination, subjects must be determined to be eligible for study vaccination 
and it must be clinically appropriate in the judgment of the investigator to vaccinate. 
Eligibility for vaccination prior to first study vaccine administration is determined by 
evaluating the entry criteria outlined in protocol sections 4.0. 
- 
Study vaccines must not be administered to individuals with known hypersensitivity 
to any component of the vaccines. 
- 
Standard immunization practices are to be observed and care should be taken to 
administer the injection intramuscularly. Before administering vaccine, the 
vaccination site is to be disinfected with a skin disinfectant (e.g., 70% alcohol). Allow 
the skin to dry. DO NOT inject intravascularly. 
- 
As with all injectable vaccines, trained medical personnel and appropriate medical 
treatment must be readily available in case of anaphylactic reactions following 
vaccine administration. For example, epinephrine 1:1000, diphenhydramine, and/or 
other medications for treating anaphylaxis should be available. 

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6.4 
Vaccine Administration Error or Overdose of Vaccine 
Vaccine administration error is defined as receiving a dose of study vaccine that was not 
reconstituted as instructed or administered by a different route from the intended route of 
administration. An overdose of study vaccine (whether accidental or intentional) is 
defined when a dosage higher than the recommended dosage is administered in one dose 
of study vaccine. 
Any vaccine administration error or overdose of study vaccine detailed in this protocol 
must be reported as an adverse event, and if the vaccine administration error or overdose 
is associated with a serious adverse event, it must be reported as such within 24 hours to 
the Sponsor. 
6.5 
Prior and Concomitant Medications and Vaccines 
All medications, vaccines and blood products taken or received by the subject within 180 
days prior to the start of the study are to be recorded in the appropriate CRF. 
Medications taken for prophylaxis are those intended to prevent the onset of symptoms. 
Medications taken for treatment are intended to reduce or eliminate the presence of 
symptoms that are present. 
NOTE: Use of antipyretics/analgesics within 24 hours prior to vaccine administration is a 
reason to delay study vaccination (see section 4.3). 
Concomitant medications include all medications (including vaccines) taken 
by/administered to the subject at and after enrolment and must be documented in the 
appropriate CRF. 
When recording concomitant medications/vaccines, they should be checked against the 
study entry criteria in section 4.0, to ensure that the subject should be enrolled in the 
study. 
6.6  
Vaccine Supply, Labeling, Storage and Tracking 
The Sponsor will ensure the following: 
▫ Supply the study vaccines. 
▫ Appropriate labeling of all study vaccines provided that complies with the legal 
requirements of each country where the study is to be performed. 

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The investigator must ensure the following: 
▫ Acknowledge receipt of the study vaccines by a designated staff member at the site, 
including: 
- 
Confirmation that the vaccines were received in good condition 
- 
Confirmation to the Sponsor of the temperature range during shipment from the  
Sponsor to the investigator’s designated storage location 
- 
Confirmation by the Sponsor that the vaccines are authorized for use. 
▫ Proper storage of the study vaccines, including: 
- 
Storage in a secure, locked, temperature-controlled location. 
- 
Proper storage according to the instructions specified on the labels. 
- 
Appropriate record keeping and inventory of the study vaccines, including regular 
documentation of adequate storage temperature. 
▫ Appropriate use of the study vaccines, including: 
- 
No use of vaccines prior to receipt of authorization for use from the Sponsor. 
- 
Use only in accordance with the approved protocol. 
- 
Proper handling, including confirmation that the vaccine has not expired prior to 
administration. 
- 
Appropriate documentation of administration of vaccines to study subjects 
including: 
▪ 
Date, dosage, batch/lot numbers, expiration dates, unique identifying 
numbers assigned to subjects and study vaccines, and time of vaccine 
administration. This information will be maintained in an accountability log 
that will be reviewed by the site monitor. 
▪ 
Reconciliation of all vaccines received from the Sponsor. Reconciliation is 
defined as maintaining records of which and how many vaccines were 
received, which vaccines were administered to subjects, which vaccines 
were destroyed at the site, and which vaccines were returned to the Sponsor, 
as applicable. 
▫ Proper adherence to the local institutional policy with respect to destruction of study 
vaccines. 

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▫ Complete record keeping of vaccine use, wastage, return or destruction, including 
documentation of: 
- 
Copy of the site’s procedure for destruction of hazardous material. 
- 
Number of doses destroyed, date of destruction, destruction code (if available), 
method of destruction, and name of individual performing destruction. 
Vaccines that have been stored differently from the manufacturer’s indications must not 
be used unless the Sponsor provides written authorization for use. In the event that the use 
cannot be authorized, the Sponsor will make every effort to replace the vaccine supply. 
All vaccines used in conjunction with this protocol must be stored separately from normal 
hospital/practice stocks to prevent unintentional use of study vaccines outside of the 
clinical study setting. 
Monitoring of vaccine accountability will be performed by the study monitor during site 
visits and at the completion of the study. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator must ensure that all unused study vaccines, packaging and supplementary 
labels are destroyed locally (upon approval from Sponsor) or returned to the Sponsor. 

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7.0 
ASSESSMENTS 
7.1 
Safety Assessment 
The measures of safety used in this study are based on previous study data and based on 
comparable routine clinical/laboratory procedures. They include a close vigilance for, and 
stringent reporting of selected local and systemic adverse events routinely monitored in 
vaccine studies as indicators of reactogenicity. 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product at any dose that does 
not necessarily have to have a causal relationship with this treatment. Therefore, an AE 
can be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the investigational product. 
This definition includes intercurrent illnesses or injuries and exacerbation of pre-existing 
conditions. 
The period of observation for AEs extends from the time the subject signs informed 
consent until he or she completes the specified safety follow-up period (Day 366) or 
terminates the study early (whichever comes first). AEs occurring after the informed 
consent form is signed but prior to receiving study vaccine/product will be documented as 
an adverse event and recorded within the source documents. However, any AEs occurring 
prior to receipt of any study vaccine will be analyzed separately from “treatment 
emergent” AEs (AEs occurring after administration of the first study vaccine). 
Adverse events are collected as either solicited or unsolicited adverse events. Solicited 
events are derived from organized data collection systems, such as Subject Diaries or 
interview. 
7.1.1 
Solicited Adverse Events 
The term “reactogenicity” refers to solicited signs and symptoms (“solicited adverse 
events”) occurring in the hours and days following a vaccination, to be collected by the 
subject after the first 24 hours inpatient observation period at Day 1until Day 14, using a 
pre-defined Subject Diary. 
The following solicited adverse events are included in the Subject Diary. Each adverse 
event is to be assessed using the scoring system shown in Appendix A (Solicited Local 
AEs) and Appendix B (Solicited Systemic AE): 

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Solicited Local Adverse Events 
Solicited local AEs include: 
- 
injection site erythema 
- 
injection site induration 
- 
injection site pain 
- 
injection site swelling Solicited Systemic Adverse Events 
Solicited systemic AEs include: 
- 
body temperature ≥38.0°C (as measured orally) 
- 
loss of appetite 
- 
nausea 
- 
fatigue 
- 
generalized myalgia 
- 
generalized arthralgia 
- 
headache 
- 
chills 
- 
vomiting 
- 
diarrhea 
- 
generalized rash 
- 
urticaria 
Other Solicited Data 
Other solicited data collected per Subject Diary include: 
▫ Use of analgesics/antipyretics recorded as “absent” or “present” and summarized by 
“for treatment” or “for prophylaxis” 
▫ Body temperature as recorded daily, ideally at same time, by the oral route 
The study staff must review the data entered into the Subject Diary as described in 
sections 3.4.2 and 5.3.1. 

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NOTE: Any solicited adverse event that meets any of the following criteria must be 
entered into the subjects’ source documents (see section 9.1) and also as an adverse event 
in the appropriate CRF: 
▫ Solicited local or systemic adverse event that continues beyond Day 14 after 
vaccination. 
▫ Solicited local or systemic adverse event that leads to a visit to a healthcare provider 
(medically attended adverse event, see section 7.1.3). 
▫ Solicited local or systemic adverse event leading to the subject withdrawing from the 
study or the subject being withdrawn from the study by the investigator (adverse event 
leading to withdrawal, see section 7.1.3). 
▫ Solicited local or systemic adverse event that otherwise meets the definition of a 
serious adverse event (see section 7.1.4). 
7.1.2  
Unsolicited Adverse Events 
An unsolicited adverse event is an adverse event that was not solicited using a Subject 
Diary and that was spontaneously communicated by a subject who has signed the 
informed consent. 
7.1.3  
Evaluation of Adverse Events 
Every effort should be made by the investigator to evaluate safety information reported by 
a subject for an underlying diagnosis and to capture this diagnosis as the event in the AE 
page. In other words, the practice of reporting only symptoms (e.g., “cough” or “ear 
pain”) are better reported according to the underlying cause (e.g., “asthma exacerbation” 
or “otitis media”). 
The severity of events reported on the appropriate CRF page will be determined by the 
investigator as: 
Mild: 
transient with no limitation in normal daily activity. 
Moderate: 
some limitation in normal daily activity. 
Severe: unable to perform normal daily activity. 
The relationship of the study treatment to an AE will be determined by the investigator 
based on the following definitions: 

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1. Not Related 
The AE is not related to an investigational vaccine if there is evidence that clearly 
indicates an alternative explanation. If the subject has not received the vaccine, the timing 
of the exposure to the vaccine and the onset of the AE are not reasonably related in time, 
or other facts, evidence or arguments exist that reasonably suggest an alternative 
explanation, then the AE is not related. 
2. Possibly Related 
The administration of the investigational vaccine and AE are considered reasonably 
related in time and the AE could be explained by exposure to the investigational vaccine 
or by other causes. 
3. Probably Related 
Exposure to the investigational vaccine and AE are reasonably related in time and no 
alternative explanation has been identified. 
The relationship of the study treatment to an unsolicited AE will be determined by the 
investigator.  
Note: solicited AEs will not be evaluated for relationship to study treatment. Grading for 
severity of solicited local and systemic AEs is described in Appendix A and Appendix B. 
Adverse events will also be evaluated by the investigator for the co-existence of any of 
the other following conditions: 
▫ “Medically attended adverse event”: an adverse event that leads to a visit to a 
healthcare provider. 
▫ “New onset of chronic disease” (NOCD): an adverse event that represents a new 
diagnosis of a chronic medical condition that was not present or suspected in a subject 
prior to study enrolment. 
▫ AEs leading to withdrawal: adverse events leading to study or vaccine withdrawal. 
All AEs, regardless of severity, will be monitored until resolution or until the investigator 
assesses them as chronic or stable. All subjects experiencing AEs - whether considered 
associated with the use of the study vaccine or not - must be monitored until symptoms 
subside and any abnormal laboratory values have returned to baseline, or until there is a 
satisfactory explanation for the changes observed, or until death, in which case a full 
pathologist’s report should be supplied, if possible. 

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7.1.4  
Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose results in one or more of the following: 
▫ Death. 
▫ Is life-threatening (i.e., the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred); it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
▫ Required or prolonged hospitalization. 
▫ Persistent or significant disability/incapacity (i.e., the event causes a substantial 
disruption of a person’s ability to conduct normal life functions). 
▫ Congenital anomaly/or birth defect. 
▫ An important and significant medical event that may not be immediately life 
threatening or resulting in death or hospitalization but, based upon appropriate 
medical judgment, may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed above. 
Adverse events which do not fall into these categories are defined as non-serious. 
It should be noted that a severe adverse event need not be serious in nature and that a 
serious adverse event need not, by definition, be severe. 
Serious adverse events will be captured both on the Vaccines Serious Adverse Event 
(VSAE) form as well as on the appropriate CRF page. All SAEs will be evaluated by the 
investigator for relationship of the event to study vaccine. SAEs that are judged to be 
possibly or probably related to the study vaccine should be reported to the Sponsor as 
related/suspected events. 
The relationship of the study treatment to an SAE will be determined by the investigator 
based on the following definitions: 
1. Related/suspected 
The SAE is judged by the investigator to be possibly or probably related to the study 
vaccine on the appropriate CRF page (see section 7.1.3). 

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2. Not Related 
The SAE is not related if exposure to the study vaccine has not occurred, or the 
occurrence of the SAE is not reasonably related in time, or the SAE is considered 
unlikely to be related to use of the study vaccine, i.e., there are no facts (evidence) or 
arguments to suggest a causal relationship. 
The relationship of the study vaccine to an SAE will be determined by the investigator. 
In addition, SAEs will be evaluated by the Sponsor or designee for “expectedness.” An 
unexpected AE is one that is not listed in the current Summary of Product Characteristics 
or the Investigator’s Brochure or an event that is by nature more specific or more severe 
than a listed event. 
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded on the appropriate CRF. If the onset of an event occurred before the subject 
entered the study (e.g., any pre-planned hospitalization for conditions like cosmetic 
treatments or for non-emergency routine visits for a pre-existing condition), the 
hospitalization would not lead to an AE being classified as serious unless, in the view of 
the investigator, hospitalization was prolonged as a result of participation in the clinical 
study or was necessary due to a worsening of the pre-existing condition. 
7.1.4.1  
Adverse Events of Special Interest 
Certain adverse events of special interest (AESIs) are monitored after the administration 
of immunostimulatory agents. All subjects enrolled in this study will be monitored for 
AESIs for the entire follow-up period. The AESIs will be defined according to MedDRA 
preferred terms. The investigator will be provided with a list of AESIs prior to study start. 
Receipt of this list will be notified and stored, along with the list of AESIs, in the 
Investigator Site File. During the course of the trial the list of AESIs may change. If this 
occurs, the investigators will be advised of the change and confirmation of receipt will be 
documented. The updated list of AESIs and documentation of receipt are also stored in 
the Investigator Site File. The occurrence of any of these adverse events will be treated as 
a serious adverse event (SAE), meeting the criterion of a “medically important event.” 
Subjects will be assessed for diagnosis of an AESI at the following visits: 
- 
Pre-vaccination clinic visit (Day -28 to Day -3)  
- 
Visit 1 (Day 1, pre-vaccination) 
- 
Visit 2 (Day 4) 

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- 
Visit 3 (Day 8) 
- 
Visit 4 (Day 15) 
- 
Visit 5 (Day 22; Safety Follow-Up Call) 
- 
Visit 6 (Day 29) 
- 
Visit 7 (Day 85) 
- 
Visit 8 (Day 113) 
- 
Visit 9 (Day 181) 
- 
Visit 10 (Day 209; Safety Follow-Up Call) 
- 
Visit 11 (Day 271; Safety Follow-Up Call) 
- 
Visit 12 (Day 366; Study Termination Visit) 
At these visits a qualified health care practitioner listed on the site’s responsibilities and 
delegation logs will conduct a review of organ systems and a targeted physical exam and 
will evaluate subjects for any new signs or symptoms that could indicate one of the 
AESIs as specified in the list of AESIs stored in the Investigator Site File. They will also 
interview the subject about recent medical history and any new diagnosis that could 
indicate an AESI. Medical records related to any new medical event or diagnosis will be 
requested, reviewed by the site staff, and recorded in the subject’s source documents. 
A diagnosis of an AESI will be reported in the same manner and time frame as an SAE 
using the VSAE form. The investigator must notify GSK within 24 hours. The AESI 
diagnosis, as well as any medications taken to treat the condition, will be recorded in the 
subject’s source documents and on the appropriate CRF. 
7.1.5  
Methods for Recording Adverse Events and Serious Adverse Events 
All findings regarding Adverse Events must be reported on the appropriate CRF page and 
on the VSAE form, if applicable, which is part of the Investigator Site File. All findings 
in subjects experiencing AEs must be reported also in the subject's source document. 
All SAEs which occur during the course of the study, whether considered to be associated 
with the study vaccination or not, must be reported within 24 hours of the site becoming 
aware of the event to GSK or its designee. Specific instructions and contact details for 
collecting and reporting SAEs to GSK will be provided to the investigator. 

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All SAEs are also to be documented on the appropriate CRF page. Any medication or 
other therapeutic measures used to treat the AE will be recorded on the appropriate 
CRF(s) in addition to the outcome of the AE. 
After receipt of the initial report, representatives of GSK or its designee will contact the 
investigator if it is necessary to obtain further information for assessment of the event. 
All SAEs must be reported by the investigator to his/her corresponding EC and applicable 
regulatory authorities in accordance with institutional policy/regulatory requirements and 
adequate documentation of this notification must be provided to the Sponsor. 
GSK or its designee must also comply with the applicable regulatory requirement(s) 
related to the reporting of suspected unexpected serious adverse vaccine reactions (also 
known as SUSARs) to the regulatory authority(ies) and the IRB/EC. If a SUSAR or other 
safety signal relating to use of one of the study vaccines is reported to GSK or its 
designee, the Sponsor will communicate the information to the investigator and the 
investigator will be responsible for submitting this information to the EC and other 
relevant authorities. 
7.1.5.1 
Post-Study Events 
Any suspected SAE that occurs outside of the protocol-specified follow-up period or after 
the end of the study but considered to be caused by the study vaccine must be reported to 
GSK or its designee. These SAEs will be processed by GSK or its designee as during the 
course of the study, until 3 months after the last scheduled study visit. Instructions and 
contact details for collecting and reporting these suspected SAEs will be provided to the 
investigator. 
7.1.6  
Pregnancies 
To ensure subjects’ safety, each pregnancy in a subject after study vaccination must be 
reported to GSK within 72 hours of the site learning of its occurrence. If the subject 
agrees to submit this information, the pregnancy must be followed to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. This follow-up should occur even if intended duration of safety follow-up 
for the study has ended. 
Pregnancy data must be recorded on a Pregnancy Report CRF (initial report) and 
Pregnancy Follow-Up CRF (outcome report). 

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Any pregnancy outcome meeting the definition of a SAE (see section 7.1.4) must also be 
reported on the VSAE Report Form. 
7.1.7  
Safety Laboratory Measurements 
Blood and urine samples will be collected from all subjects at the Pre-vaccination  
Screening, at Visit 1 (pre-vaccination and 24 hours after vaccination), at Visit 3 and at 
Visit 6 as outlined in Time and Events Table 3. The blood safety laboratory assessments 
will include sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, 
liver function tests (ALT, AST), a complete blood count and C-reactive protein. The urine 
safety laboratory assessments will include protein, glucose and red blood cells. An 
additional blood and urine sample will be collected in case of a clinic Early Termination 
Visit as outlined in section 5.5.1. 
All testing will be conducted by qualified and certified laboratories. The Investigator 
must assess all safety laboratory results. Abnormal laboratory values must be classified 
by the Investigator as clinically significant or not. Abnormal laboratory values that are 
considered clinical significant will be defined following the FDA CBER Guidance for 
Industry “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials” dated September 2007, or the institution’s normal 
ranges if they differ from CBER guidance. Please see Appendix C, D and E for further 
details on the Toxicity Grading Scales according to CBER. 
Retesting may be performed in case of abnormal values per guidance of the investigator.  
7.2  
Efficacy Assessment 
Efficacy measurement will not be performed as part of this study. 
7.3  
Immunogenicity Assessment 
The measures to assess the primary and secondary immunogenicity endpoints for this 
study are standard, i.e., widely used and generally recognized as reliable, accurate, and 
relevant (able to describe the quality and extent of the immune response). 
The assay’s used in this study to assess the primary and immunogenicity endpoints are 
human serum bactericidal assay (hSBA) and ELISA specific for MenC 
The hSBA is a functional measure of the ability of specific antibodies, in conjunction 
with human complement, to kill MenC indicator strains, and is widely used and generally 
recognized as the serological correlate of protection. The specific ELISA will be used to 

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measure the induction of antibodies directed against MenC following vaccination with the 
study vaccines. 
Blood samples (approximately 10 ml) to obtain serum for hSBA and ELISA assays will 
be collected at Day 1, Day 8, Day 29 and Day 181 (refer to section 3.5 for detailed 
specimen collection procedures). 
Testing will be conducted by a GSK or designated laboratory in a blinded manner 
towards the treatment group. Laboratory contact details are listed in the Protocol 
Ancillary Document. 
All data will be captured at the laboratory and transferred via Electronic Data Transfer  
(EDT) 
Details on all blood sample handling steps are described in the Clinical Specimen Lab 
Manual provided to the study site. 
7.4 
Exploratory Measurements 
In those subjects who agree to a separate Informed Consent, additional blood samples will 
be collected at Day 1, Day 4, Day 8, Day 29 and Day 181 for exploratory measurements. 
The purpose of these exploratory measurements is to assess the systemic exposure of 
LHD153, to further delineate vaccine induced antigen specific immune responses and to 
evaluate  biomarkers that may be predictive for safety and/or innate immune activation. 
All exploratory measurements will be conducted by a GSK or a designated laboratory. 
Laboratory contact details are listed in the Protocol Ancillary Document. 
Exploratory measurements may be performed after the Clinical Study Report (CSR) has 
been completed, in which case these data will be submitted as an addendum to the CSR. 
Systemic exposure of LHD153 
Systemic exposure of LHD153 will be assessed by analyzing LHD153 blood plasma 
levels at Day 1 (baseline, 1, 2, 4, 8 and 24h after vaccination) and Day 4 using 
LC/MS/MS. Time-points for assessment of clinical exposure of LHD153 have been 
selected based on non-clinical data in dogs and rats. 
Vaccine-induced antigen-specific immune responses 
The frequency of B cells specific for MenC polysaccharide and CRM197 will be 
determined by enzyme-linked immunosorbent spot (ELISPOT) at Day 1, Day 8, Day 29 
and Day 181 in order to evaluate the baseline specific B-cell frequency (Day 1), the peak 

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of plasmablast responses (Day 8), the peak of B cell memory responses (Day 29), and the 
persistence of memory B cell responses (Day 181). 
Subsequently, the diversity of the antigen specific B-cell repertoire as well as the specific 
antibody functionality will be analyzed in a selected subset of subjects. The selection of 
the subset will be based on the most pronounced response to the study vaccines when 
compared to baseline as determined by the primary and secondary immunogenicity 
assessment. 
The diversity of the elicited B-cell receptors will be assessed through sequence analysis of 
complementary DNA (cDNA) generated from immunoglobulin (Ig) messenger RNA 
(mRNA). The Ig cDNAs will be analyzed from antigen-specific B cells obtained at Day 
1, Day 29 and/or Day 181 and plasmablasts isolated at Day 8. The analysis of the B-cell 
receptor diversity does not have the intent nor the capability to identify or rule out any 
genetic modifications in the RNA or DNA that are presumably linked to disease or 
predisposition to disease. 
To evaluate the functionality specific antibodies induced by the study vaccines, 
biochemical and cell-based assays will be performed on a selected subset of serology 
samples collected for the assessment of the primary and secondary immunogenicity 
endpoints at Day 1, Day 8, Day 29 and Day 181. The evaluation of antigen specific 
antibody functionality includes determination of the antibody isotype and the antibody 
glycosylation state. Furthermore, the ability of the MenC-specific antibodies to fix 
complement, to promote antibody-dependent cell mediated cytoxicity (ADCC), to induce 
phagocytosis and to activate FcR+ cells in vitro will be assessed. If the quantity of serum 
available for this specific exploratory objective is limited, assessments of isotype and 
glycosylation state will be prioritized over the other assessments. 
The frequency of T cells specific for the CRM197 protein at baseline (Day 1), at Day 8 and 
at Day 29 after vaccination with the study vaccines will be determined by FACS analysis 
using intracellular staining with a panel of cytokines and surface markers to identify cell 
populations. 
Early Markers for Safety and Innate immune activation 
The evaluation of potential biomarkers of safety and innate immune activation will be 
performed on blood specimens collected at Day 1 (baseline, 6h and 24h after vaccination) 
and Day 4. 
The vaccine-induced production of inflammatory cytokines and chemokines will be 
monitored on serum samples using a commercially available electrochemoluminescence 
assay for a panel of pro-inflammatory cytokines and chemokines, including Eotaxin, 

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Eotaxin-3, GM-CSF, IFN-g, IL-1a, IL-1b, IL-10, IL-12 p70, IL-12/IL-23p40, IL-13, 
IL15, IL-16, IL-17A, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IP-10, MCP-1, MCP-
4, MDC, MIP-1a, MIP-1b, TARC, TNF-a, TNF-b, VEGF. 
The vaccine-induced expression of genes and gene families will be monitored on whole 
blood samples using of RNA microarrays by existing technologies. The RNA micro array 
analysis does not have the intent nor the capability to identify or rule out any genetic 
modifications in the RNA or DNA that are presumably linked to disease or predisposition 
to disease. 
The vaccine-induced changes in myeloid (e.g. monocytes and dendritic cells) and 
lymphoid (e.g. NK cells, NKT cells) cell numbers and their activation status will be 
assessed using flow cytometry. 
8.0  
STATISTICAL CONSIDERATIONS 
8.1  
Endpoints 
8.1.1 
Primary Endpoint(s) 
8.1.1.1  
Primary Safety Endpoint(s) 
The measures for assessing safety and tolerability (by vaccine group within each cohort 
and by LHD153R adjuvant dosage group overall) are as follows: 
▫ The frequency and percentage of subjects with solicited local and systemic  AEs 
through Day 14. Time intervals after vaccination that will be summarized are:30 
minutes post-vaccination, Days 1-4 (without 30 minutes), Days 5-8, Days 8-14, Days 
1-8 (without 30 minutes) and Days 1-14 (without 30 minutes). 
▫ The frequency and percentage of subjects with any unsolicited AEs from the day of 
vaccination (Day 1) to Day 14. 
▫ The frequency and percentage of subjects with SAEs, medically attended AEs,  AEs 
leading to study withdrawal, NOCDs, AESIs for the following time periods: day of 
signed informed consent until study completion (Day 366), day of vaccination (Day 1) 
to Day 29, and Day 29 to study completion (Day 366). 
▫ The absolute values and changes in hematology, chemistry, and urinalysis parameters 
(see section 7.1.7). 
▫ The frequency and percentage of subjects with abnormal laboratory parameter values 
as classified by investigator normal ranges (low, normal, high) and as classified by 

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CBER toxicity grading scales, when available. 8.1.1.2  
Primary Efficacy 
Endpoint(s) 
Not applicable. 
8.1.1.3  
Primary Immunogenicity Endpoint(s) 
The primary immunogenicity endpoints are the GMTs measured by hSBA directed 
against MenC from samples collected on Day 1 (baseline, before vaccination) and Day 29 
as well as the GMR of the titers (Day 29 / Day 1). 
8.1.2 
Secondary Endpoint(s) 8.1.2.1 
 Secondary Safety Endpoint(s) 
Not applicable. 
8.1.2.2  
Secondary Efficacy Endpoint(s) 
Not applicable. 
8.1.2.3  
Secondary Immunogenicity Endpoint(s) 
The secondary immunogenicity endpoints are: 
▫ GMTs and corresponding GMRs measured by hSBA directed against MenC for 
samples collected at Day 8 and Day181. 
▫ Percentage of subjects with hSBA seroresponse at Days 8, 29, and 181. Seroresponse 
is defined as a post vaccination hSBA ≥8 for subjects with a baseline hSBA <4 or 
have an increase of at least 4 times the baseline hSBA level for subjects with 
prevaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against MenC measured by ELISA 
for samples collected on Days 1 (baseline, prior to vaccination), 8, 29, and 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations to 
MenC as measured by ELISA on Day 8, 29, and 181 relative to baseline (Day 1). 
8.1.3  
Exploratory Endpoint(s) 

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The exploratory  endpoints are based on results of testing which may not be performed 
until after the study report has been finalized and will be further refined prior to testing. 
They include the following: 
▫ Serum concentration of LHD153 at Day 1 baseline (prior to vaccination), Day 1 (1h , 
2h, 4h, 8h, and 24h after vaccination), Day 4 by LC-MS/MS. 
▫ Frequency of MenC polysaccharide-specific and CRM197-specific B cells at Day 1 
(baseline), Day 8, Day 29, and Day 181 by ELISPOT. 
▫ Diversity of MenC polysaccharide-specific B-cell repertoire at Day 1 (baseline), Day 
8, Day 29, and Day 181 by immunoglobulin cDNA sequencing. 
▫ Functionality of antigen specific antibodies will be assessed at Day 1 (baseline), Day 
8, Day 29, and Day 181 by analysis of immunoglobulin isotype, glycosylation state 
and their ability to fix complement, to promote antibody-dependent cell mediated 
cytoxicity, to induce phagocytosis and to activate FcR+ cells. If the quantity of serum 
available for this specific exploratory objective is limited, assessments of 
immunoglobulin isotype and glycosylation state will be prioritized over the other 
assessments. 
▫ Frequency and quality of T cells specific for CRM197 at Day 1 (baseline), Day 8, and 
Day 29 by flow cytometry analysis using intracellular staining with a wide panel of 
cytokines and surface markers to identify cell populations. 
▫ Serum concentrations of a panel of 30 chemokines and cytokines at Day 1 baseline 
(prior to vaccination), Day 1 (6h and 24h after vaccination), Day 4, and Day 8 by 
multiplex Electro-chemo-luminescence based assay. 
▫ Gene expression profile in whole blood at Day 1 baseline (prior to vaccination), Day 1 
(6h and 24h after vaccination), Day 4, and Day 8 by RNA micro array analysis. 
▫ Number and activation status of myeloid and lymphoid cell populations at Day 1 
baseline (prior to vaccination), Day 1 (24h after vaccination), Day 4 and Day 8 by 
flow cytometry. 
8.2  
Success Criteria 
The study has no formal statistical hypotheses and will not be declared positive or 
negative according to given rules. The selection of an appropriate LHD153R adjuvant 
dosage for future studies will be determined by the joint evaluation of the 

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immunogenicity and safety profiles of each dosage group. 8.2.1  
Success Criteria 
for Primary Objective(s) Not applicable. 
8.2.2  
Success Criteria for Secondary Objective(s) 
Not applicable. 
8.3  
Analysis Sets 
8.3.1  
All Enrolled Set 
All screened subjects who provide informed consent and provide demographic and/or 
baseline screening assessments, regardless of the subject’s randomization and treatment 
status in the study and received a Subject ID. 
8.3.2  
All Exposed Set 
All subjects in the enrolled set who receive a study vaccination. 
8.3.3  
Safety Set 
Safety Set (solicited adverse events and other solicited reactions) 
All subjects in the Exposed Set who: 
▫ Provide post vaccination reactogenicity data. 
Safety Set (unsolicited adverse events) 
All subjects in the Exposed Set who: 
▫ Have post-vaccination unsolicited adverse event records. 
Safety Set (overall) 
All subjects in the Exposed Set who: 
▫ Have either post-vaccination adverse event or reactogenicity records. 
Subjects will be analyzed as “treated” (i.e., according to the vaccine a subject received, 
rather than the vaccine to which the subject may have been randomized). 
8.3.4  
Full Analysis Set (FAS) Efficacy/Immunogenicity Set 

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All subjects in the Enrolled Set who: 
▫ Receive a study vaccination AND provide efficacy/immunogenicity data at relevant 
time points. 
FAS sets will be analyzed “as randomized” (i.e., according to the vaccine a subject was 
designated to receive, which may be different from the vaccine the subject actually 
received). 
8.3.5  
Per Protocol (PP) Set Efficacy/Immunogenicity Set 
All subjects in the FAS efficacy/immunogenicity set who: 
▫ Are not excluded due to reasons (see section 8.3.8) defined prior to unblinding or 
analysis. 
PPS are subsets of FAS and should always be defined even if the objectives do not 
require it. 
Examples for subjects excluded due to other reasons than protocol deviations are: 
- 
Subjects who withdrew informed consent. 
- 
Premature withdrawal due to an adverse event. 
Exclusions need to be considered by objective/time point, i.e., sometimes not all data of a 
subject but only part of the subject's data will be removed from the PPS analysis. 
8.3.6  
Other Analysis Sets  
All subjects in the Enrolled Set who consent to additional blood draws, receive a study 
vaccination AND provide exploratory assay data at relevant time points will be included 
in an exploratory assay subset. 
8.3.7  
Subgroups 
Selected immunogenicity analyses may be provided based on seropositivity status at 
baseline. 
8.3.8  
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. A protocol deviation may be a reason to remove data from 
an analysis set at the time of analysis. Reportable protocol deviations will be defined as 

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exclusionary from the analysis according to protocol objectives and endpoints, which will 
be specified in the Statistical Analysis Plan. In some cases exclusion of data may be due 
to a reason other than a protocol deviation, e.g. early termination. 
8.4  
Statistical Analysis Plan 
This section provides a summary of the statistical methodology to be used. A more 
detailed description of analysis methods will be provided in a separate Statistical Analysis 
Plan which may also include additional exploratory analyses not explicitly mentioned in 
the following sections. 
8.4.1  
Analysis of Demographic and Baseline Characteristics 
Descriptive statistics (number of non-missing observations, mean, standard deviation, 
median, minimum and maximum) for age, height and weight at enrolment will be 
calculated overall and by vaccine group and LHD153R adjuvant dosage. 
Distributions of subjects by sex and ethnic origin will be summarized overall and by 
vaccine group and LHD153R adjuvant dosage. 
8.4.2  
Analysis of Primary Objective(s) 
8.4.2.1  
Analysis of Primary Safety Objective(s) 
Safety of the study vaccines will be assessed in all subjects in terms of the frequency and 
percentage of reported AEs as well as by changes in clinical laboratory values.  
8.4.2.1.1  
Analysis of Extent of Exposure 
The frequency and percentage of subjects with vaccinations will be summarized by 
vaccine group and LHD153R adjuvant dosage, by cohort and overall, for the Enrolled 
Set. 
8.4.2.1.2  
Analysis of Solicited Local, Systemic and Other Adverse Events 
All solicited adverse events will be summarized according to defined severity grading 
scales. Use of medication to prevent/treat fever will be summarized according to 
frequencies and percentages reporting “Yes” and “No”. 
Frequencies and percentages of subjects experiencing each adverse event will be 
presented for each symptom severity. Summary tables showing the occurrence of any 
local or systemic adverse event overall and at each time point will also be presented. 

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Post-vaccination solicited adverse events reported from Day 1 to Day 14 will be 
summarized for the intervals Day 1-4 (without 30 minutes), Day 5-8, Day 1-8 (without 30 
minutes), Day 8-14 and Day 1-14 (without 30 minutes) by maximal severity and by 
vaccine group and LHD153R adjuvant. The severity of solicited local adverse events, 
including injection-site erythema, swelling and induration will be summarized according 
to categories based on linear measurement: 25-50 mm, 51-100 mm, > 100 mm. 
Injection site pain and systemic reactions (except fever) occurring up to Day 14 will be 
summarized according to “mild”, “moderate” or “severe”. 
Each solicited local and systemic adverse event will also be further summarized as “none” 
versus “any”. 
Implausible measurements (for further definition see Statistical Analysis Plan) will be left 
out of the analysis. 
Use of antipyretics and analgesics will be summarized by frequency by type of use 
(prophylactic versus treatment) and percentage of subjects reporting use. The influence of 
antipyretics and analgesics use on the occurrence of specific adverse events (e.g., fever, 
pain) will be assessed. 
Body temperature will be summarized by 0.5 °C and 1.0 °C increments from 36.0 °C up 
to ≥40 °C. 
8.4.2.1.3  
Analysis of Unsolicited Adverse Events 
This analysis applies to all adverse events occurring during the study, judged either as 
probably related, possibly related, or not related to vaccination by the investigator, 
recorded in the CRF, with a start date on or after the date of first vaccination. AE starting 
prior to the first vaccination will only be listed. The original verbatim terms used by 
investigators to identify adverse events in the CRFs will be mapped to preferred terms 
using the MedDRA dictionary. The adverse events will then be grouped by MedDRA 
preferred terms into frequency tables according to system organ class. 
All reported adverse events, as well as adverse events judged by the investigator as at 
least possibly related to study vaccine, will be summarized according to system organ 
class and preferred term within system organ class. These summaries will be presented by 
vaccination group and LHD153R adjuvant dosage for each cohort and by interval of 
study observation. When an adverse event occurs more than once for a subject, the 
maximal severity and strongest relationship to the vaccine group will be counted. 
Separate summaries will be produced for the following categories: 

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▫ Serious adverse events. 
▫ Adverse events that are possibly or probably related to vaccine. 
▫ Adverse events of special interest. 
▫ New onset of chronic disease. 
▫ Adverse event leading to withdrawal. 
▫ Adverse events leading to a medically attended visit. 
▫ Adverse event by data source. 
Data listings of all adverse events will be provided by subject. In addition, adverse events 
in the categories above will be provided as listed data. 
8.4.2.1.4  
Analysis of Safety Laboratory Values 
The investigator must review all safety laboratory results (see Section 7.1.7). Abnormal 
laboratory values and clinically significant changes in values from pre-vaccination 
(Screening Visit) will be assessed, using medical judgment, based on the FDA CBER  
Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent  
Volunteers Enrolled in Preventive Vaccine Clinical Trials” dated September 2007, or the 
institution’s normal ranges if they differ from CBER guidance. Please see Appendix C, D 
and E for further details. 
The following information will be provided: 
▫ Change in absolute laboratory value from pre-vaccination (Screening Visit) and Day 1 
(Visit 1) baseline to Day 1 (24 hours after vaccination), Day 8 (Visit 3) and Day 29 
(Visit 6) after vaccination. 
▫ The classification of laboratory values and/or their changes from pre-vaccination 
according to the CBER toxicity grading scale. 
▫ 3 x 3 shift tables by visit using the categorization of laboratory values according to 
institutional normal reference ranges (below, within, above). 8.4.2.2  
Analysis 
of Primary Efficacy Objective(s) 
Not applicable. 
8.4.2.3  
Analysis of Primary Immunogenicity Objective(s) 

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8.4.2.3.1  
Statistical Hypotheses 
There are no statistical hypotheses associated with the primary immunogenicity 
objectives. All analyses are descriptive. 
8.4.2.3.2  
Analysis Sets 
The primary immunogenicity analyses will be based on the per-protocol set (PPS) at Day 
29. The primary analyses will be repeated using the Full Analysis Set (FAS) as a measure 
of the sensitivity/robustness of the results (further details are given in section 8.3). 
8.4.2.3.3  
Statistical Methods 
Before any statistical analysis that assumes normally distributed observations, antibody 
titers will be log10-transformed. Individual titers below the limit of quantitation (LLQ) 
will be set to half that limit. 
Geometric Mean Titers 
The logarithmically (base 10) transformed antibody titers will be modeled using an 
analysis of covariance (ANCOVA) model with a qualitative factor for LHD153R 
adjuvant dosage (0 [for unadjuvanted MenC], 12.5, 25, 50 or 100 µg) and log (base 10) 
pre-vaccination titer as a covariate. The adjusted GMT and the two-sided, 95%, 
confidence intervals (CIs) of the GMT will be calculated based on this model as will the 
ratio of GMTs and corresponding CIs. The adjusted GMT and two-sided 95% CIs will be 
constructed by exponentiation (base 10) of the least square means of the logarithmically 
transformed (base 10) antibody titer. The ratio of GMTs (LHD153R adjuvant dosage 
minus MenC), and corresponding two-sided 95% CIs, will be constructed by 
exponentiation (base 10) of the least square differences obtained from this model. The 
model can be written as:  
log10 (yik) = µ + αi + βxik + εik 
where µ represents a common overall mean, αi represents the adjuvant dose group i effect, 
β represents the common slope for the log10 pre-vaccination titer, xik for subject k in 
adjuvant dose group I, and εik represents random error for subject k in adjuvant dose 
group i. 
Geometric Mean Ratios 
The logarithmically (base 10) transformed within subject ratio of antibody titers (Day 29 / 
pre-vaccination) will be modeled using an analysis of variance model with a qualitative 

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factor for LHD153R adjuvant dosage (0 [for non-LHD153R adjuvanted MenC], 12.5, 25, 
50 or 100 µg). The adjusted GMR and the two-sided, 95% CIs of the GMR will be 
calculated based on this model. The model can be written as: 
log10 (yik) = µ + αi + εik 
where µ represents a common overall mean, αi represents the adjuvant dose group i effect 
and εik represents random error for subject k in adjuvant dose group i. 
Handling of missing values 
For immunogenicity data, it may be reasonable to consider missing immunogenicity 
values as missing completely at random (MCAR), i.e., not informative. Therefore, the 
primary analysis will comprise a complete case analysis only, without introducing any 
bias. Imputation methods will not be used. 
8.4.3  Analysis of Secondary Objective(s) 8.4.3.1 
 Analysis of Secondary Safety Objective(s) Not 
applicable. 
8.4.3.2  
Analysis of Secondary Efficacy Objective(s) 
Not applicable. 
8.4.3.3  
Analysis of Secondary Immunogenicity Objective(s) 
8.4.3.3.1  
Statistical Hypotheses 
There are no statistical hypotheses associated with the secondary immunogenicity 
objectives. All analyses are descriptive. 
8.4.3.3.2  
Analysis Sets 
The secondary immunogenicity analyses will be based on the PPS (further details are 
given in section 8.3) or the appropriate subset of subjects. 
8.4.3.3.3  
Statistical Methods 
The secondary immunogenicity endpoints are: 

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▫ GMTs and corresponding GMRs measured by hSBA directed against MenC for 
samples collected at Day 8 and Day181. 
▫ Percentage of subjects with hSBA seroresponse at Days 8, 29, and 181. seroresponse is 
defined as a post vaccination hSBA ≥8 for subjects with a baseline hSBA <4 or have 
an increase of at least 4 times the baseline hSBA level for subjects with 
prevaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against MenC measured by ELISA 
for samples collected on Days 1 (baseline, prior to vaccination), 8, 29, and 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations to 
MenC as measured by ELISA on Day 8, 29, and 181 relative to baseline (Day 1). 
The GMTs for samples collected at Day 8 and Day 181 as well as the GMCs for samples 
collected at Day 1, Day 8, Day 29, and Day 181 will be analyzed using the same approach 
as for the primary immunogenicity endpoint. 
The remaining immunogenicity endpoints are based on subjects meeting criteria for 
seroconversion or achieving a certain threshold value. These endpoints will be 
summarized using frequencies and percentages by LHD153R adjuvant dosage (0 [for 
non-LHD153R adjuvanted MenC], 12.5, 25, 50 or 100 µg). Two-sided 95% 
ClopperPearson CIs will also be provided for percentages. For analyses of 
seroconversion, separate summaries may be provided based on seropositivity status at 
baseline. 
8.4.4  
Analysis of Exploratory Objectives 
Testing and analyses of exploratory endpoints may be performed after the Clinical Study 
Report (CSR) has been completed, in which case these data will be submitted as an 
addendum to the CSR. 
In general, concentration and titer results will be summarized for each LHD153R 
adjuvant dosage group using geometric means and associated 2-sided 95% confidence 
intervals; and, categorical data will be summarized using frequencies and percentages, 
with corresponding two-sided, 95% confidence intervals. 
8.5  
Sample Size and Power Considerations of Primary Objectives 
Sample size is not driven by statistical assumptions for formal hypothesis testing, but was 
based on the safety objective for the study. The table below provides the probability for 
various combinations of sample size (N) and presumed true frequency of a given event 
within an individual vaccine group  

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Frequency 
of Event 
Probability to Observe at Least 1 Subject with a Given Event For  
Various Choices of N 
4 
8 
12 
16 
0.05 
0.1855 
0.3366 
0.4596 
0.5599 
0.10 
0.3439 
0.5695 
0.7176 
0.8147 
0.15 
0.4780 
0.7275 
0.8577 
0.9257 
0.20 
0.5904 
0.8322 
0.9313 
0.9718 
0.30 
0.8250 
0.9423 
0.9862 
0.9967 
0.40 
0.8704 
0.9832 
0.9978 
0.9997 
The proposed combinations of sample sizes within each cohort are 4 aluminium 
hydroxide adjuvanted MenC-CRM197 and 16 MenC-CRM197 plus an assigned-level of 
LHD153R adsorbed to aluminium hydroxide. If all four cohorts are fully enrolled, there 
will be 16 subjects receiving aluminium hydroxide adjuvanted MenC-CRM197. 
With 16 subjects, events which occur at a frequency of 15% or more will be detected with 
at least 90% probability; and, events which occur at a frequency of 10% or more will be 
detected with 81% probability. With 4 subjects, events which occur at a frequency of 30% 
or more will be detected with at least 80% probability. Intermediate values of 8 and 12 
are provided to correspond to sample sizes in the MenC- CRM197 after cohort 2 and 
cohort 3 are fully enrolled. 
8.6  
Interim Analysis 
The DMC will be reviewing the accumulating safety data from the study in order to 
continue enrollment of subjects within a cohort and whether to enroll subjects into the 
next cohort. 
In addition to these periodic reviews, there will be a safety and immunogenicity interim 
analysis for the selection of an LHD153R adjuvant dosage based on the data collected 
through Day 29 from subjects enrolled in all cohorts. This analysis will be performed by 
personnel not involved in study decisions. The results will be unblinded at the group level 
thereby preserving the blind for individual subjects. No adjustment to the overall alpha 
will be performed as the data collected subsequent to this analysis involve secondary and 
exploratory endpoints. 
 

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9.0  
SOURCE DOCUMENTATION, STUDY MONITORING AND 
AUDITING 
Study monitoring and auditing will be standardized and performed in accordance with the 
Sponsor’s or delegated contract research organization’s (CRO) standard operating 
procedures and applicable regulatory requirements (e.g., FDA, EMA, and ICH 
guidelines). 
Prior to enrolment of the first study subject, GSK or delegate will train investigators 
and/or their study staff on the study protocol, all applicable study procedures, 
documentation practices and all electronic systems. CRFs must be completed for each 
enrolled subject (see section 8.3.1 for definition of enrolled subject). Documentation of 
screened but not enrolled subjects must be maintained at the site and made available for 
review by the site monitor. 
9.1  
Source Documentation 
Prior to the start of the study, the site staff participating in the study conduct will be 
instructed on what documents will be required for review as source documents. The kinds 
of documents that will serve as source documents will be agreed between Sponsor or 
delegate and investigator and designees and specified in the SDA/Source Data 
Verification Form prior to subject enrolment. 
In addition, source documentation must include all of the following: subject identification 
(on each page), eligibility and participation, proper informed consent procedures, dates of 
visits, adherence to protocol procedures, adequate reporting and follow-up of adverse 
events, documentation of prior/concomitant medication/vaccines, study vaccine 
receipt/dispensing/return records, study vaccine administration information, any data 
collected by a telephone conversation with the subject and date of completion and reason. 
The subject must also allow access to the subject’s medical records. Each subject must be 
informed of this prior to the start of the study and consent for access to medical records 
may be required in accordance with local regulations. 
All safety data reported by subjects must be written down in source documents. If there 
are multiple sources of information (e.g., Subject Diary, verbal report of the subject, 
telephone contact details, medical chart) supporting the diagnosis of an adverse event, 
these sources must be identified in the source documents, discrepancies between sources 
clarified, the ultimate diagnosis must be justified and written in the source documents, 
and this diagnosis must be captured in the appropriate CRF page. The CRF must also 

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capture which source(s) of information were used to determine the adverse event (e.g., 
subject recall, medical chart, Subject Diary). 
9.2  
Study Monitoring, Auditing and Source Data Verification 
Prior to enrolment of the first study subject, GSK or its designee (e.g., a CRO) will 
develop a Monitoring Plan to specify how centralized and/or on-site monitoring, 
including clinical specimens reconciliation, will be performed for the study. Study 
progress will be monitored as frequently as necessary to ensure: 
▫ that the rights and well-being of human subjects are protected, 
▫ the reported study data are accurate, complete, and verifiable from the source 
documents and 
▫ the conduct of the study is in compliance with the current approved 
protocol/amendment(s), GCP and applicable regulatory requirements. 
Contact details for the team involved in study monitoring will be provided to the 
investigator. Study data recorded on CRFs will be verified by checking the CRF entries 
against source documents in order to ensure data completeness and accuracy as required 
by study protocol. 
Additional documents such as the investigator site file, pharmacy records, and informed 
consent documentation must also be available for review if requested. Arrangements for 
monitoring visits will be made in advance in accordance with the monitoring plan, except 
in case of emergency. 
The investigator and/or site staff must make source documents of subjects enrolled in this 
study available for inspection at the time of each monitoring visit and Sponsor audits, 
when applicable. These documents must also be available for inspection, verification and 
copying, as required by regulations, by officials of the regulatory health authorities (e.g., 
FDA, EMA and others) and/or ECs/IRBs. The investigator and study site staff must 
comply with applicable privacy, data protection and medical confidentiality laws for use 
and disclosure of information related to the study and enrolled subjects. 
10.0  
DATA MANAGEMENT 
10.1 
Data Entry and Management 
In this study, all clinical data (including, but not limited to, AE/SAEs, concomitant 
medications, medical history, and physical assessments), safety data, and immunogenicity 
data will be entered into an EDC system, which is compliant with Title 21 Part 11 

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policies of the Code of Federal Regulations (FDA, 1997). The data system includes 
password protection and internal quality checks. The EDC system will be designed and 
validated by the Sponsor prior to activation for data entry by sites. The investigator or 
designated delegate must review data entered and electronically sign the CRFs to verify 
their accuracy. 
Access to the EDC system for data entry or review will require training and distinct 
individual access code assignments to those site staff members who will be entering study 
data and those involved in study oversight who may review study data. Data are collected 
within the EDC system, to which the Sponsor and site monitors have exclusively “read 
only” access. 
Paper CRFs will be provided for each pregnant subject by the Sponsor. All appropriate 
pregnant subject data collected will be recorded on this form. One copy must be retained 
by the investigator, and all other copies (including the original copy) will be returned as 
directed by the Sponsor. Instructions on how to complete this form will be provided to the 
investigator. 
10.2  
Data Clarification 
As part of the conduct of the trial, the Sponsor may have questions about the data entered 
by the site, referred to as queries. The monitors and the Sponsor are the only parties that 
can generate a query. All corrections and clarifications will be entered into the EDC 
system and will be identified by the person entering the information, the reason for the 
change, as well as the time of the changes made. If changes are made to a previously and 
electronically signed CRF, the investigator must confirm and endorse the changes 
10.3  
Data Protection 
GSK respects the subjects’ rights to privacy and will ensure the confidentiality of their 
medical information in accordance with all applicable laws and regulations. 
The Sponsor as Data Controller according to the European Directive on the protection of 
individuals with regard to the processing of personal data and on the free movement of 
such data (95/46/EC) confirms herewith compliance to Directive 95/46/EC in all stages of 
Data Management. 
 

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11.0  
RECORD RETENTION 
Investigators must retain all study records required by GSK and by the applicable 
regulations in a secure and safe facility. The investigator must consult a GSK 
representative before disposal of any study records, and must notify the Sponsor of any 
change in the location, disposition, or custody of the study files. Essential documents 
must be retained for 15 years. “Essential documents” are defined as documents that 
individually and collectively permit evaluation of the conduct of a study and the quality 
of the data produced. These documents should be retained for a longer period, however, if 
required by the applicable national regulatory or institutional requirements.  
These principles of record retention will also be applied to the storage of laboratory 
samples, provided that the integrity of the stored sample permits testing. 
 

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12.0  
USE OF INFORMATION AND PUBLICATION 
GSK assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov, and in compliance with current regulations. 
GSK also assures that key results of this clinical study will be posted in a publicly 
accessible database within the required time-frame from the End of Study as defined in 
section 3.9. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
GSK must be notified of any intent to publish data collected from the study and prior 
approval from GSK must be obtained prior to submission for publication. 
 

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13.0  
ETHICS 
13.1  
Regulatory and Ethical Compliance 
The study will be conducted in compliance with the protocol, GCP and applicable 
regulatory requirement(s). 
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, European 
Directive 2001/20/EC, GSK codes on protection of human rights, and with the ethical 
principles laid down in the Declaration of Helsinki (European Council 2001, US Code of 
Federal Regulations, ICH 1997). 
13.2  
Informed Consent Procedures 
Eligible subjects may only be included in the study after providing written informed 
consent or assent, as described in section 5.1.1. Before the start of the study, the 
investigator will have the informed consent and any other materials that will be provided 
to the subjects reviewed and approved by the IRB/EC. This review and approval will be 
documented and stored with other study documents. The investigator or designee must 
fully inform the subject or legal guardian of all pertinent aspects of the study. A copy of 
the written informed consent will be given to the subject or the designee. The 
subject/designee must be allowed ample time to ask about the details of the study and to 
make a decision as to whether or not to participate in the study. The subject and/or legal 
guardian(s) must sign the consent form indicating their agreement to participate in the 
study before any study-related procedures are conducted. The informed consent process 
may be conducted up to 28 days prior to vaccination on Day 1. If the subject is unable to 
read and write, a witness must be present during the informed consent discussion and at 
the time of informed consent signature. 
Prior to the start of the study, GSK will provide to investigators a proposed informed 
consent form that complies with the ICH GCP guideline and regulatory requirements and 
is considered appropriate for this study. Any changes to the proposed consent form 
suggested by the investigator must be agreed to by GSK before submission to the IRB/EC 
and a copy of the approved version must be provided to GSK after IRB/EC approval. 
Women of childbearing potential should be informed that taking the study medication 
may involve unknown risks to the fetus if pregnancy were to occur during the study and 
agree that in order to participate in the study they must adhere to the contraception 
requirements indicated in the protocol for the duration of the study. In case of doubt on 

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the ability of a subject to adhere to these requirements, that subject should not be allowed 
in the study 
13.3  
Responsibilities of the Investigator and IRB/EC 
The protocol and the proposed informed consent form must be reviewed and approved by 
a properly constituted IRB/EC before study start. Properly constituted IRB/EC is defined 
in ICH Guideline for Good Clinical Practice E6 (R1), Section 3 (ICH, 1997). A signed 
and dated statement that the protocol and informed consent have been approved by the 
IRB/EC must be given to GSK before study initiation. Prior to study start and at any time 
the protocol is amended during study conduct, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance 
with these documents and all of the instructions and procedures found in this protocol and 
to give access to all relevant data and records to GSK monitors, auditors, GSK Clinical 
Quality Assurance representatives, designated agents of GSK, IRBs/ECs, and regulatory 
authorities as required. If an inspection of the clinical site is requested by a regulatory 
authority, the investigator must inform GSK immediately that this request has been made. 
The investigator also responsible for the following: 
▫ Maintaining a list of appropriately qualified persons to whom the investigator has 
delegated significant study-related duties. 
▫ Demonstrating the capability of recruiting the required number of suitable subjects 
within the recruitment period. 
▫ Demonstrating sufficient time and staffing to properly conduct and complete the study 
within the agreed study period. 
▫ Ensuring that all persons assisting with the study are adequately informed about the 
protocol, the investigational product(s), and their study-related duties and functions 
▫ Ensuring that appropriately trained health care professionals are responsible for all 
study-related medical decisions and for ensuring appropriate medical care of subjects 
experiencing any adverse event related to the study. 
▫ If permission to do so is given by the subject, ensuring that the subject’s primary 
healthcare provider is informed of the subject’s participation in the study. 
The investigator should not implement any deviation from, or changes of the protocol 
without agreement by the Sponsor and prior review and documented approval/favourable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an 
immediate hazard(s) to study subjects, or when the change(s) involves only logistical or 
administrative aspects of the study (e.g., change in monitor(s), change of telephone 

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number(s)). In addition, the investigator, or person designated by the investigator, should 
document and explain any deviation from the approved protocol. 
The investigator may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior IRB/IEC 
approval/favourable opinion. As soon as possible, the implemented deviation or change, 
the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be 
submitted: 
(a) to the IRB/IEC for review and approval/favourable opinion, 
(b) to the Sponsor for agreement and, if required, 
(c) to the regulatory authority(ies). 
13.4  
Protocol Amendments 
An amendment is a written description of change(s) to or formal clarification of a study 
protocol which may impact on the conduct of the clinical study, potential benefit of the 
clinical study, or may affect subject safety, including changes of study objectives, study 
design, subject population, sample sizes, study procedures, or significant administrative 
aspects. An administrative change of a study protocol is a minor correction or 
clarification that has no significant impact on the way the clinical study is to be conducted 
and no effect on subject safety (e.g., change of telephone number(s), logistical changes). 
Protocol amendments must be approved by GSK, health authorities where required, and 
the IRB/EC. In cases when the amendment is required in order to protect the subject 
safety, the amendment can be implemented prior to IRB/EC approval. Notwithstanding, 
the need for formal approval of a protocol amendment, the investigator is expected to take 
any immediate action required for the safety of any subject included in this study, even if 
this action represents a deviation from the protocol. In such cases, GSK should be notified 
of this action, the IRB/EC at the study site, and, if required by local regulations, the 
relevant health authority should be informed within 10 working days. 
14.0  
REFERENCE LIST 
Alving CR, Peachman KK, Rao M, Reed SG. Adjuvants for human vaccines. Curr Opin 
Immunol. 2012 Jun; 24(3):310-5 
Bauza, A et al., Pemphigus-like lesions induced by imiquimod. Clin Exp Dermatol 2009, 
34, e60-62 

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Bissett SL, Draper E, Myers RE, Godi A, Beddows S. Cross-neutralizing antibodies 
elicited by the Cervarix® human papillomavirus vaccine display a range of Alpha-9 
intertype specificities. Vaccine. 2014 Feb 26; 32(10):1139-46 
Campanelli, A et al., Topical application of imiquimod and associated fever in children. J 
Am Acad Dermatol 2005,52, E1. 
Code of Federal Regulations (1997): Food and Drug Administration, U.S. Department of 
Health and Human Services: Title 21, Part 11: Electronic Records Electronic Signatures. 
Federal Register 62: 13464 
Connolly M and Noah N, Is group C meningococcal disease increasing in Europe? A 
report of surveillance of meningococcal infection in Europe 1993-6. Epidemiol. Infect. 
1999; 122: 41-49. 
Del Giudice G, Fragapane E, Della Cioppa G, et al. Aflunov®: a vaccine tailored for 
prepandemic and pandemic approaches against influenza. Expert Opin Biol Ther. 2013; 
13: 121-35. 
European Centre for Disease Prevention and Control. Surveillance of invasive bacterial 
diseases in Europe 2008/2009. Stockholm: ECDC 2011 
European Parliament (1995): Directive 95/46/EC of the European Parliament and of the 
Council of 4 April 2001. Official Journal of the European Communities. L 281/31-39 
European Parliament (2001): Directive 2001/20/EC of the European Parliament and of the 
Council of 4 April 2001. Official Journal of the European Communities. L 121/34-44 
Hellenbrand W, Elias J, Wichmann O et al. Epidemiology of invasive meningococcal 
disease in Germany, 2002-2010, and impact of vaccination with meningococcal C 
conjugate vaccine. Journal of Infection 2013; 66: 48-56. 
ICH (1997) ICH Harmonised Tripartite ICH Guideline for Good Clinical Practices E6  
(R1). Federal Register, 62 (90): 25691-25709 
ICH (1998) ICH Harmonised Tripartite ICH Guideline for Statistical Principles for 
Clinical Trials E9. Federal Register, 63 (179): 49583 
Ilyinskii, PO, et al., Adjuvant-carrying synthetic vaccine particles augment the immune 
response to encapsulated antigen and exhibit strong local immune activation without 
inducing systemic cytokine release. Vaccine, available online 1 March 2014. 

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Khurana, S., W. Chearwae, F. Castellino, J. Manischewitz, L.R. King, A. Honorkiewicz, 
M.T. Rock, K.M. Edwards, G. Del Giudice, R. Rappuoli, and H. Golding. 2010. 
MF59adjuvanted vaccines expand antibody repertoires targeting protective sites of 
pandemic H5N1 influenza virus. Science Transl. Med. 2: 15ra5: 1-8. 
Khurana, S., N. Verma, J.W. Yewdell, A.K. Hilbert, F. Castellino, M. Lattanzi, G. Del 
Giudice, R. Rappuoli, and H. Golding. 2011. MF59 adjuvant affects human epitope 
repertoire, augments affinity maturation, and neutralization titers to pandemic influenza in 
all age groups. Science Transl. Med. 3: 85ra48. 
Levine RJ. (1988) Ethics and Regulations of Clinical Research. New Haven: Yale 
University Press. 
Meyer, T et al., Clinical investigations of Toll-like receptor agonists. Expert Opin Investig 
Drugs 2008, 17:1051-1065. 
Recommendations of the Standing Committee on Vaccination (STIKO) at the Robert  
Koch Institute / Effective: August 2013; Robert Koch Institut Epidemiologisches Bulletin 
34, 26 August 2013 
Reed SG, Orr MT, Fox CB. Key roles of adjuvants in modern vaccines. Nat Med. 
2013;19 :1597-608. 
Regules JA, Cummings, JF and Ockenhouse CF. The RTS, S vaccine candidate for 
malaria. Expert Rev Vaccines 2011; 10:589-599. 
Rosenstein N, Perkins B, Stephens DS, et al. N. Engl. J. Med. 2001; 344: 1378-1388. 
Tacken, PJ et al., Targeted delivery of TLR ligands to human and mouse dendritic cells 
strongly enhances adjuvanticity. Blood 2011, 118:6836-6844. 
Takeda K, Kaisho T, Akira S Toll-like receptors. Annu.Rev.Immunol. 2003; 21: 335-76. 
U.S. Department of Health and Human Services, Food and Drug Administration, CBER 
(2009): Guidance for Industry Patient-Reported Outcome Measures: Use in Medical  
Product Development to Support Labeling Claims 
Vasilakos JP, and Tomai MA. The use of Toll-like receptor 7/8 agonists as vaccine 
adjuvants." Expert Rev Vaccines 2013; 12: 809-819. 
World Medical Association General Assembly Declaration of Helsinki - Ethical  
Principles for Medical Research Involving Human Subjects (1996) 
 

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APPENDIX A: GRADING SCALES FOR SOLICITED LOCAL ADVERSE  
EVENTS* 
(Adapted from CBER 2007b) 
Adverse event Following  
Administration of  
Injectable Product  
Mild (Grade 
1)  
Moderate 
(Grade 2)  
Severe 
(Grade 3)  
Pain 
present but does not 
interfere with activity 
interferes with activity 
prevents daily activity 
Induration / Swelling /  
Erythema 
25 – 50 mm 
51 – 100 mm  
> 100 mm  
*This toxicity grading scale is adapted from CBER 2007 to enable ease of reporting by Subjects in the 
source documents for ‘patient reported’ solicited adverse events.. ‘Grade 4’ is not listed here but will be 
defined in the Statistical Analysis Plan as necessary. 
 

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APPENDIX B: GRADING SCALES FOR SOLICITED SYSTEMIC ADVERSE  
EVENTS* 
(Adapted from CBER 2007b) 
Systemic  
Adverse event 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Fever 
°C 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 - 102 
39.0 – 40 
102.1 - 104 
°F 
Chills 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Loss of Appetite 
Loss of appetite without 
decreased oral intake  
decreased oral intake  
without weight loss 
decreased oral intake with 
weight loss 
Nausea 
Nausea present but not 
interfering with oral intake 
Nausea leading to decreased 
oral intake 
Nausea leading to minimal to 
no oral intake 
Vomiting 
1-2 episodes/24 hours 
>2 episodes/24 hours 
requires outpatient 
hydratation 
Diarrhea 
2-3 loose stools /24 hours 
4-5 loose stools /24 hours 
6 or more watery stools /24 
hours or requires outpatient 
IV hydration 
Generalized  
Myalgia 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Generalized  
Arthralgia 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Headache 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Fatigue 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Generalized  
Rash 
localized area of the skin (1 
extremity only) 
moderate area of the skin 
(2 or more body regions 
without whole body 
involvement) 
most of the skin 
Urticaria 
localized area of the skin (1 
extremity only) 
moderate area of the skin 
(2 or more body regions 
without whole body 
involvement) 
most of the skin 

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*This toxicity grading scale is adapted from CBER 2007b to enable ease of reporting by Subjects in the 
source documents for ‘patient reported’ solicited adverse events. ‘Grade 4’ is not listed here but will be 
defined in the statistical analysis plan as necessary 
APPENDIX C: TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(SERUM CLINICAL CHEMISTRY)  
Serum*,** 
Mild (Grade 1)  
Moderate 
(Grade 2) 
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)*** 
Sodium – Hyponatremia 
mEq/L  
132 – 134  
130 – 131  
125 – 129  
< 125  
Sodium – Hypernatremia 
mEq/L  
144 – 145  
146 – 147  
148 – 150  
> 150  
Potassium – Hypokalemia 
mEq/L  
3.5 – 3.6  
3.3 – 3.4  
3.1 – 3.2  
< 3.1  
Potassium – Hyperkalemia 
mEq/L  
5.1 – 5.2  
5.3 – 5.4  
5.5 – 5.6  
> 5.6  
Blood Urea Nitrogen  
BUN mg/dL  
23 – 26  
27 – 31  
> 31  
Requires dialysis  
Creatinine – mg/dL  
1.5 – 1.7  
1.8 – 2.0  
2.1 – 2.5  
> 2.5 or requires 
dialysis  
Liver Function Tests –ALT,  
AST  
increase by factor  
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN  
5.1 – 10 x ULN  
> 10 x ULN  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 
**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 
***The clinical signs or symptoms associated with laboratory abnormalities might result in characterization 
of the laboratory abnormalities as Potentially Life Threatening (Grade 4). For example. a low sodium value 
that falls within a grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia event if 
the subject had a new seizure associated with the low sodium value. “ULN” = the upper limit of the normal 
range. 
APPENDIX D: TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(HEMATOLOGY) 
Hematology*,** 
Mild (Grade 
1)  
Moderate  
(Grade 2)  
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)  
Hemoglobin (Female) 
gm/dL  
11.0 – 12.0  
9.5 – 10.9  
8.0 – 9.4  
< 8.0  

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Hemoglobin (Female) 
change from baseline 
value - gm/dL  
Any decrease – 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
Hemoglobin (Male) 
gm/dL  
12.5 – 13.5  
10.5 – 12.4  
8.5 – 10.4  
< 8.5  
Hemoglobin (Male) 
change from baseline 
value – gm/dL  
Any decrease – 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
WBC Increase - cell/mm3 
10,800 – 15,000  
15,001 – 20,000  
20,001 – 25, 000  
> 25,000  
WBC Decrease cell/mm3 
2,500 – 3,500  
1,500 – 2,499  
1,000 – 1,499  
< 1,000  
Platelets Decreased 
cell/mm3 
125,000 – 140,000 
100,000 – 124,000 
25,000 – 99,000  
< 25,000  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate.  
**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 
APPENDIX E: TOXICITY SCALES FOR LABORATORY ABNORMALITIES 
(URINE) 
Urine*,** 
Mild (Grade 
1)  
Moderate  
(Grade 2)  
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)  
Protein  
Trace  
1+  
2+  
Hospitalization or 
dialysis  
Glucose  
Trace  
1+  
2+  
Hospitalization for 
hyperglycemia  
Blood (microscopic) – 
red blood cells per high 
power field (rbc/hpf)  
1 - 10  
11 – 50  
> 50 and/or gross 
blood  
Hospitalization or 
packed red blood 
cells (PRBC) 
transfusion  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 
**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 

 
 
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Confidential 
 
GlaxoSmithKline Biologicals  
Clinical Study Protocol V132_01EXP Amendment 4 
11 SEP 15 
Confidential 
Page 1 of 2 
 
CLINICAL STUDY PROTOCOL AMENDMENT 
Study Number: V132_01EXP 
Protocol Title:  A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study 
to Evaluate the Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R 
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium  
Hydroxide Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy 
Adults (18-45 years of age) 
Amendment Number 4 
Revised Protocol version 5.0 issued on 11 SEP 2015 
The present amendment reflects changes to the Protocol version 4.0 issued on 
18JUN15   
Property of GlaxoSmithKline 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of GlaxoSmithKline 

 
 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 
GlaxoSmithKline Biologicals 
Clinical Study Protocol V132_01EXP Amendment 4 
11 SEP 15 
Page 2 of 2 
 
DESCRIPTION OF CHANGE(S) AND RATIONALE: 
CHANGE 
LOCATION(S) OF  
CHANGE 
RATIONALE FOR  
CHANGE 
Deletion of assessment of 
functional antibody 
response from the 
exploratory objectives and 
endpoints                 
Synopsis (Pages 10, 14 and 
17) 
Section 
2.3 
‘Exploratory 
Objectives’ (Page 29) 
Section 7.4 ‘Exploratory 
measurements’ (Pages 73 
and 74) 
Section 8.1.3 ‘Exploratory  
Endpoints’ (Page 76) 
The highly-specialized 
collaborator that was 
anticipated for this 
exploratory endpoint 
expressed it could no longer 
commit to the study 
deliverables for logistic 
reasons.  
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 

 
 
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 Title:  Cluster Physician Date: Monday, 14 September 2015, 09:30   GMT  
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Page 1 of 103 
PRO-01 TEMP 06 / Atlas No. 293620 
Version No. 2 / Version Date: December 2, 2013 
CLINICAL STUDY PROTOCOL V132_01EXP Version 5 
A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study to Evaluate the 
Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R Adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium Hydroxide  
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy Adults (18-45 
years of age) 
EUDRACT No. 2014-002430-31 
Property of GlaxoSmithKline Biologicals S.A. (hereafter referred to as GSK) 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of GSK. 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................ 2 
PROTOCOL SYNOPSIS V132_01EXP.......................................................................... 7 
LIST OF ABBREVIATIONS........................................................................................ 23 
1.0  
BACKGROUND AND RATIONALE............................................................... 25 

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1.1  
Background.................................................................................................... 25 
 
1.2  
Rationale........................................................................................................ 28 
2.0  
OBJECTIVES.................................................................................................... 29 
 
2.1  
Primary Objectives......................................................................................... 29 
 
2.2  
Secondary Objectives..................................................................................... 29 
 
2.3  
Exploratory Objectives................................................................................... 29 
3.0  
STUDY DESIGN .............................................................................................. 31 
 
3.1  
Overview of Study Design............................................................................. 31 
 
3.2  
Study Period .................................................................................................. 32 
 
3.3  
Blinding Procedures....................................................................................... 33 
 
3.4  
Data Collection.............................................................................................. 33 
 
3.4.1  
Data Collected from Subjects ................................................................. 33 
 
3.4.2  
Tools Used for Data Collection .............................................................. 34 
 
3.5  
Collection of Clinical Specimens ................................................................... 35 
 
3.6  
Stopping/Pausing Guidelines.......................................................................... 37 
 
3.7  
Data Monitoring Committee........................................................................... 38 
 
3.8  
Premature Withdrawal from Study................................................................. 39 
 
3.9  
End of Study.................................................................................................. 41 
4.0  
SELECTION OF STUDY POPULATION......................................................... 42 
 
4.1  
Inclusion Criteria ........................................................................................... 42 
 
4.2  
Exclusion Criteria .......................................................................................... 42 
 
4.3  
Criteria for Delay of Vaccination or Blood Draw........................................... 44 
5.0  
STUDY PROCEDURES ................................................................................... 45 
 
5.1  
Pre-vaccination Clinic Visit(s) ....................................................................... 45 
 
5.1.1  
Informed Consent................................................................................... 45 
 
5.1.2  
Screening ............................................................................................... 46 
 
5.2  
Vaccination Clinic Visit(s)............................................................................. 47 

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5.2.1  
Pre-vaccination Procedures..................................................................... 47 
 
5.2.2  
Enrolment .............................................................................................. 48 
 
5.2.3  
Randomization ....................................................................................... 48 
 
5.2.4  
Vaccination............................................................................................ 49 
 
5.2.5  
Post-vaccination Procedures................................................................... 49 
 
5.3  
Post-vaccination Visit(s) ................................................................................ 50 
 
5.3.1  
Subject Diary Reminder, Safety Follow-up and/or Post-vaccination Blood  
Draw Clinic Visits ................................................................................................. 50 
 
5.3.2  
Safety Follow-up Calls........................................................................... 54 
 
5.4  
Unscheduled Visits ........................................................................................ 54 
 
5.5  
Study Termination Visit................................................................................. 55 
 
5.5.1  
Early Termination Visit.......................................................................... 55 
6.0  
TREATMENT OF SUBJECTS.......................................................................... 57 
 
6.1  
Study Vaccine(s)............................................................................................ 57 
 
6.2  
Non-Study Vaccines ...................................................................................... 60 
 
6.3  
Vaccine Preparation and Administration ........................................................ 60 
 
6.4  
Vaccine Administration Error or Overdose of Vaccine................................... 61 
 
6.5  
Prior and Concomitant Medications and Vaccines.......................................... 61 
 
6.6  
Vaccine Supply, Labeling, Storage and Tracking ........................................... 61 
7.0  
ASSESSMENTS................................................................................................ 64 
 
7.1  
Safety Assessment ......................................................................................... 64 
 
7.1.1  
Solicited Adverse Events........................................................................ 64 
 
7.1.2  
Unsolicited Adverse Events.................................................................... 66 
 
7.1.3  
Evaluation of Adverse Events................................................................. 66 
 
7.1.4  
Serious Adverse Events.......................................................................... 67 
 
7.1.4.1  
Adverse Events of Special Interest...................................................... 69 
 
7.1.5  
Methods for Recording Adverse Events and Serious Adverse Events ..... 70 

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7.1.5.1  
Post-Study Events .............................................................................. 71 
 
7.1.6  
Pregnancies............................................................................................ 71 
 
7.1.7  
Safety Laboratory Measurements ........................................................... 71 
 
7.2  
Efficacy Assessment ...................................................................................... 72 
 
7.3  
Immunogenicity Assessment.......................................................................... 72 
 
7.4  
Exploratory Measurements............................................................................. 73 
8.0  
STATISTICAL CONSIDERATIONS................................................................ 75 
 
8.1  
Endpoints....................................................................................................... 75 
 
8.1.1  
Primary Endpoint(s)............................................................................... 75 
 
8.1.1.1  
Primary Safety Endpoint(s) ................................................................ 75 
 
8.1.1.2  
Primary Efficacy Endpoint(s) ............................................................. 75 
 
8.1.1.3  
Primary Immunogenicity Endpoint(s)................................................. 75 
 
8.1.2  
Secondary Endpoint(s) ........................................................................... 75 
 
8.1.2.1  
Secondary Safety Endpoint(s)............................................................. 75 
 
8.1.2.2  
Secondary Efficacy Endpoint(s) ......................................................... 76 
 
8.1.2.3  
Secondary Immunogenicity Endpoint(s)............................................. 76 
 
8.1.3  
Exploratory Endpoint(s)......................................................................... 76 
 
8.2  
Success Criteria ............................................................................................. 77 
 
8.2.1  
Success Criteria for Primary Objective(s)............................................... 77 
 
8.2.2  
Success Criteria for Secondary Objective(s) ........................................... 77 
 
8.3  
Analysis Sets ................................................................................................. 77 
 
8.3.1  
All Enrolled Set...................................................................................... 77 
 
8.3.2  
All Exposed Set...................................................................................... 77 
 
8.3.3  
Safety Set............................................................................................... 77 
 
8.3.4  
Full Analysis Set (FAS) Efficacy/Immunogenicity Set ........................... 78 
 
8.3.5  
Per Protocol (PP) Set Efficacy/Immunogenicity Set................................ 78 
 
8.3.6  
Other Analysis Sets................................................................................ 78 

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8.3.7  
Subgroups.............................................................................................. 79 
 
8.3.8  
Protocol Deviations................................................................................ 79 
 
8.4  
Statistical Analysis Plan................................................................................. 79 
 
8.4.1  
Analysis of Demographic and Baseline Characteristics........................... 79 
 
8.4.2  
Analysis of Primary Objective(s)............................................................ 79 
 
8.4.2.1  
Analysis of Primary Safety Objective(s)............................................. 79 
 
8.4.2.1.1  
Analysis of Extent of Exposure.................................................... 79 
 
8.4.2.1.2  Analysis of Solicited Local, Systemic and Other Adverse Events. 80 
 
8.4.2.1.3  
Analysis of Unsolicited Adverse Events....................................... 80 
 
8.4.2.1.4  
Analysis of Safety Laboratory Values .......................................... 81 
 
8.4.2.2  
Analysis of Primary Efficacy Objective(s).......................................... 82 
 
8.4.2.3  
Analysis of Primary Immunogenicity Objective(s) ............................. 82 
 
8.4.2.3.1  
Statistical Hypotheses .................................................................. 82 
 
8.4.2.3.2  
Analysis Sets................................................................................ 82 
 
8.4.2.3.3 
Statistical Methods....................................................................... 82 
 
8.4.3  
Analysis of Secondary Objective(s)........................................................ 83 
 
8.4.3.1  
Analysis of Secondary Safety Objective(s) ......................................... 83 
 
8.4.3.2  
Analysis of Secondary Efficacy Objective(s)...................................... 83 
 
8.4.3.3  
Analysis of Secondary Immunogenicity Objective(s).......................... 83 
 
8.4.3.3.1  
Statistical Hypotheses .................................................................. 83 
 
8.4.3.3.2  
Analysis Sets................................................................................ 83 
 
8.4.3.3.3  
Statistical Methods....................................................................... 84 
 
8.4.4  
Analysis of Exploratory Objectives ........................................................ 84 
 
8.5  
Sample Size and Power Considerations of Primary Objectives....................... 84 
 
8.6  
Interim Analysis............................................................................................. 85 
9.0  
SOURCE DOCUMENTATION, STUDY MONITORING AND AUDITING... 87 
 
9.1  
Source Documentation................................................................................... 87 

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9.2  
Study Monitoring, Auditing and Source Data Verification ............................. 88 
10.0  
DATA MANAGEMENT................................................................................... 89 
 
10.1  
Data Entry and Management.......................................................................... 89 
 
10.2  
Data Clarification........................................................................................... 89 
 
10.3  
Data Protection .............................................................................................. 89 
11.0  
RECORD RETENTION.................................................................................... 91 
12.0  
USE OF INFORMATION AND PUBLICATION ............................................. 92 
13.0  
ETHICS............................................................................................................. 93 
 
13.1  
Regulatory and Ethical Compliance ............................................................... 93 
 
13.2  
Informed Consent Procedures ........................................................................ 93 
 
13.3  
Responsibilities of the Investigator and IRB/EC............................................. 94 
 
13.4  
Protocol Amendments.................................................................................... 95 
14.0  
REFERENCE LIST........................................................................................... 96 
APPENDIX A:  
GRADING SCALES FOR SOLICITED LOCAL ADVERSE  
EVENTS* 
99 
APPENDIX B:  
GRADING SCALES FOR SOLICITED SYSTEMIC ADVERSE  
EVENTS* 
100 
APPENDIX C:  
TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(SERUM CLINICAL CHEMISTRY).......................................................................... 101 
APPENDIX D: TOXICITY SCALES FOR LABORATORY ABNORMALITIES 
(HEMATOLOGY) 102 
APPENDIX E:  
TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(URINE) 
103 
PROTOCOL SYNOPSIS V132_01EXP 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Title of Study: A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study to  
Evaluate the Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R 
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium  
Hydroxide Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy Adults 
(18-45 years of age) 
Study Period: Approximately 12 months for 
each subject 
Clinical Phase: Phase 1 
Background and Rationale: 
Neisseria meningitidis (N. meningitides)serogroup C (MenC) is one of the major 
serogroups causing invasive meningocococcal disease. Case fatality in Germany has 
ranged between 6% and 8% between 1999 and 2006, and has remained generally 
consistent across the different European countries, varying between 6-11%, with the case 
fatality rate being notably higher for serogroup C disease than for serogroup B. The 
safety and immunogenicity of the GSK Meningococcal C-CRM197 Conjugate Vaccine 
(Menjugate®) has been confirmed through years of commercial use. For children over 
the age of 12 months, for adolescents and for adults a single dose is recommended. For 
infants between 2 and 12 months of age, the recommended schedule for primary 
immunization with the Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) is 
two doses given with an interval of at least 2 months A more potent Meningococcal 
CCRM197 Conjugate Vaccine formulation might enable a reduction of the antigen dosage 
and/or a reduction in the number of doses needed in infants. One approach to achieve 
more potent well-characterized sub-unit vaccines - like the Meningococcal C-CRM197 
Conjugate Vaccine - is the use of new adjuvants that activate the Toll-like receptor 
(TLR) pathway. 
GSK is developing a small molecule immune potentiator (SMIP) LHD153 that is an 
agonist for TLR7. The objective driving the development of LHD153 is to achieve a 
vaccine adjuvant with strong immunopotentiating properties and minimal side effects. In 
line with this objective, it has been postulated that the ideal SMIP should remain local 

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and target innate immune cells at the injection site. To this end, LHD153 contains a 
functional phosphonate group to allow for adsorption to aluminium hydroxide. The  
 
Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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arginine salt derivative of this compound is LHD153R. Preclinical results from animal 
models for bacterial and viral antigens, including MenC, MenB, rabies, HIV and 
respiratory syncytial virus (RSV) showed increased functional antibodies and 
antigenspecific T-cells with LHD153R adsorbed to aluminium hydroxide (Aluminium  
Hydroxide/LHD153R) when compared to aluminium hydroxide adjuvanted controls. In 
vitro toxicity screens confirmed that LHD153R is not phototoxic, genotoxic or 
mutagenic. Furthermore, toxicology studies in dog and rats showed that intramuscular 
(IM) injection of Aluminium Hydroxide/LHD153R was well tolerated. Importantly, in 
contrast to free LHD153R, toxicokinetic analysis in rats and dogs confirmed very 
limited exposure of LHD153 when LHD153R was adsorbed to aluminium hydroxide 
after IM injection. 
The aim of this Phase 1 clinical study is to assess the safety of Aluminium  
Hydroxide/LHD153R adjuvanted MenC-CRM197 conjugate vaccine 
(MenCCRM197/Aluminium Hydroxide/LHD153R) and to compare the antibody-
mediated immune response elicited by MenC-CRM197/Aluminium Hydroxide/LHD153R 
with the licensed aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate 
Vaccine (Menjugate®). Furthermore, a comprehensive set of exploratory objectives has 
been selected to assess the systemic exposure of LHD153 after intramuscular injection of 
MenC-CRM197/Aluminium Hydroxide/LHD153R, to evaluate the quality of the specific 
immune response against MenC-CRM197 in detail and to evaluate biomarkers that may 
be predictive of safety and/or innate immune activation. 
The licensed Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) has been 
selected as the primary vaccine candidate to assess the safety and immunopotentiating 
properties of Aluminium Hydroxide/LHD153R for several reasons. Firstly, the safety 
and immunogenicity profiles of the Meningococcal C-CRM197 Conjugate Vaccine 
(Menjugate®) have been well established through years of commercial use. Secondly, a 
more potent MenC-CRM197 conjugate vaccine might enable a reduction of the antigen 
dosage or the number of doses needed in infants. Finally, MenC-CRM197 is a 
wellcharacterized, single conjugate antigen preparation which provides an ideal setting 
to evaluate the potential of this new Aluminium Hydroxide/LHD153R adjuvant. 
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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Study Objectives: 
Primary Safety Objective: 
To assess the safety of MenC-CRM197/Aluminium Hydroxide/LHD153R as compared to 
that of aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
Primary Immunogenicity Objective: 
To compare the antibody responses of MenC-CRM197/Aluminium Hydroxide/LHD153R 
and aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at 
Day 29, as measured by human complement serum bactericidal assay (hSBA) directed 
against MenC. 
Secondary Immunogenicity Objectives: 
1. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine, at Day 8 and Day 181 after vaccination, as measured 
by hSBA directed against MenC. Baseline antibody titers will also be measured by 
hSBA. 
2. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine at Day 8, Day 29 and Day 181 after vaccination, as 
measured by an enzyme-linked immunosorbent assay (ELISA) to MenC. Baseline 
antibody concentrations will also be measured by ELISA. 
Exploratory Objectives: 
1. To evaluate the systemic exposure of LHD153 at several early time-points after IM 
injection of MenC-CRM197/Aluminium Hydroxide/LHD153R or aluminium 
hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
2. To explore the frequency of B cells specific for MenC polysaccharide and CRM197 
protein at baseline (Day 1) and at Day 8, Day 29 and Day 181 after vaccination with  
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
MenC-CRM197/Aluminium Hydroxide/LHD153R or the aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. Subsequently, the B cell 
repertoire of the antigen specific B cells will be analyzed in a selected subset of 
subjects. 
3. To explore the baseline T cell mediated immunity to CRM197 and to evaluate the 
frequency and quality of CRM197 specific T cells induced by MenC- 
CRM197/Aluminium Hydroxide/ LHD153R compared to aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at Day 8 and Day 29. 
4. To evaluate biomarkers that may be predictive for safety and/or innate immune 
activation. 

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Study Design: 
This Phase 1, randomized, observer-blind, dosage-escalation study will be performed at 
a single center. In total, approximately 80 healthy male and healthy non-pregnant female 
adults (18-45 years of age) will be enrolled in the study. Subjects will be randomized to 
receive a single IM vaccination of either the licensed aluminium hydroxide adjuvanted 
Meningococcal C-CRM197 Conjugate Vaccine (i.e. 10 µg MenC conjugated to CRM197,  
adjuvanted with 1 mg aluminium hydroxide) or one of four dosages of the 
investigational vaccine, MenC-CRM197/Aluminium Hydroxide/LHD153R (i.e. 10 µg 
MenC conjugated to CRM197, adjuvanted with 1 mg aluminium hydroxide and one of 
four dosages [12.5, 25, 50 or 100 µg] of LHD153R). 
For the dosage-escalation of LHD153R, the subjects will be enrolled into 1 of 4 cohorts, 
in a stepwise manner with 20 subjects per cohort. Subjects in all cohorts will be 
randomized in a 1:4 ratio, to receive either aluminium hydroxide adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine (control) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R with increasing doses of LHD153R.Cohort 1 will receive 12.5 μg 
of LHD153R; Cohort 2 will receive 25 μg of LHD153R; Cohort 3 will receive 50 μg of 
LHD 153; and Cohort 4 will receive 100 μg of LHD153R (Table 1). 
 
Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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 Table 1: 
Subjects Randomized per Cohort and Treatment Dosage Group 
Cohort 
Group 
Subjects/ 
Group 
MenC  
Dosage*  
(µg) 
Adjuvant Dosages  
Total 
Volume/Dose 
Total 
Subjects/Cohort 
Aluminium  
Hydroxide  
(mg) 
LHD153R  
(µg) 
1 
A 
4 
10 
1 
0 
0.5 mL 
20 
 
 
 
 
 
 
 
B 
16 
10 
1 
12.5 
0.5 mL 
 
2 
A 
4 
10 
1 
0 
0.5 mL 
20 
C 
16 
10 
1 
25 
0.5 mL 
3 
A 
4 
10 
1 
0 
0.5 mL 
20 
D 
16 
10 
1 
50 
0.5 mL 
4 
A 
4 
10 
1 
0 
0.5 mL 
20 
E 
16 
10 
1 
100 
0.5 mL 
*Conjugated to 12.5-25 µg CRM197 
After vaccination, all subjects will be confined to the clinical site for 24 hours for clinical 
observation, including but not limited to observations for solicited and unsolicited 
adverse events, body temperature measurements and blood sampling for exploratory 
endpoint measurements. 
Importantly, all cohorts will have a staggered entry based on Data Monitoring 
Committee (DMC) reviews. 
▫ For each cohort, the first 5 subjects (i.e. the first 1:4 randomization block) to receive 
either aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate 
Vaccine (n=1) or MenC-CRM197/Aluminium Hydroxide/LHD153R (n=4) will be 
treated at a vaccination rate of 1 subject each day. 
▫ After entry of the first 5 subjects in each cohort, the enrollment will be paused. The 
remaining 15 subjects for each cohort will be enrolled only after DMC review of the 
safety results obtained through Day 14 has been finalized (Table 2). 
▫ In addition, enrollment of the first 5 subjects in the next cohort will only proceed after 
the Day 14 safety results of the first 5 subjects of the previous cohort have been 
reviewed by the DMC (Table 2). 
▫ Furthermore, all available Day 14 and Day 29 safety results will be included in DMC 
reviews between the different enrollment stages. 
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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 Table 2: 
Overview of staggered entry of subjects based on DMC reviews 
Stage 
Dosage Cohort 
MenC-CRM197/ 
Aluminium Hydroxide (n) 
MenC-CRM197/ 
Aluminium Hydroxide 
/LHD153R (n) 
1   
1  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 14 Safety Results 
2 
1  
3 
12 
2  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 29 and Stage 2 Day 14 Safety Results 
3 
2  
3 
12 
3  
1 
4 
Enrollment pause until DMC review of Stage 2 Day 29 and Stage 3 Day 14 Safety Results 
4 
3  
3 
12 
4  
1 
4 
Enrollment pause until DMC review of Stage 3 Day 29 and Stage 4 Day 14 Safety Results 
5 
4  
3 
12 
The DMC review will be performed according to predefined stopping/pausing guidelines 
used to ensure the safety of study subjects. These stopping/pausing guidelines are based 
on FDA guidance and with grading scales from the CBER Guidance for Industry 
“Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials”. See protocol section 3.6 for further details. 
Safety Measurements 
Schedule of safety data collection: 
▫ Solicited local and systemic adverse events (AEs), body temperature and all 
unsolicited AEs will be collected until Day 14. 
▫ All serious adverse events (SAEs), medically attended AEs, AEs leading to study 
withdrawal, new onset of chronic disease (NOCDs), and adverse events of special 
interest (AESIs) will be collected from the date of signed informed consent to study 
completion at Day 366. 
▫ All concomitant medications administered in relation to the reported AEs will be  
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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collected from vaccination to study completion at Day 366. 
Solicited local AEs include injection site erythema, injection site induration, injection 
site pain and injection site swelling. Solicited systemic AEs include body temperature ≥ 
38.0°C (as measured orally), loss of appetite, nausea, fatigue, generalized myalgia, 
generalized arthralgia, headache, chills, vomiting, diarrhea, generalized rash and 
urticaria. 
All AESIs will be reported in the same manner as SAEs. All AEs will be monitored until 
resolution or, if the AE becomes chronic, a cause is identified. If an AE is unresolved at 
the conclusion of the study, a clinical assessment will be made by the investigator and 
the medical monitor to determine whether or not continued follow-up of the AE is 
warranted. 
The relationship of the study treatment to any AE will be determined by the investigator 
as probably related, possibly related, or not related; the relationship of the study 
treatment to any SAE will be determined by the investigator as probably 
related/suspected, or not related. 
Safety Laboratory Parameters 
To assess laboratory AEs, blood and urine samples will be collected from each subject as 
outlined in Table 3 to perform blood chemistry, hematology, and urine analyses. 
Safety laboratory samples will be drawn from all subjects at pre-vaccination screening 
(between Day -28 and Day -3) at Day 1 (pre-vaccination and 24h after vaccination), at 
Day 8 and at Day 29. Safety laboratory assessments will include sodium, potassium, 
chloride, bicarbonate, blood urea nitrogen, creatinine, liver function tests (ALT, AST), a 
complete blood count and C-reactive protein. A urine sample will be collected at the 
same time-points and will be assessed for the presence of protein, glucose and red blood 
cells. 
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Primary and Secondary Immunogenicity Measurements 
Four blood samples per subject (i.e. at Day 1, Day 8, Day 29 and Day 181) will be 
collected for serum preparation and determination of antibody-mediated immune 
responses to MenC-CRM197 as outlined in Table 3 and Table 4. See section 7.3 for 
further details. 
Exploratory Measurements 
In all subjects who agree by signing a separate Informed Consent, additional blood 
samples will be collected at Day 1, Day 4, Day 8, Day 29 and Day 181 for exploratory 
assays as outlined in Table 3 and Table 4. The purpose of these assays is to assess the 
systemic exposure of LHD153, to determine the frequency and quality of B- and T-cells 
specific for MenC polysaccharide and/or CRM197 and to evaluate biomarkers that may 
be predictive of safety and/or innate immune activation. Subsequently, MenC-CRM197 
specific B-cell repertoires will be analyzed in a selected subset of subjects, dependent on 
the results from primary and secondary immunogenicity measurements and the volume 
of  blood  remaining for additional testing. See section 7.4 for further details. All 
exploratory analyses may be performed after the Clinical Study Report (CSR) has been 
completed, in which case these data will be submitted as an addendum to the CSR. 
Number of Subjects planned: 
Approximately 80 adult subjects will be randomized, with anticipated dropout rates of 
5% by Day 181 (last serology time point), and 10%, by Day 366 (last safety time point). 
Sample size is not driven by statistical assumptions for formal hypothesis testing, but the 
proposed number of subjects will be sufficient to provide a descriptive summary of the 
safety and immunogenicity of the study vaccine. 
Study Population and Subject Characteristics: 
Healthy adult male and female volunteers between 18-45 years of age, inclusive. 
The list of inclusion and exclusion criteria is included in protocol section 4.0. 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Study Vaccines: 
The MenC-CRM197 conjugate is a lyophilized powder consisting of 10 µg of MenC 
polysaccharide conjugated to 12.5-25 µg CRM197 carrier protein. The MenC-CRM197 
lyophilized powder will be reconstituted with adjuvant by the unblinded designated site 
staff member who is to follow the procedure as described in the vaccine preparation 
instructions in the Investigator Site File (i.e. the vaccine will be prepared in the clinic 
prior to administration). 
The lyophilized MenC-CRM197 powder will be reconstituted with either: 
(a) aluminium hydroxide adjuvant 
(b) Aluminium Hydroxide/LHD153R adjuvant with specified dosages of LHD153R 
(12.5, 25, 50 or 100 µg) 
The components for each formulation of MenC-CRM197 will be provided in a separate 
kit. 
Aluminium Hydroxide/LHD153R with specified dosages of LHD153R will be prepared  
by dilution of the highest Aluminium Hydroxide/LHD153R dosage (100 µg of 
LHD153R) with aluminium hydroxide. 
In each cohort, subjects will be randomized to receive one injection of MenC- 
CRM197/Aluminium Hydroxide/LHD153R adjuvant or aluminium hydroxide adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine. The 0.5 mL of vaccine will be injected 
IM in the deltoid muscle, with preference that the injection is administered in the 
nondominant arm. 

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Primary Safety Endpoint: 
Safety will be assessed by measuring the frequency of local and systemic solicited AEs, 
unsolicited AEs, SAEs, AESIs, NOCDs, and safety laboratory data for all subjects.  
Specifically, 
▫ The frequency and percentage of subjects with solicited local and systemic AEs 
through Day 14. Time intervals after vaccination that will be summarized are: 30  
 
Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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min post-vaccination, Days 1-4 (without 30 min), Days 5-8, Days 8-14, Days 1-8 
(without 30 min) and Days 1-14 (without 30 min). 
▫ The frequency and percentage of subjects with any unsolicited AEs from the day of 
vaccination (Day 1) to Day 14. 
▫ The frequency and percentage of subjects with SAEs, medically attended AEs,  AEs 
leading to study withdrawal, NOCDs, AESIs for the following time periods: day of 
signed informed consent until study completion (Day 366), day of vaccination (Day 
1) to Day 29 and Day 29 to study completion (Day 366). 
▫ The absolute values and changes in hematology, chemistry, and urinalysis parameters. 
▫ The frequency and percentage of subjects with abnormal laboratory parameter values 
as classified by investigator normal ranges (low, normal, high) and as classified by 
CBER toxicity grading scales, when available. 
Primary Immunogenicity Endpoint: 
Geometric mean titers (GMTs) measured by hSBA directed against MenC from samples 
collected on Day 1 (baseline, before vaccination) and Day 29 as well as the GMR of the 
titers (Day 29 / Day 1). 
Secondary Immunogenicity Endpoints: 
▫ GMTs and corresponding GMRs measured by hSBA directed against MenC for samples 
collected at Day 8 and Day181. 
▫ Percentage of subjects with hSBA seroresponse at Day 8, Day 29, and Day 181. 
seroresponse is defined as a post vaccination hSBA ≥8 for subjects with a baseline 
hSBA <4 or have an increase of at least 4 times the baseline hSBA level for subjects 
with pre-vaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against MenC measured by ELISA 
for samples collected on Day 1 (baseline, prior to vaccination), Day 8, Day 29, and 
Day 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations  
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
to MenC measured by ELISA on Day 8, Day 29, and Day 181 relative to baseline (Day 
1). 
Exploratory Endpoints: 
Testing and analyses of exploratory endpoints may be performed after the Clinical Study 
Report (CSR) has been completed, in which case these data will be submitted as an 
addendum to the CSR. 
1. Serum concentration of LHD153 at Day 1 baseline (prior to vaccination), Day 1 (1h , 
2h, 4h, 8h, and 24h after vaccination) and Day 4 by LC-MS/MS. 
2. Frequency of MenC polysaccharide-specific and CRM197-specific B cells at Day 1 
(baseline), Day 8, Day 29, and Day 181 by ELISPOT. 
3. Diversity of the MenC polysaccharide-specific B-cell repertoire at Day 1 (baseline), 
Day 8, Day 29, and Day 181 by immunoglobulin cDNA sequencing. 
4. Frequency and quality of T cells specific for CRM197 at Day 1 (baseline), Day 8, and 
Day 29 by flow cytometry using intracellular staining with a panel of cytokines and 
staining of surface markers to identify cell populations. 
5. Serum concentrations of a panel of 30 chemokines and cytokines at Day 1 baseline 
(prior to vaccination), Day 1 (6h and 24h after vaccination), Day 4, and Day 8 by 
electrochemo-luminescence based assay. 
6. Gene expression profile in whole blood at Day 1 baseline (prior to vaccination), Day 
1 (6h and 24h after vaccination), Day 4, and Day 8 by RNA micro array analysis. 
7. Number and activation status of myeloid and lymphoid cell populations at Day 1 
baseline (prior to vaccination), Day 1 (24h after vaccination), Day 4 and Day 8 by 
flow cytometry. 

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Statistical Analyses: 
The study is exploratory in nature, thus analyses will be descriptive and no formal 
hypothesis testing will be performed. 
Primary Safety Analyses 
 
Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
The primary safety analyses will be based on the safety set for solicited and unsolicited 
adverse events. There is no statistical null hypothesis associated with the safety 
objective, which will be analyzed descriptively. 
Immunogenicity Analyses 
The primary immunogenicity analyses will be based on the per-protocol set (PPS) on 
Day 29. The primary analyses will also be performed using the Full Analysis Set (FAS) 
as a measure of the sensitivity/robustness of the results. All other immunogenicity 
assessments will be performed using the PPS or the appropriate subset of subjects. The 
antibody concentrations/titers will be summarized using GMC/GMTs and two-sided 
95% confidence intervals (CIs) constructed by exponentiation (base 10) of the least 
square means of the logarithmically transformed (base 10) antibody titer. The 95% CIs 
will be obtained from an analysis of covariance (ANCOVA) with baseline 
concentration/titer as a covariate. Additional details will be further described in the 
Statistical Analysis Plan. 
The immunogenicity endpoints based on subjects meeting criteria for seroconversion or 
achieving a certain threshold value will be summarized using frequencies and 
percentages and associated two-sided 95% Clopper-Pearson CIs. For analyses of 
seroconversion, separate summaries may be provided based on seropositivity status at 
baseline. 

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Interim Analysis: 
An Interim Analysis will be performed on the immunogenicity and safety data collected 
from all subjects until Day 29, after all cohorts have been enrolled. Further details 
regarding the interim analysis are contained in section 8.6. 
Data Monitoring Committee: 
A DMC will be implemented to review safety data during scheduled periodic reviews. 
The DMC will review safety data collected until Day 14, as described in the DMC 
charter and in the Statistical Analysis Plan, after enrollment of the first 5 subjects in each 
cohort, before proceeding with enrollment of the remaining 15 subjects in each cohort.  
 
Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
In addition, enrollment of the first 5 subjects of the next cohort will only proceed after 
the Day 14 safety results of the first 5 subjects of the previous cohort have been 
reviewed. Furthermore, all available Day 14 and Day 29 safety results will be included 
in DMC reviews between the different enrollment stages. Further information regarding 
the DMC is discussed in more detail in the protocol, section 3.7. 

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Table 3: 
Time and Events Table – Treatment Period (until Day 29) 
 
Visit Type 
Clinic Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
 
Study Day 
-28 to -3 
1 
4 
8 
15 
22 
29 
 
Visit Window (Days) 
n/a 
n/a 
n/a 
-1/+1 
+1 
n/a 
-2/+2 
 
Visit Number 
Screening  
1 
2 
3 
4 
5 
6 
Study Event 
References 
 
 
 
 
 
 
 
Study Treatment 
 
 
 
 
 
 
 
 
Vaccination 
Section 5.2 
 
X 
 
 
 
 
 
Screening and Safety 
 
 
 
 
 
 
 
 
Informed Consent  
Section 5.1.1 
X 
 
 
 
 
 
 
Demographic Data & Medical History 
Sections 5.1.2 
X 
 
 
 
 
 
 
Physical Exam 
Sections 5.1.2 and 5.2.1 
X 
Xa 
 
 
 
 
 
Safety Laboratory blood draw (10 ml) 
Section 7.1.7 
X 
Xb 
 
X 
 
 
X 
Urinalysis 
Sections 7.1.7 
X 
Xb 
 
X 
 
 
X 
Pregnancy Test 
Sections 5.1.2 and 5.2.1 
X 
Xa 
 
 
 
 
 
Exclusion/Inclusion Criteria 
Section 4.0 
X 
Xa 
 
 
 
 
 
Randomization 
Section 5.2.3 
 
Xa 
 
 
 
 
 
30 min and 24 hr Post Injection Assessment 
Section 5.2.5 
 
Xc 
 
 
 
 
 
Subject Diary Dispensed with Training 
Section 5.2.5 
 
X 
 
 
 
 
 
Subject Diary Reminder 
Section 5.2.5 
 
 
X 
X 
 
 
 

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Subject Diary Reviewed and Collected 
Section 5.3.1 
 
 
 
 
X 
 
 
Assess all solicited AEs 
Section 7.1.1 and 7.1.3 
 
 
 
 
X 
 
 
Assess all unsolicited AEs 
Sections 7.1.2 and 7.1.3 
X 
X 
X 
X 
X 
 
 
PRO-01 TEMP 06 / Atlas No. 293620 
Visit Type 
Clinic Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Study Day 
-28 to -3 
1 
4 
8 
15 
22 
29 
Visit Window (Days) 
n/a 
n/a 
n/a 
-1/+1 
+1 
n/a 
-2/+2 
Visit Number 
Screening  
1 
2 
3 
4 
5 
6 
Study Event 
References 
Assess SAEs 
Section 7.1.4 
X 
X 
X 
X 
X 
X 
X 
Assess AESIs 
Section 7.1.4.1 
X 
X 
X 
X 
X 
X 
X 
Assess NOCDs, medically attended AEs, AEs 
leading to withdrawal  
Sections 7.1.3 
X 
X 
X 
X 
X 
X 
X 
Assess relevant medications 
Sections 5.1.2 and 6.5 
X 
X 
X 
X 
X 
X 
X 
Blood draws for Immunogenicity and Exploratory Objectives 
Serum Blood Draws (Primary/Secondary Objectives; 10 mL)  
Section 3.5 
Xa 
X 
X 
Serum Blood Draws (Exploratory Objectives; 5 mL)  
Section 3.5 
Xd 
X 
X 
Whole Blood Draws (Exploratory Objectives; 3 mL) 
Section 3.5 
Xe 
X 
Whole Blood Draws (Exploratory Objectives; 5 mL) 
Section 3.5 
Xf 
X 
X 
Whole Blood Draws (Exploratory Objectives; 20 mL) 
Section 3.5 
Xg 
X 
Whole Blood Draws (Exploratory Objectives; 50 mL) 
Section 3.5 
X 

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Whole Blood Draws (Exploratory Objectives; 70 mL) 
Section 3.5 
Xa 
X 
Notes: 
a. 
Procedure must be performed prior to vaccination. 
b. 
Two blood draws (2 x 10 ml) and two urine samples must be taken at Study Day 1, i.e. at baseline (prior to vaccination) and at 24h after 
vaccinati 
c. 
Body temperature measurement must be performed at 30 min, 2, 4, 6, 8, 10, 12, 18 and 24h after vaccination. 
d. 
Three Serum Blood Draws (3 x 5ml) must be taken at Study Day 1, i.e. at baseline (prior to vaccination), at 6h and at 24h after vaccination. 
e. 
Six Whole Blood Draws (6 x 3 mL) must be taken at Study Day 1, i.e. at baseline (prior to vaccination) and at 1, 2, 4, 8 and 24h after 
vaccination. 
f. 
Three Whole Blood Draws (3 x 5 mL) must be taken at Study Day 1, i.e. at baseline (prior to vaccination), at 6h and at 24h after vaccination. 
g. Whole Blood Draw (20 mL) at Study Day 1 must be taken at 24h after vaccination. 
on. 
PRO-01 TEMP 06 / Atlas No. 293620 
Table 4: 
Time and Events Table – Follow-up Period (until Day 366) 
Visit Type 
Clinic Visit 
Clinic Visit 
Clinic Visit 
Phone Call 
Phone Call 
Clinic Visit 
Study Day 
85 
113 
181 
209 
271 
366 
Visit Window (Days) 
-7 to +7 
-7 to +7 
-7 to +7 
-14 to +14 
-14 to +14 
-14 to +14 
Visit Number 
7 
8 
9 
10 
11 
12 
Study Event 
References 
 
 
Safety 
 
Assess SAEs 
Section 7.1.4 
X 
X 
X 
X 
X 
X 
Assess AESI 
Section 7.1.4.1 
X 
X 
X 
X 
X 
X 
Assess NOCDs, medically attended 
AEs, AEs leading to withdrawal 
Sections 7.1.3 
X 
X 
X 
X 
X 
X 
Assess relevant medications 
Sections 5.1.2 and 6.5 
X 
X 
X 
X 
X 
X 
Blood draws for Immunogenicity and Exploratory Objectives 
 

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Serum Blood Draw (Secondary 
Objective; 10 mL) 
Section 3.5 
 
 
X 
 
 
 
Whole Blood Draw  
(Exploratory Objectives; 50 mL) 
Section 3.5 
 
 
X 
 
 
 
Study Completion Procedures 
 
Study Terminationa 
Section 5.5 
 
 
 
 
 
X 
Notes: 
a. Subjects who terminate the study early are recommended to complete certain study-related procedures. See section 5.5 for further details. 
 
PRO-01 TEMP 06 / Atlas No. 293620 

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LIST OF ABBREVIATIONS 
ADCC 
Antibody-dependent cell mediated cytotoxicity 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BZN 
Benzonaphthyridines 
CBER 
Center for Biologics Evaluation and Research 
cDNA 
Complementary deoxyribonucleic acid 
CI 
Confidence interval 
CRF 
Case report form 
CRM197 
Cross Reacting Material 197 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
EC 
Ethics committee 
EDC 
Electronic data capture 
ELISA 
Enzyme-linked immunosorbent assay 
ELISPOT 
Enzyme-Linked ImmunoSpot 
EMA 
European Medicines Agency 
FACS 
Fluorescence-activated cell sorting 
FAS 
Full analysis set 
FDA 
Federal Drug Agency 
GCP 
Good clinical practice 
GMC 
Geometric mean concentration 
GMP 
Good manufacturing practice 

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GMT 
Geometric mean titer 
GMR 
Geometric mean ratio 
HEENT  
Head, ears, eyes, nose and throat 
HIV 
Human immunodeficiency virus 
 
HPV 
Human papillomavirus 
hSBA 
Human complement serum bactericidal assay 
ICF 
Informed consent form 
ICH 
International Committee for Harmonization 
IM 
Intramuscular 
IRB 
Institutional review board 
IV 
Intravenous 
LLQ 
Lower limit of quantification 
MenC 
Meningococcal type C 
MPL 
Monophosphoryl lipid A 
NCR 
No carbon required 
NOCD 
New Onset of Chronic Disease 
PEG 
Polyethylene glycol 
PO 
Per oral 
PP 
Per protocol 
RNA 
Ribonucleic acid (RNA 
SAE 
Serious Adverse Event 
SMIP 
Small molecule immune potentiator 
TLR 
Toll-like receptor 
VSAE 
Vaccine serious adverse event 
1.0  
BACKGROUND AND RATIONALE 
1.1  
Background 

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MenC-CRM197 Conjugate Vaccine 
Meningococcal disease worldwide is predominantly a disease of infants and young 
children. N. meningitidis serogroup B and C remain the most prevalent strains in North 
America and Europe, (Rosenstein, N. et al., 2001) and together cause more than 95% of 
reported cases of meningococcal disease in Europe (Connolly, M, et al., 1999). In Europe, 
N. meningitidis serogroup C (MenC) is one of the major serogroups causing invasive 
disease. Case fatality in Germany has ranged between 6% and 8% between 1999 and 
2006, and has remained generally consistent across the different European countries, 
varying between 6-11%, with the case fatality rate being notably higher for serogroup C 
disease than for serogroup B (European Centre for Disease Prevention and Control, 
2011). Since MenC vaccination was added to Germany’s routine schedule for children in 
2006, there has been a reported decline in MenC incidence. However, the decline was not 
as rapid when compared to other European countries (Hellenbrand, W. et al., 2013). 
The GSK Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) comprises MenC 
oligosaccharides conjugated to the protein carrier, CRM197, a nontoxic mutant of 
diphtheria toxin. The vaccine has been shown to be safe and immunogenic and able to 
prime infants, toddlers and young children for immunological memory (see 
Meningococcal C-CRM197 Conjugate Vaccine Summary of Product Characteristics).  
In Germany, the Standing Committee on Vaccination (STIKO) of the Robert Koch  
Institute recommends a single dose of MenC conjugate vaccine in children over the age of  
12 months as part of the routine vaccination campaign (Robert Koch Institute 
Epidemiologisches Bulletin, August 2013). For specific indications, e.g. in case of 
postexposure prophylaxis, the recommended schedule for primary immunization of 
infants between 2 to 12 months of age with a MenC conjugate vaccine is two dosages 
given with an interval of at least 2 months. 
Although the Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) represents an 
example of how vaccination with a well characterized, purified polysaccharide antigen 
can yield pivotal public health triumphs, there remains a need for further improvement of 
the MenC vaccine. A more potent MenC vaccine formulation might yield an increase in 
the magnitude of the antigen-specific immune response enabling a reduction of the 
antigen dosage. Furthermore, induction of a more rapid antigen-specific immune response 
may enable a reduction in the number of doses needed for post-exposure prophylaxis in 
infants. 

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Vaccine Adjuvants 
Immunization with purified protein or polysaccharide antigens typically results in the 
induction of a modest antibody response with little or no T cell response when compared 
to vaccines comprised of whole or killed bacteria or viruses that have inherent 
immunepotentiating activity. The need to increase the immunogenic response of 
wellcharacterized and purified antigens that display suboptimal immunogenicity when 
used alone affirms the essential role for the use of adjuvants. Vaccine adjuvants may 
significantly reduce the amount of antigen needed (Del Giudice, G, et al., 2013) and may 
induce a more rapid immune response enabling a reduction in the number of doses in a 
regimen. 
Besides reducing the antigen dosage or number of doses in the vaccine regimen, there is 
now an increased appreciation of the capacity of adjuvants to increase not just overall 
antibody titer but also to increase the number of functional antibodies and/or antibodies 
with higher affinity for vaccine antigens. Many pathogens, such as influenza viruses, 
HIV, human papilloma virus (HPV) and the malaria parasite, display substantial antigenic 
drift, subtype and/or strain variations. Therefore, the ability of adjuvants to broaden an 
immune response profile could be crucial to the success of vaccines against such targets. 
Previous studies have shown that the broadening effect of adjuvants may be mediated via 
expansion of B cell diversity, not merely through increased titers (Khurana, et al., 2010, 
2011). Clinically, antibody response broadening by adjuvants such as AS04 or oil-inwater 
emulsions has been demonstrated in HPV vaccines and influenza, respectively (Bissett, 
SL et al., 2014; Del Giudice, G et al., 2013). 
One unmet need is the development of vaccines for effective T cell responses. Several 
vaccines in development are aimed at eliciting T cell responses, which historically have 
not been induced by the most commonly used adjuvants in vaccines for human use, such 
as aluminium hydroxide. Therefore, an objective of many adjuvant discovery and 
development programs is to elicit more effective engagement of T-helper cells for 
optimizing the quality, breadth and durability of antibody responses, or, to induce effector 
CD4+ or CD8+ T cells to kill intracellular pathogens. One approach for new generation 
vaccines is the use of agonists for Toll-like receptors (TLRs) that activate innate immune 
receptors, mainly on antigen presenting cells, and facilitate the generation of T helper cell 
responses. 
Adjuvants that are currently employed in human vaccines licensed for use in the USA 
and/or Europe include aluminium salts, oil-in-water emulsions (MF59, AS03 and AF03), 
virosomes, and AS04 (Alving, CR, et al., 2012). Among the most advanced adjuvants 
systems is AS04 which is used in the Cervarix® HPV vaccine and consist of the TLR4 
ligand monophosphoryl lipid A (MPL) combined with aluminium salt. MPL, along with 

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QS21, is also part of the adjuvant system (AS01) in the RTS, S malaria vaccine which has 
been evaluated in a Phase 3 clinical trial (Regules, JA, et al., 2011). Another clinically 
advanced adjuvant is CpG oligodeoxynucleotide (ODN), a TLR9 ligand contained in the 
Heplisav® vaccine candidate for hepatitis B from Dynavax, that has completed a Phase 3 
clinical trial (Reed, SG, et al., 2013). 
Small molecule immune potentiators as a new class of vaccine adjuvants 
A new class of adjuvants, small molecule immune potentiators (SMIPs), has been 
identified that activate immune cells by targeting TLR7 and TLR8. Imiquimod and 
Resiquimod (R848) are clinically advanced TLR7 and/or TLR8 SMIPs that are used as 
immunotherapeutics. Although Imiquimod and Resiquimod have been studied 
extensively as vaccine adjuvants in preclinical models (Vasilakos et al. 2013), they were 
never optimized for this use and, in general, compare poorly to other pre-clinical and 
clinical adjuvant candidates. Furthermore, when Imiquimod is applied topically (it is a 
licensed topical treatment for viral and malignant skin lesions) it induces strong local and 
systemic inflammatory reactions, and is poorly tolerated (Bauza, et al. 2009; Campanelli, 
et al. 2005; Meyer, et al. 2008). 
Unlike traditional drugs, TLR7 SMIPs activate innate immunity and initiate a cascade of 
immune responses that can have systemic impact and endure after the compound has been 
cleared from the organism. For SMIPs as vaccine adjuvants this difference is highlighted 
further by the fact that 2-3 local IM injections drive antigen-specific B and T cell 
responses at distal sites and these can provide protection in the form of immunologic 
memory (Tacken,  et al. 2011; Ilyinskii, et al., 2014). Therefore, limiting the systemic 
exposure of the SMIP adjuvants has been postulated as an approach to both increase 
vaccine efficacy and minimize side effects associated with systemic and generalized 
inflammation. GSK is currently developing a novel adjuvant, containing a SMIP from the 
benzonaphthryridines (BZN) series, LHD153, which targets TLR7. The objective driving 
the discovery of this new TLR7 ligand was to develop a vaccine adjuvant with high 
efficacy in increasing the vaccine specific immune response and with minimal side 
effects. To obtain this objective it was postulated that the ideal compound would remain 
localized at the site of injection to help trigger the immune reaction to vaccine antigens, 
yet maintain a low systemic distribution. At the same time this compound had to be 
soluble to make industrial scale-up and manufacturing feasible. Soluble BZN were 
engineered so that they could be formulated with aluminium salts with the aim of limiting 
their systemic exposure and keeping them localized in the muscle for short time after 
immunization. The strongest adsorption to aluminium hydroxide particles is obtained 
through ligand exchange of hydroxyl and/or phosphate groups on the surface of 
aluminium hydroxide or phosphate with soft anionic moieties such as phosphates, 
phosphonates, phosphites, sulfates and carboxylates. To drive the adsorption to 

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aluminium hydroxide through ligand exchange, LHD153 was functionalized with a 
polyethylene glycol (PEG) linker and a terminal phosphonate. Furthermore, LHD153 was  
stabilized with arginine salt to allow scale up for GMP manufacturing, yielding 
LHD153R. As predicted, unformulated LHD153R exhibited high levels of systemic 
exposure when injected IM in mice, rats and dogs, whereas the serum concentrations of 
LHD153R adsorbed to aluminium hydroxide (Aluminium Hydroxide/LHD153R) was 
dramatically reduced. Moreover, Aluminium Hydroxide/LHD153R remained localized to 
the injection site. 
Preclinical studies using Aluminium Hydroxide/LHD153R to date confirm the activation 
of the TLR7 pathway and subsequent boost of both the humoral and cellular immune 
response. Moreover, Aluminium Hydroxide/LHD153R displays a unique 
pharmacokinetic profile as demonstrated by its minimal systemic exposure, potentially 
minimizing any systemic inflammatory response associated with tolerability issues. 
Aluminium hydroxide/LHD153R has achieved proof of concept in animal models using 
several vaccine antigens including MenC, MenB, rabies, HIV and respiratory syncytial 
virus (RSV). In vitro toxicity of LDH153R has been assessed, and in vivo nonclinical 
tolerability and safety of LHD153R and Aluminium Hydroxide/LHD153R have been 
evaluated in rats, dogs and non-human primates. LHD153R was not phototoxic, 
genotoxic or mutagenic (Ames and chromosomal aberration tests), and did not cause local 
or systemic toxicity in dogs or rats. Furthermore, Aluminium Hydroxide/LHD153R was 
well tolerated in rhesus monkeys. 
1.2  
Rationale 
The aim of this study is to assess the safety of Aluminium Hydroxide/LHD153R 
adjuvanted MenC-CRM197 conjugate vaccine (MenC-CRM197/Aluminium  
Hydroxide/LHD153R) and to compare the antibody-mediated immune response elicited 
by MenC-CRM197/Aluminium Hydroxide/LHD153R with the licensed aluminium 
hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®). 
Furthermore, a comprehensive set of exploratory objectives has been selected to assess 
the systemic exposure of LHD153 after intramuscular injection and to evaluate the quality 
of the specific immune response against MenC-CRM197 in detail and to evaluate 
biomarkers that may be predictive of safety and/or innate immune activation. 
The licensed Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) has been 
chosen as the primary vaccine candidate to assess the safety and immunopotentiating 
properties of Aluminium Hydroxide/LHD153R for several reasons. Firstly, the safety and 
immunogenicity profiles of the Meningococcal C-CRM197 Conjugate Vaccine have been 
well established through years of commercial use. Secondly, a more potent 

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Meningococcal C-CRM197 Conjugate Vaccine might enable a reduction of the antigen 
dosage or the number of doses needed in infants between 2 and 12 months of age. Finally, 
Meningococcal C-CRM197 is a well-characterized, single conjugate antigen preparation 
which provides an ideal setting to explore the potential of this new Aluminium 
Hydroxide/LHD153R adjuvant. 
2.0  
OBJECTIVES 
2.1  
Primary Objectives 
Primary Safety Objective 
To assess the safety of MenC-CRM197/Aluminium Hydroxide/LHD153R as compared to 
that of aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
Primary Immunogenicity Objective 
To compare the antibody responses of MenC-CRM197/Aluminium Hydroxide/LHD153R 
and aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at 
Day 29, as measured by human complement serum bactericidal assay (hSBA) directed 
against MenC. 
2.2  
Secondary Objectives 
Secondary Immunogenicity Objective(s) 
1. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine at Day 8 and Day 181 after vaccination, as measured by 
hSBA directed against MenC. Baseline antibody titers will also be measured by 
hSBA. 
2. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine, at Day 8, Day 29 and Day 181 after vaccination, as 
measured by an enzyme-linked immunosorbent assay (ELISA) to MenC. Baseline 
antibody concentrations will also be measured by ELISA. 
2.3  
Exploratory Objectives 

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1. To evaluate the systemic exposure of LHD153 at several early time-points after IM 
injection of MenC-CRM197/Aluminium Hydroxide/LHD153R or Meningococcal 
CCRM197 Conjugate Vaccine. 
2. To explore the frequency of B cells specific for MenC polysaccharide and CRM197 
protein at baseline (Day 1) and at Day 8, Day 29 and Day 181 after vaccination with 
MenC-CRM197/Aluminium Hydroxide/LHD153R or the aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. Subsequently, the B cell 
repertoire of the antigen specific B cells will be analyzed in a selected subset of 
subjects. 
3. To explore the baseline T cell mediated immunity to CRM197 and to evaluate the 
frequency and quality of CRM197 specific T cells induced by 
MenCCRM197/Aluminium Hydroxide/ LHD153R compared to aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at Day 8 and Day 29. 
4. To evaluate biomarkers that may be predictive for safety and/or innate immune 
activation. 
 

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3.0 
STUDY DESIGN 
3.1 
Overview of Study Design 
This is a Phase 1, randomized, observer blind, adjuvant dosage-escalation study. It will be 
performed at a single center. In total, approximately 80 healthy male and healthy 
nonpregnant female adults (18-45 years of age) will be enrolled in the study. 
Subjects will be randomized to receive a single IM vaccination of either the licensed 
aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine 
(Menjugate®) or the investigational vaccine, MenC-CRM197/Aluminium 
Hydroxide/LHD153R. 
The dosage of LHD153R will be escalated from 12.5 µg to 100 µg.  For the 
dosageescalation of LHD153R, the subjects will be enrolled into 1 of 4 cohorts, in a 
stepwise manner with 20 subjects per cohort. Subjects in all cohorts will be randomized 
in a 1:4 ratio, to receive either aluminium hydroxide adjuvanted Meningococcal C-
CRM197 Conjugate Vaccine (control) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R with increasing doses of LHD153R. Subjects assigned to MenC-
CRM197/Aluminium Hydroxide/LHD153R in Cohort 1 will receive 12.5 μg of LHD153R; 
Subjects in Cohort 2 will receive 25 μg of LHD153R; Subjects in Cohort 3 will receive 
50 μg of LHD153R; Subjects in Cohort 4 will receive 100 μg of LHD153R (Table 3.1-1). 
Table 3.1-1: Subjects Randomized per Cohort and Treatment Dosage Group 
Cohort 
Group 
Subjects/ 
Group 
MenC 
Dosage* 
(µg) 
Adjuvant Dosages 
Total 
Volume/Dose 
Total 
Subjects/Cohort 
Aluminium  
Hydroxide  
(mg) 
LHD153R  
(µg) 
1 
A 
4 
10 
1 
0 
0.5 mL 
20 
 
 
 
 
 
 
 
B 
16 
10 
1 
12.5 
0.5 mL 
 
2 
A 
4 
10 
1 
0 
0.5 mL 
20 
C 
16 
10 
1 
25 
0.5 mL 
3 
A 
4 
10 
1 
0 
0.5 mL 
20 
D 
16 
10 
1 
50 
0.5 mL 
4 
A 
4 
10 
1 
0 
0.5 mL 
20 
E 
16 
10 
1 
100 
0.5 mL 
*Conjugated to 12.5-25 µg CRM197 
All cohorts will have a staggered entry. For each cohort, the first 5 subjects (i.e. the first  
1:4 randomization block) to receive either aluminium hydroxide adjuvanted  

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Meningococcal C-CRM197 Conjugate Vaccine (n=1) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R (n=4) will be vaccinated at rate of 1 subject each day. 
After entry of the first 5 subjects in each cohort, the enrollment will be paused. The 
remaining 15 subjects for each cohort will be enrolled only after DMC review of the 
safety results obtained through Day 14 has been finalized (Table 3.1-2). In addition, 
enrollment of the first 5 subjects of the next cohort will only proceed after the Day 14 
safety results of the first 5 subjects of the previous cohort have been reviewed by the 
DMC. Furthermore, all available Day 14 and Day 29 safety results will be included in 
DMC review between the different enrollment stages. 
Table 3.1-2: Overview of staggered entry of subjects based on DMC reviews 
Stage 
Dosage Cohort 
MenC-CRM197/ 
Aluminium Hydroxide (n) 
MenC-CRM197/ 
Aluminium Hydroxide 
/LHD153R (n) 
1   
1  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 14 Safety Results 
2 
1  
3 
12 
2  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 29 and Stage 2 Day 14 Safety Results 
3 
2  
3 
12 
3  
1 
4 
Enrollment pause until DMC review of Stage 2 Day 29 and Stage 3 Day 14 Safety Results 
4 
3  
3 
12 
4  
1 
4 
Enrollment pause until DMC review of Stage 3 Day 29 and Stage 4 Day 14 Safety Results 
5 
4  
3 
12 
Post-vaccination procedures include collection of urine specimens at Day 1, Day 8 and 
Day 29 for safety assessment and blood specimens at Day 1, Day 8, Day 29 and Day 181 
for safety assessment and evaluation of the primary and secondary immunogenicity 
endpoints. Furthermore, additional blood specimens will be collected for assessment of 
exploratory endpoints at Day 1, Day 4, Day 8, Day 29 and Day 181 from those subjects 
that signed an additional informed consent concerning blood collection for exploratory 
assessment. 
3.2  
Study Period 
Each subject should expect to participate in the study for approximately 12 months, from 
the time of enrolment through the last study visit. 

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3.3  
Blinding Procedures 
This study is designed as an observer-blind study. For each dosage cohort, subjects, 
investigators, laboratories and the sponsor will be blinded to vaccine assignments. 
To maintain the blindness within each cohort, designated nurse(s) or physician(s) will be 
responsible for administering the study vaccines to the subjects, and will be instructed not 
to reveal the identity of the study vaccines neither to the subject nor to the investigative 
site personnel (investigator, study nurse, monitor) involved in the conduct or monitoring 
of the trial. This (these) designated individual(s) will have no contact with the subjects 
after the administration of the study vaccine. Furthermore, unblinded monitors are 
assigned to reconcile actual vaccine treatment. 
Study unblinding, at the group level, is planned for an Interim Analysis of the safety and 
immunogenicity data obtained up to Day 29 after all cohorts are enrolled and for full 
unblinding at the End of Study. 
Except in the case of medical necessity, a subject’s treatment should not be unblinded 
without the approval of the Sponsor. In such instance of medical emergency, every effort 
should be made to contact the Sponsor prior to unblinding. If unblinding should occur (by 
either accidental unblinding or emergency unblinding for a serious adverse event) prior to 
completion of the study, the investigator must promptly contact the Sponsor and 
document the circumstances on the appropriate forms. Instructions regarding emergency 
unblinding will be provided to the investigator. 
3.4  
Data Collection 
3.4.1  
Data Collected from Subjects 
The following data will be collected from each subject over the duration of their study 
participation: 
▫ Demographic Information 
▫ Adverse Events 
▫ Medical History 
▫ Concomitant Medications 
▫ Vital signs 

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All data collected must only be identified using the Subject ID, as described in section 
5.2.3. 
3.4.2  
Tools Used for Data Collection 
Data will be recorded in the Subject Diary and collected on Case Report Forms (CRFs). 
Subject Diary 
Subject Diaries will be the only source document allowed for solicited local and systemic 
adverse events (including body temperature measurements), starting after the initial 24 
hours post-vaccination observation period at the clinic. The following additional rules 
apply to documentation of safety information collected in the Subject Diary: 
1. No corrections or additions to the Subject Diary will be allowed after it is delivered to 
the site. 
2. Any blank or illegible fields on the Subject Diary must be described as missing in the 
CRF. 
3. Any corrections to the Subject Diary must be performed by the person completing the 
Subject Diary and should include a single strike through line through the incorrect 
value or text with a brief explanation for each change, the initials of that person, and 
date of correction. 
Case Report Forms 
This study utilizes CRFs to collect study-related data from each subject. A qualified site 
staff member(s) is required to enter subject data in the CRFs based on the medical 
information available in each subject’s record. The following additional rules apply to 
documentation of Subject Diary information collected in the CRFs: 
1. The site must enter all readable entries in the Subject Diary into the CRF, including 
those values that may be biologically implausible (e.g. body temperature: 400°C). 
2. Any illegible or implausible data should be reviewed with the subject. If an 
underlying solicited or unsolicited adverse event is described on review with the 
subject, this should be described in the source document and reported as an 
unsolicited adverse event in the appropriate CRF (e.g., if the subject above confirms 
body temperature of 40°C on the day in which body temperature: 400°C was written 
into his/her Subject Diary, this fever of 40°C should be recorded in the appropriate 
CRF). 

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3. Any newly described safety information (including a solicited adverse event) must not 
be written into the Subject Diary and must be described in the study file as a verbally 
reported adverse event. Any adverse event reported in this fashion must be described 
as an unsolicited adverse event and therefore, entered in the appropriate CRF. 
Data should be entered into the CRF in a timely fashion following each subject’s clinic 
visit, study procedure, or phone call. Each subject’s CRF casebook will be compared with 
the subject’s source records by a GSK-approved study monitor (or designee) over the 
duration of the study in order to ensure data collection accuracy. 
3.5  
Collection of Clinical Specimens 
The following clinical specimens are required to be collected from each subject in this 
study: 
▫ Blood 
▫ Urine 
Processing of each specimen should be completed by a qualified site member. Testing of 
clinical specimens will be performed by a GSK or designated laboratory. 
Blood Specimens 
Before Vaccination 
▫ At the Pre-vaccination Screening Visit (between Day -28 to -3) one sample of 
approximately 10 ml blood will be drawn from all subjects. 
▫ At Visit 1 (Day 1) - prior to vaccination – two samples of approximately 10 ml blood 
will be drawn from all subjects. 
▫ At Visit 1 (Day 1) - prior to vaccination - the following blood samples will be drawn 
from subjects that gave additional informed consent for blood collection for 
exploratory assays: 
- 
One sample of approximately 3 ml 
- 
Two samples of approximately 5 ml 
- 
One sample of approximately 70 ml 

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After Vaccination 
▫ At Visit 1 (Day 1) - 1 hour after vaccination - one sample of approximately 3 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 2 hours after vaccination - one sample of approximately 3 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 4 hours after vaccination - one sample of approximately 3 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 6 hours after vaccination – two samples of approximately 5 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 8 hours after vaccination - one sample of approximately 3 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 24 hours after vaccination - one sample of approximately 10 ml 
blood will be drawn from all subjects. 
▫ At Visit 1 (Day 1) - 24 hours after vaccination - the following blood samples will be 
drawn from subjects that gave additional informed consent for blood collection for 
exploratory assays: 
- 
One sample of approximately 3 ml 
- 
Two samples of  approximately 5 ml 
- 
One sample of approximately 20 ml 
▫ At Visit 2 (Day 4) the following blood samples will be drawn from subjects that gave 
additional informed consent for blood collection for exploratory assays: 
- 
One sample of  approximately 3 ml 
- 
Two samples of  approximately 5 ml 
- 
One sample of approximately 20 ml 
▫ At Visit 3 (Day 8) two samples of approximately 10 ml blood will be drawn from all 
subjects. 

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▫ At Visit 3 (Day 8) the following blood samples will be drawn from subjects that gave 
additional informed consent for blood collection for exploratory assays 
- 
Two samples of approximately 5 ml 
- 
One sample of approximately 70 ml 
▫ At Visit 6 (Day 29) two samples of approximately 10 ml blood will be drawn from all 
subjects. 
▫ At Visit 6 (Day 29) one sample of approximately 50 ml blood will be drawn from 
subjects that gave additional informed consent for blood collection for exploratory 
assays. 
▫ At Visit 9 (Day 181) one sample of approximately 10 ml blood will be drawn from all 
subjects. 
▫ At Visit 9 (Day 181) one sample of approximately 50 ml blood will be drawn from 
subjects that gave additional informed consent for blood collection for exploratory 
assays. 
The blood will be used for screening and safety laboratory assessments, immunological 
serology assays, pharmacokinetic analysis, cell mediated immunity assays and gene 
expression and protein production assays. See section 5.1.2, section 5.2.1 and section 7.0 
for additional details. 
Processing of each blood specimen should be completed in accordance with the study 
specific Clinical Specimen Laboratory Manual. 
The total amount of blood collected over the study period for all subjects will be 
approximately 90 ml. 
For subjects that signed an additional informed consent for blood collection for 
exploratory assays the total amount of blood collected over the study period will be 
approximately 441 ml. 
Urine Specimens 
Urine will be collected at the Pre-vaccination Screening Visit (between Day -28- to -3), at 
Visit 1 (Day 1; before vaccination and 24 hours after vaccination), at Visit 3 (Day 8) and 
at Visit 6 (Day 29). Results will be recorded in the source document and CRF. 

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Urine will be collected from all subjects for safety laboratory assessments and drugs-
ofabuse testing. Furthermore, urine will be collected for pregnancy testing in all females. 
3.6  
Stopping/Pausing Guidelines 
Stopping/pausing guidelines are predefined criteria that halt the conduct of a study (either 
a vaccine group or the entire study). These guidelines are used to ensure the safety of study 
subjects.  
The following criteria, based on FDA guidance and with grading scales adapted from the 
CBER Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive vaccine Clinical Trials”, will be used for this study: 
1. The study will be halted (no new enrollments and no further investigational product 
administered until a full safety review by the DMC and consultation with the IRB/EC 
and the health authorities is completed) if one of the following occurs 
a. One subject experiences a serious adverse event (SAE) assessed as possibly or 
probably related to investigational product or, 
b. There is a subject death assessed as possibly or probably related to the 
investigational product. 
2. If one or more subjects experience a Grade 4 AE (see Appendix C, D, and E), vital 
sign or clinically significant laboratory abnormality that cannot be clearly attributed to 
another cause, vaccination will be suspended until a full safety review by the DMC is 
performed. 
3. If six or more subjects experience a Grade 3 AE (see Appendix A, B, C, D, and E), 
vital sign or clinically significant laboratory abnormality, dosage escalation will be 
suspended for that vaccine until a full safety review by the DMC is performed.  
The sponsor or the investigator (following consultation with the sponsor) has the right to 
discontinue the study at any time. If the clinical study is prematurely terminated, the 
investigator must promptly inform the study subjects and must assure appropriate therapy 
and follow-up for the subjects.  All procedures and requirements pertaining to the 
archiving of the documents must be followed.  All other study materials (such as study 
vaccines) must be returned to the sponsor or destroyed after sponsor approval. 
3.7  
Data Monitoring Committee 
A DMC will be formed to review safety data during scheduled periodic reviews. The 

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DMC may also perform reviews on an ad hoc basis as needed. DMC membership will 
consist of at least 3 individuals who are external to the site and sponsor, and will include 
1 statistician who is independent from the study team.  
Subjects will be enrolled in a stepwise manner in each of the four vaccine dosage cohorts  
(Cohort 1: 12.5 μg LHD153R, Cohort 2: 25 μg of LHD153R, Cohort 3: 50 μg of  
LHD153R and Cohort 4: 100 μg of LHD153R). The DMC will review all safety data, as 
described in the DMC charter and in the Statistical Analysis Plan, after the first 5 subjects 
in each cohort have completed Visit 4 and their data are available for analysis, and before 
enrollment of the remaining subjects in the respective cohort and before enrollment of the 
first 5 subjects in the subsequent cohort. In addition, in between the different enrollment 
stages, the DMC will review all available safety data of subjects that have completed 
Visit 4 and all available safety data of subjects that have completed Visit 6. 
The specific roles and responsibilities of the DMC members and other personnel involved 
will be documented in the DMC charter. The DMC charter will be finalized before the 
start of the study and will outline in detail all pausing and stopping rules according to the 
Clinical Study Protocol. 
3.8  
Premature Withdrawal from Study 
Subjects may withdraw at any time, or be dropped from the study at the discretion of the 
investigator should any untoward effects occur and/or for safety reasons. In addition, a 
subject may be withdrawn by the investigator or the Sponsor if he/she violates the study 
plan or for administrative reasons. The investigator or study coordinator must notify the 
Sponsor immediately when a subject has been withdrawn due to an adverse event. 
The circumstances above are referred to as premature withdrawal from the study, and the 
reason for premature withdrawal should be clearly documented and detailed in the source 
documentation. The investigator should make every attempt to evaluate the subject’s 
safety, including resolution of ongoing AEs, at the time of premature withdrawal. If a 
subject wants to withdraw from the study prior to the last planned study visit, the subject 
will be asked to be followed for safety for the duration of the study. When a subject 
withdraws, or is withdrawn, from the study, the procedures described in section 5.5.1 
should be completed if possible. 
The reasons for premature withdrawal from the study include: Adverse event, death, 
withdrawal of consent, lost to follow-up, administrative reason, and protocol deviation. 
These reasons are described in greater detail below. 
Adverse Event 

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For any subject withdrawn from study participation prior to the planned Study  
Termination Visit, it is important to determine if an AE was associated with the reason for 
discontinuing the study. This AE must be identified on the appropriate CRF page by 
indicating “Withdrawn from study due to AE”. Any ongoing AEs at the time of study 
withdrawal must be followed until resolution or stabilization. 
Death 
For any subject withdrawn from study participation due to death, this should be noted on 
the appropriate CRF page and the associated SAE that led to the death must be reported. 
Withdrawal of consent 
The subject can withdraw consent for participation in the study at any time without 
penalty or loss of benefit to which the subject is otherwise entitled. Reason for early 
termination should be deemed as “withdrawal of consent” if the subject withdraws from 
participation due to a non-medical reason (i.e., reason other than AE). If the subject 
intends to withdraw consent from the study, the investigator should clarify if the subject 
will withdraw completely from the study or if the subject will continue study participation 
for safety, or a subset of other study procedures. If the subject requests complete 
withdrawal from the study, no further study interventions will be performed with the 
subject. 
Lost to Follow-Up 
For subjects who fail to show up for study visits (clinic or telephone contacts), study staff 
is encouraged to make at least three documented attempts to contact the subject by 
telephone and at least one documented written attempt to contact the subject to encourage 
the completion of study termination procedures. These efforts to contact the subject must 
be recorded in the source document. The termination date for the subject to be captured 
on the appropriate CRF page is the date of the last contact (clinic visit or telephone) with 
the subject. 
Administrative Reason 
Examples for subjects withdrawn from the study due to administrative reason can include: 
Sponsor decision to terminate the study, subject meeting a pre-specified withdrawal 
criterion, subject discontinuation for insurance issues, moving, no time, etc. This reason 
should be noted in the appropriate CRF page and any ongoing AEs at the time of study 
withdrawal must be followed until resolution/stabilization. 

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If the clinical study is prematurely terminated by the Sponsor, the investigator is to 
promptly inform the study subjects and local EC/IRB and should assure appropriate 
therapy and follow up for the subjects. All procedures and requirements pertaining to the 
archiving of study documents should be followed. All other study materials (study 
medication/vaccines, etc.) must be returned to the Sponsor. 
For subjects who are withdrawn from the study due to receipt of an excluded 
medication/vaccination or due to significant protocol non-compliance, this reason should 
be noted in the appropriate CRF page. 
Protocol Deviation 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. In general, subjects associated with protocol deviations 
may remain in the study unless continuation in the study jeopardizes the subject’s health, 
safety, or rights. 
Investigators will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact GSK or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are 
permitted. If the investigator feels a change to the protocol would improve the conduct of 
the study this must be considered a protocol amendment, and unless such an amendment 
is agreed upon by GSK and approved by the IRB/EC and health authorities it cannot be 
implemented. 
Any subject who becomes pregnant during the study should be encouraged to continue 
participating in the study for safety follow-up. The site must complete a Pregnancy 
Report CRF (initial report) as soon as possible after learning of pregnancy occurrence 
(see section 7.1.6 for further details). If the subject withdraws from the study for any of 
the above categories except death, the site will obtain permission from the subject to 
continue to remain in contact with her until the outcome of the pregnancy is known, even 
if the outcome is not known until after the subject reaches the end of the routine study 
period. 
3.9  
End of Study 
Most clinical trials intended to support the efficacy/immunogenicity and safety of an 
Investigational Product proceed to full completion of planned sample size accrual. 

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A subject is considered to have completed this study when he/she has: (1) received the 
intended dose of study vaccine and (2) completed 365 days (Visit 12) of safety follow-up 
after receiving the study vaccine. 
Evaluation of the primary and secondary immunogenicity objectives requires the testing 
of biological samples from all study subjects, which can only be completed after all 
samples are collected. The last samples for the analysis of the primary and/or secondary 
objectives will be taken at Visit 9 (Day 181). For the purpose of this protocol, End of 
Study is defined as the completion of the testing of such biological samples, to be 
achieved no later than 8 months after collection of the last biological sample at Visit 9. 
4.0  
SELECTION OF STUDY POPULATION 
4.1  
Inclusion Criteria 
In order to participate in this study, all subjects must meet all of the inclusion criteria 
described. 
1. Male or female individuals of 18 through 45 years of age on the day of informed 
consent. 
2. Healthy volunteers with good physical and mental health status, determined on the 
basis of the medical history, a physical examination and the results of the screening 
tests as judged by the investigator. 
3. Individuals who have voluntarily given written informed consent after the nature of 
the study has been explained according to local regulatory requirements, prior to 
study entry. 
4. Individuals who can comply with study procedures including follow-up1. 
5. Individuals that are able to understand, read and write German language. 
6. Females of childbearing potential who are using an effective birth control method2 
which they intend to use for at least 30 days after the study vaccination. 
4.2  
Exclusion Criteria 
Each subject must not have or must not be: 
1. Progressive, unstable or uncontrolled clinical conditions. 
2. Hypersensitivity, including allergy, to any component of vaccines, medicinal products 
or medical equipment whose use is foreseen in this study. 

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1 A subject is considered to be compliant if the Investigator judges that the subject will complete the Subject 
Diary, return for all the follow-up visits and be available for telephone calls as scheduled in the study. 
2 The following birth control methods are considered effective: 
- 
Hormonal contraceptive (such as oral, injection, transdermal patch, implant) if used for at least 30 
days prior to informed consent 
- 
Diaphragm with spermicide, tubal occlusion device 
- 
Intrauterine device (IUD) 
- 
Tubal ligation 
- 
Male partner using condom with spermicide 
- 
Male partner having been vasectomized at least six months prior to informed consent 
3. Clinical conditions representing a contraindication to intramuscular vaccination and 
blood draws. 
4. Abnormal function of the immune system resulting from: 
a. Clinical conditions. 
b. Systemic administration of corticosteroids (PO/IV/IM) for more than 14 
consecutive days within 90 days prior to informed consent. 
c. Administration of antineoplastic and prescription immunomodulating agents or 
radiotherapy within 90 days prior to informed consent. 
5. Received immunoglobulins or any blood products within 180 days prior to informed 
consent. 
6. Received an investigational or non-registered medicinal product within 30 days prior 
to informed consent or intend to participate in another clinical study at any time 
during the conduct of this study. 
7. Vulnerable subjects (e.g. persons kept in detention), study personnel or an immediate 
family or household member of study personnel, subjects with legal incapacity or 
limited legal capacity 
8. Any relevant deviation from the laboratory parameters at screening as judged by the 
investigator. 
9. Previously received any vaccine that included a MenC antigen. 
10. Previously suspected or confirmed disease caused by N. meningitides. 
11. Had household contact with and/or intimate exposure to an individual with culture 
proven MenC. 

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12. A positive serum or urine pregnancy test prior to the study vaccine administration or 
are currently lactating. 
13. A positive drugs-of-abuse test prior to the study vaccine administration 
14. Received any other vaccines within 30 days prior to enrolment in this study or who 
are planning to receive any vaccine within 30 days from the administration of study 
vaccines. 
15. Any other condition that, in the opinion of the investigator, might interfere with the 
results of the study or pose additional risk to the subject due to participation in the 
study. 
4.3  
Criteria for Delay of Vaccination or Blood Draw 
There may be instances when individuals meet all eligibility criteria for vaccination or 
blood draw yet have a transient clinical circumstance which may warrant delay of 
vaccination or blood draw. Under such circumstances, a subject may be considered 
eligible for study enrolment after the appropriate window for delay has passed and 
inclusion/exclusion criteria have been rechecked, and if the subject is confirmed to be 
eligible. 
Reasons for delay of vaccination include: 
▫ Body temperature elevation ≥38.0°C (measured orally) within 3 days prior to intended 
study vaccination. 
▫ Use of antipyretics and/or analgesic medications within 24 hours prior to vaccination. 
Reasons for delay of blood draw include: 
▫ Subject has received a dose of systemic antibiotics less than 6 days before blood 
collection for the hSBA directed against MenC. 
 

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5.0  
STUDY PROCEDURES 
The sections that follow provide an overview of the procedures that are to be followed in 
enrolling, evaluating, and following subjects who participate in this clinical study. Visits 
can be either clinic visits or safety follow-up telephone calls, as specified in the Table 
below and in the Time and Events Tables 3 and 4 of the Study Synopsis. 
Table 5.0-1: Study procedures 
Visit Category 
Procedures 
Pre-vaccination Clinic Visit 
Section 5.1 describes procedures to be followed 
prior to subject enrollment, including: informed 
consent and screening procedures. 
Vaccination Clinic Visit 
Section 5.2 describes procedures to be followed 
during the vaccination clinic visit, including: 
prevaccination procedures, enrolment, 
randomization, vaccination and post-vaccination 
procedures. 
Post-vaccination Visits 
Section 5.3 describes follow-up clinic visits and 
safety follow-up calls. 
Unscheduled Visits 
Section 5.4 describes possible procedures to be 
followed at unscheduled clinic visit. 
Study Termination Visit 
Section 5.5 describes procedures to be followed at 
the last study visit for a subject (may include early 
termination visit). 
5.1 
Pre-vaccination Clinic Visit(s) 
The Pre-vaccination Clinic Visit must be performed in the period between Day -28 and 
Day -3. 
This section describes the procedures that must be performed for each potential subject 
prior to enrollment, including obtaining informed consent and screening. 
5.1.1  
Informed Consent 
"Informed consent" is the voluntary agreement of an individual or his/her legal 
guardian(s) to participate in research. Consent must be given with free will of choice, and 
without undue inducement. The individual must have sufficient knowledge and 
understanding of the nature of the proposed research, the anticipated risks and potential 
benefits, and the requirements of the research to be able to make an informed decision. 

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Informed consent following local IRB/EC guidance must be obtained before conducting 
any study-specific procedure (i.e., all of the procedures described in the protocol). Prior to 
any additional blood sample collection for exploratory objectives, a secondary informed 
consent must be signed by subjects. The process of obtaining informed consent should be 
documented in the subject source document in addition to maintaining a copy of the 
signed and dated informed consent. 
5.1.2  
Screening 
After an individual has consented to participate in the study and informed consent is 
signed, that individual will be given a unique Screening Number. The subject’s unique 
Screening Number will be documented in the Screening and Enrolment log. The 
eligibility of the subject will be determined based on the inclusion and exclusion criteria 
listed in section 4.0 and evaluated during this screening procedure. 
Screening procedures at the Pre-vaccination Clinical Visit (between Day -28 and Day -3) 
will include the following: 
▫ Review of demographic data, including age, gender, race, body weight and height. 
▫ Review of medical history, including but not limited to any medical history, ongoing 
illnesses or injuries that may be relevant to subject eligibility for study participation. 
Relevant medical history can also include any medical history that contributes to the 
understanding of an adverse event that occurs during study participation, if it 
represents an exacerbation of an underlying disease/pre-existing problem. 
▫ Perform physical examination, including but not limited to: 
- 
Assessment of general appearance 
- 
Collection of vital signs, including body temperature, blood pressure, heart rate 
and respiratory rate 
- 
Examination of head, ears, eyes, nose and throat (HEENT) 
- 
Examination of skin 
- 
Auscultation of heart and lungs 
▫ Collection and review of prior and concomitant medications or vaccinations taken 
prior to start of study (refer to section 6.5 for further details). 
▫ Collection of any unsolicited AEs occurring prior to administration of the study 
vaccine. 

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▫ Blood draw (approximately 10 ml) for Safety Laboratory assessments, measurement of 
Hepatitis B surface antigen, anti-Hepatitis C virus antibodies, anti-HIV 1 and 2 
antibodies and serum pregnancy test (all women). 
▫ Urine sample for Safety Laboratory assessments and drugs-of-abuse testing. 
NOTE: A general physical examination is to be performed by a qualified health care 
practitioner. “Qualified health care practitioner” refers to any licensed health care 
professional who is permitted by institutional policy to perform physical examinations 
and who is identified within the Study Staff Signature Log. 
Data collected during the Pre-vaccination Screening Clinic Visit must be written in the 
source document (see section 9.1) and will be captured in the screening CRF Forms. In 
the event that the individual is determined ineligible for study participation, he/she is 
considered a screen failure. The reason for screen failure must be documented in the 
Screening and Enrolment log. 
5.2  
Vaccination Clinic Visit(s) 
This section describes the procedures to be performed at the Vaccination Clinic Visit 
(Visit 1, Day 1), including: pre-vaccination procedures, enrolment, randomization, 
prevaccination blood draw, vaccination and post-vaccination procedures. 
5.2.1  
Pre-vaccination Procedures 
During pre-vaccination procedures at Visit 1 (Day 1), the eligibility of the subject will be 
confirmed based on the inclusion and exclusion criteria listed in section 4.0. 
Pre-vaccination procedures at Visit 1 (Day 1) will include the following: 
▫ Review of systems by means of a structured interview that queries the subject as to any 
complaints the subject has experienced across each organ system. 
▫ Perform physical examination, including but not limited to: 
- 
Assessment of general appearance 
- 
Assessment of body weight and collection of vital signs, including body 
temperature, blood pressure, heart rate, and respiratory rate 
- 
Examination of head, ears, eyes, nose and throat (HEENT) 
- 
Examination of skin 
- 
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▫ Collection and review of prior and concomitant medications or vaccinations taken, or 
recalled, since the last visit (refer to section 6.5 for further details). 
▫ Collection of any unsolicited AEs occurring prior to administration of the study 
vaccine. 
▫ One blood sample (approximately 10 ml) will be drawn from all subjects for serology 
testing. 
▫ One blood sample (approximately 10 ml) will be drawn from all subjects for baseline 
Safety Laboratory assessments. 
▫ One urine sample for baseline Safety Laboratory assessments, pregnancy testing (all 
women) and drugs-of-abuse testing. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of blood draws are provided in section 3.5. 
NOTE: A general physical examination is to be performed by a qualified health care 
practitioner. “Qualified health care practitioner” refers to any licensed health care 
professional who is permitted by institutional policy to perform physical examinations 
and who is identified within the Study Staff Signature Log. 
Data collected during pre-vaccination procedures at Visit 1 must be written in the source 
document (see section 9.1). In the event that the individual is determined ineligible for 
study participation, he/she is considered a screen failure. The reason for screen failure 
must be documented in the Screening and Enrolment log. If the individual is determined 
to be eligible for the study, he/she can be enrolled into the study. 
5.2.2 
Enrolment 
After an individual is determined to be eligible for study participation, the investigator 
will enroll the subject into an Electronic Data Capture (EDC) system where the 
randomization to the treatment group will occur. The Screening Number ceases to be used 
and remains in the Screening and Enrolment Log only. 
If for any reason, after signing the informed consent form (ICF), the subject who is 
eligible and enrolled fails to be randomized, this is called a randomization failure. In this 
case the early termination study procedures must be applied. The reason for all 
randomization failures should be recorded in the Screening and Enrolment Log and in the 
source document as specified in the Source Data Agreement. The information on subjects 

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who are randomization failures should be kept distinct from subjects who are screen 
failures, as described in section 5.1.2 and section 5.2.1. 
5.2.3 
Randomization 
Enrolled subjects will be randomized and automatically assigned a unique Subject ID. 
The Subject ID will be the subject’s unique identification number for all CRFs and 
associated study documentation that will be used for the duration of the study. 
If for any reason, after signing the informed consent form (ICF), the eligible subject is 
enrolled and randomized but fails to undergo treatment, this is an Early Termination and 
the reason should be recorded in source document as specified in the Source Data 
Agreement/Source Data Verification Form. The information on these Early Termination 
subjects should be kept distinct in the source documentation from randomization failures, 
which are described in section 5.2.2. 
5.2.4 
Vaccination 
After completing the pre-vaccination procedures at Visit 1 (Day 1), administer the 
vaccine to the subject according to the procedures described in section 6.3. Observe the 
blinding procedures described in section 3.3. 
5.2.5 
Post-vaccination Procedures 
The following post-vaccination procedures will be performed at Visit 1 (Day 1): 
▫ After vaccination, the subject will be observed for at least 30 minutes for any 
immediate solicited and unsolicited AEs and a body temperature measurement at 30 
min after vaccination. All safety and body temperature data collected during this time 
are to be recorded in the subject’s source document. 
▫ After vaccination, the subject will be observed for at least 24 hours at the clinic 
including observation for solicited and unsolicited AEs and body temperature 
measurements. Body temperature measurements must be performed at 2, 4, 6, 8, 10, 
12, 18 and 24 hours after vaccination. All safety and body temperature data collected 
during this time are to be recorded in the subject’s source. 
▫ One blood sample (approximately 10 ml) will be drawn from all subjects at 24 hours 
after vaccination for Safety Laboratory assessments. 
▫ One urine sample will be collected from all subjects at 24 hours after vaccination for 
Safety Laboratory assessments. 

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▫ From those subjects that signed an additional Informed Consent for exploratory assays, 
additional blood samples will be drawn in the first 24 hours after vaccination. Details 
regarding the number and volume of post-vaccination blood draws are provided in 
section 3.5. 
After the initial 24 hours inpatient observation period, a Subject Diary will be used in this 
study to document solicited and unsolicited AEs until Day 14. The Subject Diary is the 
only source for collection of solicited AEs after the initial 24 hours inpatient observation 
period. Therefore, it is critical that the subject completes the Subject Diary correctly. 
The following training regarding completion of the Subject Diary must be provided: 
▫ The subject should be trained on how and when to complete each field of the Subject 
Diary. 
▫ The subject should be trained on how to self-measure local solicited adverse events 
and body temperature. The measurement of solicited local adverse events is to be 
performed using the ruler provided by the site. 
▫ The subject should be instructed how to perform body temperature measurement using 
the thermometer provided by the site. If the subject feels unusually hot or cold during 
the day, the subject should check their body temperature. If the subject has fever, the 
highest body temperature observed that day should be recorded in the Subject Diary. 
Subject Diary training should be directed at the individual(s) who will perform the 
measurements of adverse events and who will enter the information into the Subject 
Diary. This individual may not be the subject, but if a person other than the subject enters 
information into the Subject Diary, this person’s identity must be documented in the 
Subject Diary. Any individual that writes in the Subject Diary must receive training on 
completion of the Diary Card at the time of the visit. This training must be documented in 
the subject’s source record. 
The site should schedule the next study activity (clinic visit) with the subject. 
The subject will receive a written reminder of the next planned study activity. The subject 
will be reminded to complete the Subject Diary and to contact the site if there are any 
questions, and to contact the site immediately (or as soon as the subject is medically 
stable) if the subject has a medical condition that leads to a hospitalization or an 
emergency room visit. 
5.3  
Post-vaccination Visit(s) 

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5.3.1 Subject Diary Reminder, Safety Follow-up and/or Post-vaccination Blood 
Draw Clinic Visits 
Subject Diary reminder, Safety follow-up and/or post-vaccination blood draw clinic visits 
will be performed on Day 4 (Visit 2), Day 8 (Visit 3), Day 15 (Visit 4), Day 29 (Visit 6), 
Day 85 (Visit 7), Day 113 (Visit 8) and Day 181 (Visit 9) 
At Day 4 (Visit 2) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. All unsolicited AEs, SAEs, AESIs, 
medically attended AEs, AEs leading to study withdrawal and NOCD must be 
recorded on source documents. Any concomitant medications or vaccinations 
associated with those events must also be recorded on the source documents. 
▫ All subjects will be reminded to complete the Subject Diary and to contact the site if 
there are any questions, and to contact the site immediately (or as soon as the subject 
is medically stable) if the subject has a medical condition that leads to a 
hospitalization or an emergency room visit. No changes to the Subject Diary should 
be done at the clinic visit. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of blood draws are provided in section 3.5. 
▫ The site should schedule the next study activity (clinic visit) with the subject and the 
subject will receive a written reminder of the next planned study activity. 
At Day 8 (Visit 3) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. All unsolicited AEs, SAEs, AESIs, 
medically attended AEs, AEs leading to study withdrawal and NOCD must be 
recorded on source documents. Any concomitant medications or vaccinations 
associated with those events must also be recorded on the source documents. 

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▫ The subject will be reminded to complete the Subject Diary and to contact the site if 
there are any questions, and to contact the site immediately (or as soon as the subject 
is medically stable) if the subject has a medical condition that leads to hospitalization 
or an emergency room visit. No changes to the Subject Diary should be done at the 
clinic visit. 
▫ Blood draw (approximately 10 ml) from all subjects for Safety Laboratory 
assessments. 
▫ Urine sample from all subjects for Safety Laboratory assessments. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 

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▫ From those subjects who signed an additional Informed Consent for exploratory 
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volume of blood draws are provided in section 3.5. 
The site should schedule the next study activity (clinic visit) with the subject and the 
subject will receive a written reminder of the next planned study activity. 
At Day 15 (Visit 4) the following procedures will be performed: 
▫ The Subject Diary will be collected and reviewed. No changes to the Subject Diary 
should be done at the clinic visit. For details on the Subject Diary see sections 3.4.2, 
and 5.2.5. The healthcare professional reviewing these data will discuss the symptoms 
(if any) reported by the subject and will determine if any additional diagnoses and/or 
adverse events are present. All unsolicited AEs until Day 14, solicited local and 
systemic AEs persisting at Day 14, SAEs, AESIs, medically attended AEs, AEs 
leading to study withdrawal and NOCD must be recorded on source documents. All 
concomitant medications or vaccinations associated with those events must also be 
recorded on the source documents. 
▫ The site should schedule the next study activity (safety phone call) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 29 (Visit 6) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events 
occurred and if any concomitant medications or vaccines were taken / received in the 
time since the last clinic visit. The healthcare professional reviewing these data will 
discuss the symptoms (if any) reported by the subject and will determine if any 
additional diagnoses and/or adverse events are present. Any solicited local and 
systemic AEs continuing beyond Day 14, SAEs, AESIs, medically attended AEs, 
AEs leading to study withdrawal and NOCD must be recorded on source documents. 
All concomitant medications or vaccinations associated with those events must also 
be recorded on the source documents. 

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▫ From those subjects who signed an additional Informed Consent for exploratory 
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▫ Blood draw (approximately 10 ml) from all subjects for Safety Laboratory 
assessments. 
▫ Urine sample from all subjects for Safety Laboratory assessments. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 
volume of post-vaccination blood draws are provided in section 3.5. 
The site should schedule the next study activity (clinic visit) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 85 and Day 113 (Visit 7 and Visit 8), the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events 
occurred and if any concomitant medications or vaccines were taken / received in the 
time since the last clinic visit. The healthcare professional reviewing these data will 
discuss the symptoms (if any) reported by the subject and will determine if any 
additional diagnoses and/or adverse events are present. Any solicited local and 
systemic AEs continuing beyond Day 14, SAEs, AESIs, medically attended AEs, 
AEs leading to study withdrawal and NOCD must be recorded on source documents. 
All concomitant medications or vaccinations associated with those events must also 
be recorded on the source documents. 
▫ The site should schedule the next study activity (clinic visit) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 181 (Visit 9), the following procedures will be performed: 

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▫ The subject will be interviewed to determine if any unsolicited adverse events 
occurred and if any concomitant medications or vaccines were taken / received in the 
time since the last clinic visit. The healthcare professional reviewing these data will 
discuss the symptoms (if any) reported by the subject and will determine if any 
additional diagnoses and/or adverse events are present. Any solicited local and 
systemic AEs continuing beyond Day 14, SAEs, AESIs, medically attended AEs, 
AEs leading to study withdrawal and NOCD must be recorded on source documents. 
All concomitant medications or vaccinations associated with those events must also 
be recorded on the source documents. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 
volume of post-vaccination blood draws are provided in section 3.5. 
The site should schedule the next study activity (safety phone call) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
5.3.2  
Safety Follow-up Calls 
Safety follow-up calls will be performed on Day 22 (Visit 5), Day 209 (Visit 10) and Day 
271 (Visit 11) and include the following procedures: 
▫ Safety follow-up calls are calls made to the subject by a healthcare professional 
designated on the site log. These calls will follow a script which will facilitate the 
collection of relevant safety information. The subject will be interviewed according to 
the script, and information relating to solicited local and systemic AEs persisting 
beyond Day 14 and unsolicited adverse events including SAEs, AESIs, medically 
attended AEs, AEs leading to study withdrawal, and/or NOCD and concomitant 
medications or vaccinations associated with those events. All safety information 
described by the subject must be written down in a designated location within the 
source document and not written on the script used for the telephone call. 

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▫ The site should schedule the next study activity (clinic visit or study termination visit) 
with the subject. 
▫ The subject will be reminded to contact the site if there are any questions and to 
contact the site immediately (or as soon as the subject is medically stable) if the 
subject has a medical condition that leads to a hospitalization or an emergency room 
visit. 
5.4  
Unscheduled Visits  
An unscheduled visit describes a non-routine study visit triggered by a specific event. 
These could include anticipated or unanticipated adverse events or interventions. 
The following procedures should be carried out for all unscheduled visits: 
1. Evaluate the subject’s vital signs body temperature, heart rate, and blood pressure and 
perform a symptom-directed physical examination. 
2. Record any observed AEs in the source documents. 

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3. Record any concomitant medications or vaccinations associated with AEs in the 
source documents. 
5.5  
Study Termination Visit 
The study termination visit is scheduled on Day 366 (Visit 12). The termination visit is a 
clinic visit. For visit procedures to be performed for a subject whose planned study 
participation ends prematurely, please see section 5.5.1. 
At the Study Termination clinic visit the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. 
▫ The healthcare professional reviewing these data will discuss the symptoms (if any) 
reported by the subject and will determine if any additional diagnoses and/or adverse 
events are present. 
▫ Medically attended AEs, SAEs, NOCDs, or AESIs will be recorded on source 
documents. 
▫ All medications taken or vaccines received will also be recorded on the source 
documents. 
▫ The site will review with the subject the plan of when information relating to the 
subject’s participation in the study may be available (e.g., study results, treatment 
assignments). It will also be discussed how information relating to the subject’s 
participation in the study will be shared with the subject’s healthcare provider, if the 
subject chooses to share this information. 
▫ The site will complete the termination CRF page and this will mark the completion of 
the subject’s participation in the study. 
5.5.1  
Early Termination Visit 
The date of termination is the date of the last contact in which the subject’s health status 
was assessed or, in cases where the subject does not agree to any further safety follow-up, 
it is the date consent is withdrawn. This date should be recorded on the appropriate CRF 
page. 
When a subject is withdrawn from treatment or withdraws from the study, the investigator 
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The reason(s) for the early termination must be included in the subject’s source 
documentation. If the Early Termination Visit is a telephone call, collect as much 
information as possible. Early Termination Visits include subjects who were randomized 
but not treated. 
At the clinic visit or during the telephone call, the following procedures should be 
performed, when possible: 
▫ Collection and review of Subject Diary (if not already collected). 
▫ Interview of subject to collect unsolicited adverse events, medically attended AEs, 
AEs leading to withdrawal, SAEs, AESIs, and NOCD. 
▫ Interview of subject to collect concomitant medications and/or vaccinations. 
▫ Symptom-directed physical assessment, at least including measurement of vital signs 
(body temperature, respiratory rate, blood pressure, heart rate) and a check of general 
appearance (in case of clinic early termination visit). 
▫ Draw a blood sample (approximately 10 ml) and a urine sample for Safety Laboratory 
assessment (in case of clinic early termination visit). 
▫ The site will review with the subject the plan of when information relating to the 
subject’s participation in the study may be available (e.g., study results, treatment 
assignments). It will also be discussed how information relating to the subject’s 
participation in the study will be shared with the subject’s healthcare provider, if the 
subject chooses to share this information. 
▫ The site will complete the appropriate CRF page and this will mark the completion of 
the subject’s participation in the study. 
6.0  
TREATMENT OF SUBJECTS 
All vaccines associated with this study are to be stored separately from other vaccines and 
medications in a secure location under appropriate storage conditions with temperature 
monitoring. All vaccines associated with this study must be checked for expiration 
date prior to use. Expired vaccines must not be administered to subjects. 
6.1  
Study Vaccine(s) 
The term ‘study vaccine’ refers to those vaccines provided by the Sponsor, which will be 
evaluated as part of the study objectives. The study vaccines specific to this study are 
described in Table 6.1-1. 

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Table 6.1-1: Study Vaccine Composition 
Group A (Control) Meningococcal C-CRM197 Conjugate Vaccine 
 
Vaccine Component 
Quantity per 0.5 ml dose 
 
 
Vial Containing Vaccine Conjugate 
 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
 
Aluminum Hydroxide Solvent Components (for 0.5 mL dose) 
 
Aluminum hydroxide 
1.0 mg 
Sodium Chloride 
3.5 mg 
Sterile water for injection, up to 
0.5 ml 
 
 
Group B (12.5µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
12.5 µg 
Sodium Chloride 
3.4 mg 

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Histidine  
0.1 mg 
Tris 
30 µg 
Sterile water for injection, up to 
0.5 ml 
 
 
Group C (25 µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
25 µg 
Sodium Chloride 
3.4 mg  
Histidine 
0.2 mg 
Tris 
61 µg 
Sterile water for injection, up to 
0.5 ml 
 
 
Group D (50µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 

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Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
50 µg 
Sodium Chloride 
3.2 mg 
Histidine 
0.4 mg 
Tris 
121 µg 
Sterile water for injection, up to 
0.5 ml 
 
Group E (100µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
100 µg 
Sodium Chloride 
2.9 mg 
Histidine 
0.8 mg 
Tris 
243 µg 
Sterile water for injection, up to 
0.5 ml 
6.2  
Non-Study Vaccines 

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The term ‘non-study vaccine’ refers to those vaccines which will be intentionally given to 
study subjects but not formally included in the analysis of study objectives. 
No non-study vaccines are planned for this study. Any non-study vaccines administered 
during the study conduct will be captured in the CRF as concomitant medications and/or 
vaccinations. 
6.3  
Vaccine Preparation and Administration 
The investigator or designee will be responsible for oversight of the administration of 
vaccine to subjects enrolled in the study according to the procedures stipulated in this 
study protocol. All vaccines will be administered only by unblinded personnel who are 
qualified to perform that function under applicable local laws and regulations for the 
specific study site. 
The vaccine components will be provided in 5 separate kits (i.e. one for the control and 
one for each of the 4 dosage groups). The vaccine components must be mixed prior to 
vaccination taking into account the appropriate aseptic procedures. Detailed vaccine 
preparation and administration instructions, including the maximal administration period, 
will be provided to investigators prior to study start and must be filed in the Investigator 
Site File. 
PRECAUTIONS TO BE OBSERVED IN ADMINISTERING STUDY VACCINE: 
- 
Prior to vaccination, subjects must be determined to be eligible for study vaccination 
and it must be clinically appropriate in the judgment of the investigator to vaccinate. 
Eligibility for vaccination prior to first study vaccine administration is determined by 
evaluating the entry criteria outlined in protocol sections 4.0. 
- 
Study vaccines must not be administered to individuals with known hypersensitivity 
to any component of the vaccines. 
- 
Standard immunization practices are to be observed and care should be taken to 
administer the injection intramuscularly. Before administering vaccine, the 
vaccination site is to be disinfected with a skin disinfectant (e.g., 70% alcohol). Allow 
the skin to dry. DO NOT inject intravascularly. 
- 
As with all injectable vaccines, trained medical personnel and appropriate medical 
treatment must be readily available in case of anaphylactic reactions following 
vaccine administration. For example, epinephrine 1:1000, diphenhydramine, and/or 
other medications for treating anaphylaxis should be available. 

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6.4 
Vaccine Administration Error or Overdose of Vaccine 
Vaccine administration error is defined as receiving a dose of study vaccine that was not 
reconstituted as instructed or administered by a different route from the intended route of 
administration. An overdose of study vaccine (whether accidental or intentional) is 
defined when a dosage higher than the recommended dosage is administered in one dose 
of study vaccine. 
Any vaccine administration error or overdose of study vaccine detailed in this protocol 
must be reported as an adverse event, and if the vaccine administration error or overdose 
is associated with a serious adverse event, it must be reported as such within 24 hours to 
the Sponsor. 
6.5 
Prior and Concomitant Medications and Vaccines 
All medications, vaccines and blood products taken or received by the subject within 180 
days prior to the start of the study are to be recorded in the appropriate CRF. 
Medications taken for prophylaxis are those intended to prevent the onset of symptoms. 
Medications taken for treatment are intended to reduce or eliminate the presence of 
symptoms that are present. 
NOTE: Use of antipyretics/analgesics within 24 hours prior to vaccine administration is a 
reason to delay study vaccination (see section 4.3). 
Concomitant medications include all medications (including vaccines) taken 
by/administered to the subject at and after enrolment and must be documented in the 
appropriate CRF. 
When recording concomitant medications/vaccines, they should be checked against the 
study entry criteria in section 4.0, to ensure that the subject should be enrolled in the 
study. 
6.6  
Vaccine Supply, Labeling, Storage and Tracking 
The Sponsor will ensure the following: 
▫ Supply the study vaccines. 
▫ Appropriate labeling of all study vaccines provided that complies with the legal 
requirements of each country where the study is to be performed. 

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The investigator must ensure the following: 
▫ Acknowledge receipt of the study vaccines by a designated staff member at the site, 
including: 
- 
Confirmation that the vaccines were received in good condition 
- 
Confirmation to the Sponsor of the temperature range during shipment from the  
Sponsor to the investigator’s designated storage location 
- 
Confirmation by the Sponsor that the vaccines are authorized for use. 
▫ Proper storage of the study vaccines, including: 
- 
Storage in a secure, locked, temperature-controlled location. 
- 
Proper storage according to the instructions specified on the labels. 
- 
Appropriate record keeping and inventory of the study vaccines, including regular 
documentation of adequate storage temperature. 
▫ Appropriate use of the study vaccines, including: 
- 
No use of vaccines prior to receipt of authorization for use from the Sponsor. 
- 
Use only in accordance with the approved protocol. 
- 
Proper handling, including confirmation that the vaccine has not expired prior to 
administration. 
- 
Appropriate documentation of administration of vaccines to study subjects 
including: 
▪ 
Date, dosage, batch/lot numbers, expiration dates, unique identifying 
numbers assigned to subjects and study vaccines, and time of vaccine 
administration. This information will be maintained in an accountability log 
that will be reviewed by the site monitor. 
▪ 
Reconciliation of all vaccines received from the Sponsor. Reconciliation is 
defined as maintaining records of which and how many vaccines were 
received, which vaccines were administered to subjects, which vaccines 
were destroyed at the site, and which vaccines were returned to the Sponsor, 
as applicable. 
▫ Proper adherence to the local institutional policy with respect to destruction of study 
vaccines. 

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▫ Complete record keeping of vaccine use, wastage, return or destruction, including 
documentation of: 
- 
Copy of the site’s procedure for destruction of hazardous material. 
- 
Number of doses destroyed, date of destruction, destruction code (if available), 
method of destruction, and name of individual performing destruction. 
Vaccines that have been stored differently from the manufacturer’s indications must not 
be used unless the Sponsor provides written authorization for use. In the event that the use 
cannot be authorized, the Sponsor will make every effort to replace the vaccine supply. 
All vaccines used in conjunction with this protocol must be stored separately from normal 
hospital/practice stocks to prevent unintentional use of study vaccines outside of the 
clinical study setting. 
Monitoring of vaccine accountability will be performed by the study monitor during site 
visits and at the completion of the study. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator must ensure that all unused study vaccines, packaging and supplementary 
labels are destroyed locally (upon approval from Sponsor) or returned to the Sponsor. 

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7.0 
ASSESSMENTS 
7.1 
Safety Assessment 
The measures of safety used in this study are based on previous study data and based on 
comparable routine clinical/laboratory procedures. They include a close vigilance for, and 
stringent reporting of selected local and systemic adverse events routinely monitored in 
vaccine studies as indicators of reactogenicity. 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product at any dose that does 
not necessarily have to have a causal relationship with this treatment. Therefore, an AE 
can be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the investigational product. 
This definition includes intercurrent illnesses or injuries and exacerbation of pre-existing 
conditions. 
The period of observation for AEs extends from the time the subject signs informed 
consent until he or she completes the specified safety follow-up period (Day 366) or 
terminates the study early (whichever comes first). AEs occurring after the informed 
consent form is signed but prior to receiving study vaccine/product will be documented as 
an adverse event and recorded within the source documents. However, any AEs occurring 
prior to receipt of any study vaccine will be analyzed separately from “treatment 
emergent” AEs (AEs occurring after administration of the first study vaccine). 
Adverse events are collected as either solicited or unsolicited adverse events. Solicited 
events are derived from organized data collection systems, such as Subject Diaries or 
interview. 
7.1.1 
Solicited Adverse Events 
The term “reactogenicity” refers to solicited signs and symptoms (“solicited adverse 
events”) occurring in the hours and days following a vaccination, to be collected by the 
subject after the first 24 hours inpatient observation period at Day 1until Day 14, using a 
pre-defined Subject Diary. 
The following solicited adverse events are included in the Subject Diary. Each adverse 
event is to be assessed using the scoring system shown in Appendix A (Solicited Local 
AEs) and Appendix B (Solicited Systemic AE): 

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Solicited Local Adverse Events 
Solicited local AEs include: 
- 
injection site erythema 
- 
injection site induration 
- 
injection site pain 
- 
injection site swelling Solicited Systemic Adverse Events 
Solicited systemic AEs include: 
- 
body temperature ≥38.0°C (as measured orally) 
- 
loss of appetite 
- 
nausea 
- 
fatigue 
- 
generalized myalgia 
- 
generalized arthralgia 
- 
headache 
- 
chills 
- 
vomiting 
- 
diarrhea 
- 
generalized rash 
- 
urticaria 
Other Solicited Data 
Other solicited data collected per Subject Diary include: 
▫ Use of analgesics/antipyretics recorded as “absent” or “present” and summarized by 
“for treatment” or “for prophylaxis” 
▫ Body temperature as recorded daily, ideally at same time, by the oral route 
The study staff must review the data entered into the Subject Diary as described in 
sections 3.4.2 and 5.3.1. 

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NOTE: Any solicited adverse event that meets any of the following criteria must be 
entered into the subjects’ source documents (see section 9.1) and also as an adverse event 
in the appropriate CRF: 
▫ Solicited local or systemic adverse event that continues beyond Day 14 after 
vaccination. 
▫ Solicited local or systemic adverse event that leads to a visit to a healthcare provider 
(medically attended adverse event, see section 7.1.3). 
▫ Solicited local or systemic adverse event leading to the subject withdrawing from the 
study or the subject being withdrawn from the study by the investigator (adverse event 
leading to withdrawal, see section 7.1.3). 
▫ Solicited local or systemic adverse event that otherwise meets the definition of a 
serious adverse event (see section 7.1.4). 
7.1.2  
Unsolicited Adverse Events 
An unsolicited adverse event is an adverse event that was not solicited using a Subject 
Diary and that was spontaneously communicated by a subject who has signed the 
informed consent. 
7.1.3  
Evaluation of Adverse Events 
Every effort should be made by the investigator to evaluate safety information reported by 
a subject for an underlying diagnosis and to capture this diagnosis as the event in the AE 
page. In other words, the practice of reporting only symptoms (e.g., “cough” or “ear 
pain”) are better reported according to the underlying cause (e.g., “asthma exacerbation” 
or “otitis media”). 
The severity of events reported on the appropriate CRF page will be determined by the 
investigator as: 
Mild: 
transient with no limitation in normal daily activity. 
Moderate: 
some limitation in normal daily activity. 
Severe: unable to perform normal daily activity. 
The relationship of the study treatment to an AE will be determined by the investigator 
based on the following definitions: 

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1. Not Related 
The AE is not related to an investigational vaccine if there is evidence that clearly 
indicates an alternative explanation. If the subject has not received the vaccine, the timing 
of the exposure to the vaccine and the onset of the AE are not reasonably related in time, 
or other facts, evidence or arguments exist that reasonably suggest an alternative 
explanation, then the AE is not related. 
2. Possibly Related 
The administration of the investigational vaccine and AE are considered reasonably 
related in time and the AE could be explained by exposure to the investigational vaccine 
or by other causes. 
3. Probably Related 
Exposure to the investigational vaccine and AE are reasonably related in time and no 
alternative explanation has been identified. 
The relationship of the study treatment to an unsolicited AE will be determined by the 
investigator.  
Note: solicited AEs will not be evaluated for relationship to study treatment. Grading for 
severity of solicited local and systemic AEs is described in Appendix A and Appendix B. 
Adverse events will also be evaluated by the investigator for the co-existence of any of 
the other following conditions: 
▫ “Medically attended adverse event”: an adverse event that leads to a visit to a 
healthcare provider. 
▫ “New onset of chronic disease” (NOCD): an adverse event that represents a new 
diagnosis of a chronic medical condition that was not present or suspected in a subject 
prior to study enrolment. 
▫ AEs leading to withdrawal: adverse events leading to study or vaccine withdrawal. 
All AEs, regardless of severity, will be monitored until resolution or until the investigator 
assesses them as chronic or stable. All subjects experiencing AEs - whether considered 
associated with the use of the study vaccine or not - must be monitored until symptoms 
subside and any abnormal laboratory values have returned to baseline, or until there is a 
satisfactory explanation for the changes observed, or until death, in which case a full 
pathologist’s report should be supplied, if possible. 

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7.1.4  
Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose results in one or more of the following: 
▫ Death. 
▫ Is life-threatening (i.e., the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred); it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
▫ Required or prolonged hospitalization. 
▫ Persistent or significant disability/incapacity (i.e., the event causes a substantial 
disruption of a person’s ability to conduct normal life functions). 
▫ Congenital anomaly/or birth defect. 
▫ An important and significant medical event that may not be immediately life 
threatening or resulting in death or hospitalization but, based upon appropriate 
medical judgment, may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed above. 
Adverse events which do not fall into these categories are defined as non-serious. 
It should be noted that a severe adverse event need not be serious in nature and that a 
serious adverse event need not, by definition, be severe. 
Serious adverse events will be captured both on the Vaccines Serious Adverse Event 
(VSAE) form as well as on the appropriate CRF page. All SAEs will be evaluated by the 
investigator for relationship of the event to study vaccine. SAEs that are judged to be 
possibly or probably related to the study vaccine should be reported to the Sponsor as 
related/suspected events. 
The relationship of the study treatment to an SAE will be determined by the investigator 
based on the following definitions: 
1. Related/suspected 
The SAE is judged by the investigator to be possibly or probably related to the study 
vaccine on the appropriate CRF page (see section 7.1.3). 

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2. Not Related 
The SAE is not related if exposure to the study vaccine has not occurred, or the 
occurrence of the SAE is not reasonably related in time, or the SAE is considered 
unlikely to be related to use of the study vaccine, i.e., there are no facts (evidence) or 
arguments to suggest a causal relationship. 
The relationship of the study vaccine to an SAE will be determined by the investigator. 
In addition, SAEs will be evaluated by the Sponsor or designee for “expectedness.” An 
unexpected AE is one that is not listed in the current Summary of Product Characteristics 
or the Investigator’s Brochure or an event that is by nature more specific or more severe 
than a listed event. 
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded on the appropriate CRF. If the onset of an event occurred before the subject 
entered the study (e.g., any pre-planned hospitalization for conditions like cosmetic 
treatments or for non-emergency routine visits for a pre-existing condition), the 
hospitalization would not lead to an AE being classified as serious unless, in the view of 
the investigator, hospitalization was prolonged as a result of participation in the clinical 
study or was necessary due to a worsening of the pre-existing condition. 
7.1.4.1  
Adverse Events of Special Interest 
Certain adverse events of special interest (AESIs) are monitored after the administration 
of immunostimulatory agents. All subjects enrolled in this study will be monitored for 
AESIs for the entire follow-up period. The AESIs will be defined according to MedDRA 
preferred terms. The investigator will be provided with a list of AESIs prior to study start. 
Receipt of this list will be notified and stored, along with the list of AESIs, in the 
Investigator Site File. During the course of the trial the list of AESIs may change. If this 
occurs, the investigators will be advised of the change and confirmation of receipt will be 
documented. The updated list of AESIs and documentation of receipt are also stored in 
the Investigator Site File. The occurrence of any of these adverse events will be treated as 
a serious adverse event (SAE), meeting the criterion of a “medically important event.” 
Subjects will be assessed for diagnosis of an AESI at the following visits: 
- 
Pre-vaccination clinic visit (Day -28 to Day -3)  
- 
Visit 1 (Day 1, pre-vaccination) 
- 
Visit 2 (Day 4) 

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- 
Visit 3 (Day 8) 
- 
Visit 4 (Day 15) 
- 
Visit 5 (Day 22; Safety Follow-Up Call) 
- 
Visit 6 (Day 29) 
- 
Visit 7 (Day 85) 
- 
Visit 8 (Day 113) 
- 
Visit 9 (Day 181) 
- 
Visit 10 (Day 209; Safety Follow-Up Call) 
- 
Visit 11 (Day 271; Safety Follow-Up Call) 
- 
Visit 12 (Day 366; Study Termination Visit) 
At these visits a qualified health care practitioner listed on the site’s responsibilities and 
delegation logs will conduct a review of organ systems and a targeted physical exam and 
will evaluate subjects for any new signs or symptoms that could indicate one of the 
AESIs as specified in the list of AESIs stored in the Investigator Site File. They will also 
interview the subject about recent medical history and any new diagnosis that could 
indicate an AESI. Medical records related to any new medical event or diagnosis will be 
requested, reviewed by the site staff, and recorded in the subject’s source documents. 
A diagnosis of an AESI will be reported in the same manner and time frame as an SAE 
using the VSAE form. The investigator must notify GSK within 24 hours. The AESI 
diagnosis, as well as any medications taken to treat the condition, will be recorded in the 
subject’s source documents and on the appropriate CRF. 
7.1.5  
Methods for Recording Adverse Events and Serious Adverse Events 
All findings regarding Adverse Events must be reported on the appropriate CRF page and 
on the VSAE form, if applicable, which is part of the Investigator Site File. All findings 
in subjects experiencing AEs must be reported also in the subject's source document. 
All SAEs which occur during the course of the study, whether considered to be associated 
with the study vaccination or not, must be reported within 24 hours of the site becoming 
aware of the event to GSK or its designee. Specific instructions and contact details for 
collecting and reporting SAEs to GSK will be provided to the investigator. 

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All SAEs are also to be documented on the appropriate CRF page. Any medication or 
other therapeutic measures used to treat the AE will be recorded on the appropriate 
CRF(s) in addition to the outcome of the AE. 
After receipt of the initial report, representatives of GSK or its designee will contact the 
investigator if it is necessary to obtain further information for assessment of the event. 
All SAEs must be reported by the investigator to his/her corresponding EC and applicable 
regulatory authorities in accordance with institutional policy/regulatory requirements and 
adequate documentation of this notification must be provided to the Sponsor. 
GSK or its designee must also comply with the applicable regulatory requirement(s) 
related to the reporting of suspected unexpected serious adverse vaccine reactions (also 
known as SUSARs) to the regulatory authority(ies) and the IRB/EC. If a SUSAR or other 
safety signal relating to use of one of the study vaccines is reported to GSK or its 
designee, the Sponsor will communicate the information to the investigator and the 
investigator will be responsible for submitting this information to the EC and other 
relevant authorities. 
7.1.5.1 
Post-Study Events 
Any suspected SAE that occurs outside of the protocol-specified follow-up period or after 
the end of the study but considered to be caused by the study vaccine must be reported to 
GSK or its designee. These SAEs will be processed by GSK or its designee as during the 
course of the study, until 3 months after the last scheduled study visit. Instructions and 
contact details for collecting and reporting these suspected SAEs will be provided to the 
investigator. 
7.1.6  
Pregnancies 
To ensure subjects’ safety, each pregnancy in a subject after study vaccination must be 
reported to GSK within 72 hours of the site learning of its occurrence. If the subject 
agrees to submit this information, the pregnancy must be followed to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. This follow-up should occur even if intended duration of safety follow-up 
for the study has ended. 
Pregnancy data must be recorded on a Pregnancy Report CRF (initial report) and 
Pregnancy Follow-Up CRF (outcome report). 

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Any pregnancy outcome meeting the definition of a SAE (see section 7.1.4) must also be 
reported on the VSAE Report Form. 
7.1.7  
Safety Laboratory Measurements 
Blood and urine samples will be collected from all subjects at the Pre-vaccination  
Screening, at Visit 1 (pre-vaccination and 24 hours after vaccination), at Visit 3 and at 
Visit 6 as outlined in Time and Events Table 3. The blood safety laboratory assessments 
will include sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, 
liver function tests (ALT, AST), a complete blood count and C-reactive protein. The urine 
safety laboratory assessments will include protein, glucose and red blood cells. An 
additional blood and urine sample will be collected in case of a clinic Early Termination 
Visit as outlined in section 5.5.1. 
All testing will be conducted by qualified and certified laboratories. The Investigator 
must assess all safety laboratory results. Abnormal laboratory values must be classified 
by the Investigator as clinically significant or not. Abnormal laboratory values that are 
considered clinical significant will be defined following the FDA CBER Guidance for 
Industry “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials” dated September 2007, or the institution’s normal 
ranges if they differ from CBER guidance. Please see Appendix C, D and E for further 
details on the Toxicity Grading Scales according to CBER. 
Retesting may be performed in case of abnormal values per guidance of the investigator.  
7.2  
Efficacy Assessment 
Efficacy measurement will not be performed as part of this study. 
7.3  
Immunogenicity Assessment 
The measures to assess the primary and secondary immunogenicity endpoints for this 
study are standard, i.e., widely used and generally recognized as reliable, accurate, and 
relevant (able to describe the quality and extent of the immune response). 
The assay’s used in this study to assess the primary and immunogenicity endpoints are 
human serum bactericidal assay (hSBA) and ELISA specific for MenC 
The hSBA is a functional measure of the ability of specific antibodies, in conjunction 
with human complement, to kill MenC indicator strains, and is widely used and generally 
recognized as the serological correlate of protection. The specific ELISA will be used to 

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measure the induction of antibodies directed against MenC following vaccination with the 
study vaccines. 
Blood samples (approximately 10 ml) to obtain serum for hSBA and ELISA assays will 
be collected at Day 1, Day 8, Day 29 and Day 181 (refer to section 3.5 for detailed 
specimen collection procedures). 
Testing will be conducted by a GSK or designated laboratory in a blinded manner 
towards the treatment group. Laboratory contact details are listed in the Protocol 
Ancillary Document. 
All data will be captured at the laboratory and transferred via Electronic Data Transfer  
(EDT) 
Details on all blood sample handling steps are described in the Clinical Specimen Lab 
Manual provided to the study site. 
7.4 
Exploratory Measurements 
In those subjects who agree to a separate Informed Consent, additional blood samples will 
be collected at Day 1, Day 4, Day 8, Day 29 and Day 181 for exploratory measurements. 
The purpose of these exploratory measurements is to assess the systemic exposure of 
LHD153, to further delineate vaccine induced antigen specific immune responses and to 
evaluate biomarkers that may be predictive for safety and/or innate immune activation. 
All exploratory measurements will be conducted by a GSK or a designated laboratory. 
Laboratory contact details are listed in the Protocol Ancillary Document. 
Exploratory measurements may be performed after the Clinical Study Report (CSR) has 
been completed, in which case these data will be submitted as an addendum to the CSR. 
Systemic exposure of LHD153 
Systemic exposure of LHD153 will be assessed by analyzing LHD153 blood plasma 
levels at Day 1 (baseline, 1, 2, 4, 8 and 24h after vaccination) and Day 4 using 
LC/MS/MS. Time-points for assessment of clinical exposure of LHD153 have been 
selected based on non-clinical data in dogs and rats. 
Vaccine-induced antigen-specific immune responses 
The frequency of B cells specific for MenC polysaccharide and CRM197 will be 
determined by enzyme-linked immunosorbent spot (ELISPOT) at Day 1, Day 8, Day 29 
and Day 181 in order to evaluate the baseline specific B-cell frequency (Day 1), the peak 

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of plasmablast responses (Day 8), the peak of B cell memory responses (Day 29), and the 
persistence of memory B cell responses (Day 181). 
Subsequently, the diversity of the antigen specific B-cell repertoire will be analyzed in a 
selected subset of subjects. The selection of the subset will be based on the most 
pronounced response to the study vaccines when compared to baseline as determined by 
the primary and secondary immunogenicity assessment. 
The diversity of the elicited B-cell receptors will be assessed through sequence analysis of 
complementary DNA (cDNA) generated from immunoglobulin (Ig) messenger RNA 
(mRNA). The Ig cDNAs will be analyzed from antigen-specific B cells obtained at Day 
1, Day 29 and/or Day 181 and plasmablasts isolated at Day 8. The analysis of the B-cell 
receptor diversity does not have the intent nor the capability to identify or rule out any 
genetic modifications in the RNA or DNA that are presumably linked to disease or 
predisposition to disease. 
The frequency of T cells specific for the CRM197 protein at baseline (Day 1), at Day 8 and 
at Day 29 after vaccination with the study vaccines will be determined by FACS analysis 
using intracellular staining with a panel of cytokines and surface markers to identify cell 
populations. 
Early Markers for Safety and Innate immune activation 
The evaluation of potential biomarkers of safety and innate immune activation will be 
performed on blood specimens collected at Day 1 (baseline, 6h and 24h after vaccination) 
and Day 4. 
The vaccine-induced production of inflammatory cytokines and chemokines will be 
monitored on serum samples using a commercially available electrochemoluminescence 
assay for a panel of pro-inflammatory cytokines and chemokines, including Eotaxin, 
Eotaxin-3, GM-CSF, IFN-g, IL-1a, IL-1b, IL-10, IL-12 p70, IL-12/IL-23p40, IL-13, 
IL15, IL-16, IL-17A, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IP-10, MCP-1, MCP-
4, MDC, MIP-1a, MIP-1b, TARC, TNF-a, TNF-b, VEGF. 
The vaccine-induced expression of genes and gene families will be monitored on whole 
blood samples using of RNA microarrays by existing technologies. The RNA micro array 
analysis does not have the intent nor the capability to identify or rule out any genetic 
modifications in the RNA or DNA that are presumably linked to disease or predisposition 
to disease. 

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The vaccine-induced changes in myeloid (e.g. monocytes and dendritic cells) and 
lymphoid (e.g. NK cells, NKT cells) cell numbers and their activation status will be 
assessed using flow cytometry. 
8.0  
STATISTICAL CONSIDERATIONS 
8.1  
Endpoints 
8.1.1 
Primary Endpoint(s) 
8.1.1.1  
Primary Safety Endpoint(s) 
The measures for assessing safety and tolerability (by vaccine group within each cohort 
and by LHD153R adjuvant dosage group overall) are as follows: 
▫ The frequency and percentage of subjects with solicited local and systemic  AEs 
through Day 14. Time intervals after vaccination that will be summarized are:30 
minutes post-vaccination, Days 1-4 (without 30 minutes), Days 5-8, Days 8-14, Days 
1-8 (without 30 minutes) and Days 1-14 (without 30 minutes). 
▫ The frequency and percentage of subjects with any unsolicited AEs from the day of 
vaccination (Day 1) to Day 14. 
▫ The frequency and percentage of subjects with SAEs, medically attended AEs,  AEs 
leading to study withdrawal, NOCDs, AESIs for the following time periods: day of 
signed informed consent until study completion (Day 366), day of vaccination (Day 1) 
to Day 29, and Day 29 to study completion (Day 366). 
▫ The absolute values and changes in hematology, chemistry, and urinalysis parameters 
(see section 7.1.7). 
▫ The frequency and percentage of subjects with abnormal laboratory parameter values 
as classified by investigator normal ranges (low, normal, high) and as classified by 
CBER toxicity grading scales, when available. 8.1.1.2  
Primary Efficacy 
Endpoint(s) 
Not applicable. 
8.1.1.3  
Primary Immunogenicity Endpoint(s) 

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The primary immunogenicity endpoints are the GMTs measured by hSBA directed 
against MenC from samples collected on Day 1 (baseline, before vaccination) and Day 29 
as well as the GMR of the titers (Day 29 / Day 1). 
8.1.2 
Secondary Endpoint(s) 8.1.2.1 
 Secondary Safety Endpoint(s) 
Not applicable. 
8.1.2.2  
Secondary Efficacy Endpoint(s) 
Not applicable. 
8.1.2.3  
Secondary Immunogenicity Endpoint(s) 
The secondary immunogenicity endpoints are: 
▫ GMTs and corresponding GMRs measured by hSBA directed against MenC for 
samples collected at Day 8 and Day181. 
▫ Percentage of subjects with hSBA seroresponse at Days 8, 29, and 181. Seroresponse 
is defined as a post vaccination hSBA ≥8 for subjects with a baseline hSBA <4 or 
have an increase of at least 4 times the baseline hSBA level for subjects with 
prevaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against MenC measured by ELISA 
for samples collected on Days 1 (baseline, prior to vaccination), 8, 29, and 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations to 
MenC as measured by ELISA on Day 8, 29, and 181 relative to baseline (Day 1). 
8.1.3  
Exploratory Endpoint(s) 
The exploratory  endpoints are based on results of testing which may not be performed 
until after the study report has been finalized and will be further refined prior to testing. 
They include the following: 
▫ Serum concentration of LHD153 at Day 1 baseline (prior to vaccination), Day 1 (1h , 
2h, 4h, 8h, and 24h after vaccination), Day 4 by LC-MS/MS. 
▫ Frequency of MenC polysaccharide-specific and CRM197-specific B cells at Day 1 
(baseline), Day 8, Day 29, and Day 181 by ELISPOT. 

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▫ Diversity of MenC polysaccharide-specific B-cell repertoire at Day 1 (baseline), Day 
8, Day 29, and Day 181 by immunoglobulin cDNA sequencing. 
▫ Frequency and quality of T cells specific for CRM197 at Day 1 (baseline), Day 8, and 
Day 29 by flow cytometry analysis using intracellular staining with a wide panel of 
cytokines and surface markers to identify cell populations. 
▫ Serum concentrations of a panel of 30 chemokines and cytokines at Day 1 baseline 
(prior to vaccination), Day 1 (6h and 24h after vaccination), Day 4, and Day 8 by 
multiplex Electro-chemo-luminescence based assay. 
▫ Gene expression profile in whole blood at Day 1 baseline (prior to vaccination), Day 1 
(6h and 24h after vaccination), Day 4, and Day 8 by RNA micro array analysis. 
▫ Number and activation status of myeloid and lymphoid cell populations at Day 1 
baseline (prior to vaccination), Day 1 (24h after vaccination), Day 4 and Day 8 by 
flow cytometry. 
8.2  
Success Criteria 
The study has no formal statistical hypotheses and will not be declared positive or 
negative according to given rules. The selection of an appropriate LHD153R adjuvant 
dosage for future studies will be determined by the joint evaluation of the 
immunogenicity and safety profiles of each dosage group. 8.2.1  
Success Criteria 
for Primary Objective(s) Not applicable. 
8.2.2  
Success Criteria for Secondary Objective(s) 
Not applicable. 
8.3  
Analysis Sets 
8.3.1  
All Enrolled Set 
All screened subjects who provide informed consent and provide demographic and/or 
baseline screening assessments, regardless of the subject’s randomization and treatment 
status in the study and received a Subject ID. 
8.3.2  
All Exposed Set 
All subjects in the enrolled set who receive a study vaccination. 

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8.3.3  
Safety Set 
Safety Set (solicited adverse events and other solicited reactions) 
All subjects in the Exposed Set who: 
▫ Provide post vaccination reactogenicity data. 
Safety Set (unsolicited adverse events) 
All subjects in the Exposed Set who: 
▫ Have post-vaccination unsolicited adverse event records. 
Safety Set (overall) 
All subjects in the Exposed Set who: 
▫ Have either post-vaccination adverse event or reactogenicity records. 
Subjects will be analyzed as “treated” (i.e., according to the vaccine a subject received, 
rather than the vaccine to which the subject may have been randomized). 
8.3.4  
Full Analysis Set (FAS) Efficacy/Immunogenicity Set 
All subjects in the Enrolled Set who: 
▫ Receive a study vaccination AND provide efficacy/immunogenicity data at relevant 
time points. 
FAS sets will be analyzed “as randomized” (i.e., according to the vaccine a subject was 
designated to receive, which may be different from the vaccine the subject actually 
received). 
8.3.5  
Per Protocol (PP) Set Efficacy/Immunogenicity Set 
All subjects in the FAS efficacy/immunogenicity set who: 
▫ Are not excluded due to reasons (see section 8.3.8) defined prior to unblinding or 
analysis. 
PPS are subsets of FAS and should always be defined even if the objectives do not 
require it. 
Examples for subjects excluded due to other reasons than protocol deviations are: 

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- 
Subjects who withdrew informed consent. 
- 
Premature withdrawal due to an adverse event. 
Exclusions need to be considered by objective/time point, i.e., sometimes not all data of a 
subject but only part of the subject's data will be removed from the PPS analysis. 
8.3.6  
Other Analysis Sets  
All subjects in the Enrolled Set who consent to additional blood draws, receive a study 
vaccination AND provide exploratory assay data at relevant time points will be included 
in an exploratory assay subset. 
8.3.7  
Subgroups 
Selected immunogenicity analyses may be provided based on seropositivity status at 
baseline. 
8.3.8  
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. A protocol deviation may be a reason to remove data from 
an analysis set at the time of analysis. Reportable protocol deviations will be defined as 
exclusionary from the analysis according to protocol objectives and endpoints, which will 
be specified in the Statistical Analysis Plan. In some cases exclusion of data may be due 
to a reason other than a protocol deviation, e.g. early termination. 
8.4  
Statistical Analysis Plan 
This section provides a summary of the statistical methodology to be used. A more 
detailed description of analysis methods will be provided in a separate Statistical Analysis 
Plan which may also include additional exploratory analyses not explicitly mentioned in 
the following sections. 
8.4.1  
Analysis of Demographic and Baseline Characteristics 
Descriptive statistics (number of non-missing observations, mean, standard deviation, 
median, minimum and maximum) for age, height and weight at enrolment will be 
calculated overall and by vaccine group and LHD153R adjuvant dosage. 
Distributions of subjects by sex and ethnic origin will be summarized overall and by 
vaccine group and LHD153R adjuvant dosage. 

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8.4.2  
Analysis of Primary Objective(s) 
8.4.2.1  
Analysis of Primary Safety Objective(s) 
Safety of the study vaccines will be assessed in all subjects in terms of the frequency and 
percentage of reported AEs as well as by changes in clinical laboratory values.  
8.4.2.1.1  
Analysis of Extent of Exposure 
The frequency and percentage of subjects with vaccinations will be summarized by 
vaccine group and LHD153R adjuvant dosage, by cohort and overall, for the Enrolled 
Set. 
8.4.2.1.2  
Analysis of Solicited Local, Systemic and Other Adverse Events 
All solicited adverse events will be summarized according to defined severity grading 
scales. Use of medication to prevent/treat fever will be summarized according to 
frequencies and percentages reporting “Yes” and “No”. 
Frequencies and percentages of subjects experiencing each adverse event will be 
presented for each symptom severity. Summary tables showing the occurrence of any 
local or systemic adverse event overall and at each time point will also be presented. 
Post-vaccination solicited adverse events reported from Day 1 to Day 14 will be 
summarized for the intervals Day 1-4 (without 30 minutes), Day 5-8, Day 1-8 (without 30 
minutes), Day 8-14 and Day 1-14 (without 30 minutes) by maximal severity and by 
vaccine group and LHD153R adjuvant. The severity of solicited local adverse events, 
including injection-site erythema, swelling and induration will be summarized according 
to categories based on linear measurement: 25-50 mm, 51-100 mm, > 100 mm. 
Injection site pain and systemic reactions (except fever) occurring up to Day 14 will be 
summarized according to “mild”, “moderate” or “severe”. 
Each solicited local and systemic adverse event will also be further summarized as “none” 
versus “any”. 
Implausible measurements (for further definition see Statistical Analysis Plan) will be left 
out of the analysis. 
Use of antipyretics and analgesics will be summarized by frequency by type of use 
(prophylactic versus treatment) and percentage of subjects reporting use. The influence of 

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antipyretics and analgesics use on the occurrence of specific adverse events (e.g., fever, 
pain) will be assessed. 
Body temperature will be summarized by 0.5 °C and 1.0 °C increments from 36.0 °C up 
to ≥40 °C. 
8.4.2.1.3  
Analysis of Unsolicited Adverse Events 
This analysis applies to all adverse events occurring during the study, judged either as 
probably related, possibly related, or not related to vaccination by the investigator, 
recorded in the CRF, with a start date on or after the date of first vaccination. AE starting 
prior to the first vaccination will only be listed. The original verbatim terms used by 
investigators to identify adverse events in the CRFs will be mapped to preferred terms 
using the MedDRA dictionary. The adverse events will then be grouped by MedDRA 
preferred terms into frequency tables according to system organ class. 
All reported adverse events, as well as adverse events judged by the investigator as at 
least possibly related to study vaccine, will be summarized according to system organ 
class and preferred term within system organ class. These summaries will be presented by 
vaccination group and LHD153R adjuvant dosage for each cohort and by interval of 
study observation. When an adverse event occurs more than once for a subject, the 
maximal severity and strongest relationship to the vaccine group will be counted. 
Separate summaries will be produced for the following categories: 
▫ Serious adverse events. 
▫ Adverse events that are possibly or probably related to vaccine. 
▫ Adverse events of special interest. 
▫ New onset of chronic disease. 
▫ Adverse event leading to withdrawal. 
▫ Adverse events leading to a medically attended visit. 
▫ Adverse event by data source. 
Data listings of all adverse events will be provided by subject. In addition, adverse events 
in the categories above will be provided as listed data. 
8.4.2.1.4  
Analysis of Safety Laboratory Values 

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The investigator must review all safety laboratory results (see Section 7.1.7). Abnormal 
laboratory values and clinically significant changes in values from pre-vaccination 
(Screening Visit) will be assessed, using medical judgment, based on the FDA CBER  
Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” dated September 2007, or the 
institution’s normal ranges if they differ from CBER guidance. Please see Appendix C, D 
and E for further details. 
The following information will be provided: 
▫ Change in absolute laboratory value from pre-vaccination (Screening Visit) and Day 1 
(Visit 1) baseline to Day 1 (24 hours after vaccination), Day 8 (Visit 3) and Day 29 
(Visit 6) after vaccination. 
▫ The classification of laboratory values and/or their changes from pre-vaccination 
according to the CBER toxicity grading scale. 
▫ 3 x 3 shift tables by visit using the categorization of laboratory values according to 
institutional normal reference ranges (below, within, above). 
8.4.2.2  
Analysis of Primary Efficacy Objective(s) 
Not applicable. 
8.4.2.3  
Analysis of Primary Immunogenicity Objective(s) 
8.4.2.3.1  
Statistical Hypotheses 
There are no statistical hypotheses associated with the primary immunogenicity 
objectives. All analyses are descriptive. 
8.4.2.3.2  
Analysis Sets 
The primary immunogenicity analyses will be based on the per-protocol set (PPS) at Day 
29. The primary analyses will be repeated using the Full Analysis Set (FAS) as a measure 
of the sensitivity/robustness of the results (further details are given in section 8.3). 
8.4.2.3.3  
Statistical Methods 
Before any statistical analysis that assumes normally distributed observations, antibody 
titers will be log10-transformed. Individual titers below the limit of quantitation (LLQ) 
will be set to half that limit. 

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Geometric Mean Titers 
The logarithmically (base 10) transformed antibody titers will be modeled using an 
analysis of covariance (ANCOVA) model with a qualitative factor for LHD153R 
adjuvant dosage (0 [for unadjuvanted MenC], 12.5, 25, 50 or 100 µg) and log (base 10) 
pre-vaccination titer as a covariate. The adjusted GMT and the two-sided, 95%, 
confidence intervals (CIs) of the GMT will be calculated based on this model as will the 
ratio of GMTs and corresponding CIs. The adjusted GMT and two-sided 95% CIs will be 
constructed by exponentiation (base 10) of the least square means of the logarithmically 
transformed (base 10) antibody titer. The ratio of GMTs (LHD153R adjuvant dosage 
minus MenC), and corresponding two-sided 95% CIs, will be constructed by 
exponentiation (base 10) of the least square differences obtained from this model. The 
model can be written as:  
log10 (yik) = µ + αi + βxik + εik 
where µ represents a common overall mean, αi represents the adjuvant dose group i effect, 
β represents the common slope for the log10 pre-vaccination titer, xik for subject k in 
adjuvant dose group I, and εik represents random error for subject k in adjuvant dose 
group i. 
Geometric Mean Ratios 
The logarithmically (base 10) transformed within subject ratio of antibody titers (Day 29 / 
pre-vaccination) will be modeled using an analysis of variance model with a qualitative 
factor for LHD153R adjuvant dosage (0 [for non-LHD153R adjuvanted MenC], 12.5, 25, 
50 or 100 µg). The adjusted GMR and the two-sided, 95% CIs of the GMR will be 
calculated based on this model. The model can be written as: 
log10 (yik) = µ + αi + εik 
where µ represents a common overall mean, αi represents the adjuvant dose group i effect 
and εik represents random error for subject k in adjuvant dose group i. 
Handling of missing values 
For immunogenicity data, it may be reasonable to consider missing immunogenicity 
values as missing completely at random (MCAR), i.e., not informative. Therefore, the 
primary analysis will comprise a complete case analysis only, without introducing any 
bias. Imputation methods will not be used. 

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8.4.3  Analysis of Secondary Objective(s) 8.4.3.1 
 Analysis of Secondary Safety Objective(s) Not 
applicable. 
8.4.3.2  
Analysis of Secondary Efficacy Objective(s) 
Not applicable. 
8.4.3.3  
Analysis of Secondary Immunogenicity Objective(s) 
8.4.3.3.1  
Statistical Hypotheses 
There are no statistical hypotheses associated with the secondary immunogenicity 
objectives. All analyses are descriptive. 
8.4.3.3.2  
Analysis Sets 
The secondary immunogenicity analyses will be based on the PPS (further details are 
given in section 8.3) or the appropriate subset of subjects. 
8.4.3.3.3  
Statistical Methods 
The secondary immunogenicity endpoints are: 
▫ GMTs and corresponding GMRs measured by hSBA directed against MenC for 
samples collected at Day 8 and Day181. 
▫ Percentage of subjects with hSBA seroresponse at Days 8, 29, and 181. seroresponse is 
defined as a post vaccination hSBA ≥8 for subjects with a baseline hSBA <4 or have 
an increase of at least 4 times the baseline hSBA level for subjects with 
prevaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against MenC measured by ELISA 
for samples collected on Days 1 (baseline, prior to vaccination), 8, 29, and 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations to 
MenC as measured by ELISA on Day 8, 29, and 181 relative to baseline (Day 1). 
The GMTs for samples collected at Day 8 and Day 181 as well as the GMCs for samples 
collected at Day 1, Day 8, Day 29, and Day 181 will be analyzed using the same approach 
as for the primary immunogenicity endpoint. 

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The remaining immunogenicity endpoints are based on subjects meeting criteria for 
seroconversion or achieving a certain threshold value. These endpoints will be 
summarized using frequencies and percentages by LHD153R adjuvant dosage (0 [for 
non-LHD153R adjuvanted MenC], 12.5, 25, 50 or 100 µg). Two-sided 95% 
ClopperPearson CIs will also be provided for percentages. For analyses of 
seroconversion, separate summaries may be provided based on seropositivity status at 
baseline. 
8.4.4  
Analysis of Exploratory Objectives 
Testing and analyses of exploratory endpoints may be performed after the Clinical Study 
Report (CSR) has been completed, in which case these data will be submitted as an 
addendum to the CSR. 
In general, concentration and titer results will be summarized for each LHD153R 
adjuvant dosage group using geometric means and associated 2-sided 95% confidence 
intervals; and, categorical data will be summarized using frequencies and percentages, 
with corresponding two-sided, 95% confidence intervals. 
8.5  
Sample Size and Power Considerations of Primary Objectives 
Sample size is not driven by statistical assumptions for formal hypothesis testing, but was 
based on the safety objective for the study. The table below provides the probability for 
various combinations of sample size (N) and presumed true frequency of a given event 
within an individual vaccine group  
Frequency 
of Event 
Probability to Observe at Least 1 Subject with a Given Event For  
Various Choices of N 
4 
8 
12 
16 
0.05 
0.1855 
0.3366 
0.4596 
0.5599 
0.10 
0.3439 
0.5695 
0.7176 
0.8147 
0.15 
0.4780 
0.7275 
0.8577 
0.9257 
0.20 
0.5904 
0.8322 
0.9313 
0.9718 
0.30 
0.8250 
0.9423 
0.9862 
0.9967 
0.40 
0.8704 
0.9832 
0.9978 
0.9997 

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The proposed combinations of sample sizes within each cohort are 4 aluminium 
hydroxide adjuvanted MenC-CRM197 and 16 MenC-CRM197 plus an assigned-level of 
LHD153R adsorbed to aluminium hydroxide. If all four cohorts are fully enrolled, there 
will be 16 subjects receiving aluminium hydroxide adjuvanted MenC-CRM197. 
With 16 subjects, events which occur at a frequency of 15% or more will be detected with 
at least 90% probability; and, events which occur at a frequency of 10% or more will be 
detected with 81% probability. With 4 subjects, events which occur at a frequency of 30% 
or more will be detected with at least 80% probability. Intermediate values of 8 and 12 
are provided to correspond to sample sizes in the MenC- CRM197 after cohort 2 and 
cohort 3 are fully enrolled. 
8.6  
Interim Analysis 
The DMC will be reviewing the accumulating safety data from the study in order to 
continue enrollment of subjects within a cohort and whether to enroll subjects into the 
next cohort. 
In addition to these periodic reviews, there will be a safety and immunogenicity interim 
analysis for the selection of an LHD153R adjuvant dosage based on the data collected 
through Day 29 from subjects enrolled in all cohorts. This analysis will be performed by 
personnel not involved in study decisions. The results will be unblinded at the group level 
thereby preserving the blind for individual subjects. No adjustment to the overall alpha 
will be performed as the data collected subsequent to this analysis involve secondary and 
exploratory endpoints. 
 

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9.0  
SOURCE DOCUMENTATION, STUDY MONITORING AND 
AUDITING 
Study monitoring and auditing will be standardized and performed in accordance with the 
Sponsor’s or delegated contract research organization’s (CRO) standard operating 
procedures and applicable regulatory requirements (e.g., FDA, EMA, and ICH 
guidelines). 
Prior to enrolment of the first study subject, GSK or delegate will train investigators 
and/or their study staff on the study protocol, all applicable study procedures, 
documentation practices and all electronic systems. CRFs must be completed for each 
enrolled subject (see section 8.3.1 for definition of enrolled subject). Documentation of 
screened but not enrolled subjects must be maintained at the site and made available for 
review by the site monitor. 
9.1  
Source Documentation 
Prior to the start of the study, the site staff participating in the study conduct will be 
instructed on what documents will be required for review as source documents. The kinds 
of documents that will serve as source documents will be agreed between Sponsor or 
delegate and investigator and designees and specified in the SDA/Source Data 
Verification Form prior to subject enrolment. 
In addition, source documentation must include all of the following: subject identification 
(on each page), eligibility and participation, proper informed consent procedures, dates of 
visits, adherence to protocol procedures, adequate reporting and follow-up of adverse 
events, documentation of prior/concomitant medication/vaccines, study vaccine 
receipt/dispensing/return records, study vaccine administration information, any data 
collected by a telephone conversation with the subject and date of completion and reason. 
The subject must also allow access to the subject’s medical records. Each subject must be 
informed of this prior to the start of the study and consent for access to medical records 
may be required in accordance with local regulations. 
All safety data reported by subjects must be written down in source documents. If there 
are multiple sources of information (e.g., Subject Diary, verbal report of the subject, 
telephone contact details, medical chart) supporting the diagnosis of an adverse event, 
these sources must be identified in the source documents, discrepancies between sources 
clarified, the ultimate diagnosis must be justified and written in the source documents, 
and this diagnosis must be captured in the appropriate CRF page. The CRF must also 

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capture which source(s) of information were used to determine the adverse event (e.g., 
subject recall, medical chart, Subject Diary). 
9.2  
Study Monitoring, Auditing and Source Data Verification 
Prior to enrolment of the first study subject, GSK or its designee (e.g., a CRO) will 
develop a Monitoring Plan to specify how centralized and/or on-site monitoring, 
including clinical specimens reconciliation, will be performed for the study. Study 
progress will be monitored as frequently as necessary to ensure: 
▫ that the rights and well-being of human subjects are protected, 
▫ the reported study data are accurate, complete, and verifiable from the source 
documents and 
▫ the conduct of the study is in compliance with the current approved 
protocol/amendment(s), GCP and applicable regulatory requirements. 
Contact details for the team involved in study monitoring will be provided to the 
investigator. Study data recorded on CRFs will be verified by checking the CRF entries 
against source documents in order to ensure data completeness and accuracy as required 
by study protocol. 
Additional documents such as the investigator site file, pharmacy records, and informed 
consent documentation must also be available for review if requested. Arrangements for 
monitoring visits will be made in advance in accordance with the monitoring plan, except 
in case of emergency. 
The investigator and/or site staff must make source documents of subjects enrolled in this 
study available for inspection at the time of each monitoring visit and Sponsor audits, 
when applicable. These documents must also be available for inspection, verification and 
copying, as required by regulations, by officials of the regulatory health authorities (e.g., 
FDA, EMA and others) and/or ECs/IRBs. The investigator and study site staff must 
comply with applicable privacy, data protection and medical confidentiality laws for use 
and disclosure of information related to the study and enrolled subjects. 
10.0  
DATA MANAGEMENT 
10.1 
Data Entry and Management 
In this study, all clinical data (including, but not limited to, AE/SAEs, concomitant 
medications, medical history, and physical assessments), safety data, and immunogenicity 
data will be entered into an EDC system, which is compliant with Title 21 Part 11 

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policies of the Code of Federal Regulations (FDA, 1997). The data system includes 
password protection and internal quality checks. The EDC system will be designed and 
validated by the Sponsor prior to activation for data entry by sites. The investigator or 
designated delegate must review data entered and electronically sign the CRFs to verify 
their accuracy. 
Access to the EDC system for data entry or review will require training and distinct 
individual access code assignments to those site staff members who will be entering study 
data and those involved in study oversight who may review study data. Data are collected 
within the EDC system, to which the Sponsor and site monitors have exclusively “read 
only” access. 
Paper CRFs will be provided for each pregnant subject by the Sponsor. All appropriate 
pregnant subject data collected will be recorded on this form. One copy must be retained 
by the investigator, and all other copies (including the original copy) will be returned as 
directed by the Sponsor. Instructions on how to complete this form will be provided to the 
investigator. 
10.2  
Data Clarification 
As part of the conduct of the trial, the Sponsor may have questions about the data entered 
by the site, referred to as queries. The monitors and the Sponsor are the only parties that 
can generate a query. All corrections and clarifications will be entered into the EDC 
system and will be identified by the person entering the information, the reason for the 
change, as well as the time of the changes made. If changes are made to a previously and 
electronically signed CRF, the investigator must confirm and endorse the changes 
10.3  
Data Protection 
GSK respects the subjects’ rights to privacy and will ensure the confidentiality of their 
medical information in accordance with all applicable laws and regulations. 
The Sponsor as Data Controller according to the European Directive on the protection of 
individuals with regard to the processing of personal data and on the free movement of 
such data (95/46/EC) confirms herewith compliance to Directive 95/46/EC in all stages of 
Data Management. 
 

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11.0  
RECORD RETENTION 
Investigators must retain all study records required by GSK and by the applicable 
regulations in a secure and safe facility. The investigator must consult a GSK 
representative before disposal of any study records, and must notify the Sponsor of any 
change in the location, disposition, or custody of the study files. Essential documents 
must be retained for 15 years. “Essential documents” are defined as documents that 
individually and collectively permit evaluation of the conduct of a study and the quality 
of the data produced. These documents should be retained for a longer period, however, if 
required by the applicable national regulatory or institutional requirements.  
These principles of record retention will also be applied to the storage of laboratory 
samples, provided that the integrity of the stored sample permits testing. 
 

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12.0  
USE OF INFORMATION AND PUBLICATION 
GSK assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov, and in compliance with current regulations. 
GSK also assures that key results of this clinical study will be posted in a publicly 
accessible database within the required time-frame from the End of Study as defined in 
section 3.9. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
GSK must be notified of any intent to publish data collected from the study and prior 
approval from GSK must be obtained prior to submission for publication. 
 

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13.0  
ETHICS 
13.1  
Regulatory and Ethical Compliance 
The study will be conducted in compliance with the protocol, GCP and applicable 
regulatory requirement(s). 
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, European 
Directive 2001/20/EC, GSK codes on protection of human rights, and with the ethical 
principles laid down in the Declaration of Helsinki (European Council 2001, US Code of 
Federal Regulations, ICH 1997). 
13.2  
Informed Consent Procedures 
Eligible subjects may only be included in the study after providing written informed 
consent or assent, as described in section 5.1.1. Before the start of the study, the 
investigator will have the informed consent and any other materials that will be provided 
to the subjects reviewed and approved by the IRB/EC. This review and approval will be 
documented and stored with other study documents. The investigator or designee must 
fully inform the subject or legal guardian of all pertinent aspects of the study. A copy of 
the written informed consent will be given to the subject or the designee. The 
subject/designee must be allowed ample time to ask about the details of the study and to 
make a decision as to whether or not to participate in the study. The subject and/or legal 
guardian(s) must sign the consent form indicating their agreement to participate in the 
study before any study-related procedures are conducted. The informed consent process 
may be conducted up to 28 days prior to vaccination on Day 1. If the subject is unable to 
read and write, a witness must be present during the informed consent discussion and at 
the time of informed consent signature. 
Prior to the start of the study, GSK will provide to investigators a proposed informed 
consent form that complies with the ICH GCP guideline and regulatory requirements and 
is considered appropriate for this study. Any changes to the proposed consent form 
suggested by the investigator must be agreed to by GSK before submission to the IRB/EC 
and a copy of the approved version must be provided to GSK after IRB/EC approval. 
Women of childbearing potential should be informed that taking the study medication 
may involve unknown risks to the fetus if pregnancy were to occur during the study and 
agree that in order to participate in the study they must adhere to the contraception 
requirements indicated in the protocol for the duration of the study. In case of doubt on 

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the ability of a subject to adhere to these requirements, that subject should not be allowed 
in the study 
13.3  
Responsibilities of the Investigator and IRB/EC 
The protocol and the proposed informed consent form must be reviewed and approved by 
a properly constituted IRB/EC before study start. Properly constituted IRB/EC is defined 
in ICH Guideline for Good Clinical Practice E6 (R1), Section 3 (ICH, 1997). A signed 
and dated statement that the protocol and informed consent have been approved by the 
IRB/EC must be given to GSK before study initiation. Prior to study start and at any time 
the protocol is amended during study conduct, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance 
with these documents and all of the instructions and procedures found in this protocol and 
to give access to all relevant data and records to GSK monitors, auditors, GSK Clinical 
Quality Assurance representatives, designated agents of GSK, IRBs/ECs, and regulatory 
authorities as required. If an inspection of the clinical site is requested by a regulatory 
authority, the investigator must inform GSK immediately that this request has been made. 
The investigator also responsible for the following: 
▫ Maintaining a list of appropriately qualified persons to whom the investigator has 
delegated significant study-related duties. 
▫ Demonstrating the capability of recruiting the required number of suitable subjects 
within the recruitment period. 
▫ Demonstrating sufficient time and staffing to properly conduct and complete the study 
within the agreed study period. 
▫ Ensuring that all persons assisting with the study are adequately informed about the 
protocol, the investigational product(s), and their study-related duties and functions 
▫ Ensuring that appropriately trained health care professionals are responsible for all 
study-related medical decisions and for ensuring appropriate medical care of subjects 
experiencing any adverse event related to the study. 
▫ If permission to do so is given by the subject, ensuring that the subject’s primary 
healthcare provider is informed of the subject’s participation in the study. 
The investigator should not implement any deviation from, or changes of the protocol 
without agreement by the Sponsor and prior review and documented approval/favourable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an 
immediate hazard(s) to study subjects, or when the change(s) involves only logistical or 
administrative aspects of the study (e.g., change in monitor(s), change of telephone 

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number(s)). In addition, the investigator, or person designated by the investigator, should 
document and explain any deviation from the approved protocol. 
The investigator may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior IRB/IEC 
approval/favourable opinion. As soon as possible, the implemented deviation or change, 
the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be 
submitted: 
(a) to the IRB/IEC for review and approval/favourable opinion, 
(b) to the Sponsor for agreement and, if required, 
(c) to the regulatory authority(ies). 
13.4  
Protocol Amendments 
An amendment is a written description of change(s) to or formal clarification of a study 
protocol which may impact on the conduct of the clinical study, potential benefit of the 
clinical study, or may affect subject safety, including changes of study objectives, study 
design, subject population, sample sizes, study procedures, or significant administrative 
aspects. An administrative change of a study protocol is a minor correction or 
clarification that has no significant impact on the way the clinical study is to be conducted 
and no effect on subject safety (e.g., change of telephone number(s), logistical changes). 
Protocol amendments must be approved by GSK, health authorities where required, and 
the IRB/EC. In cases when the amendment is required in order to protect the subject 
safety, the amendment can be implemented prior to IRB/EC approval. Notwithstanding, 
the need for formal approval of a protocol amendment, the investigator is expected to take 
any immediate action required for the safety of any subject included in this study, even if 
this action represents a deviation from the protocol. In such cases, GSK should be notified 
of this action, the IRB/EC at the study site, and, if required by local regulations, the 
relevant health authority should be informed within 10 working days. 
14.0  
REFERENCE LIST 
Alving CR, Peachman KK, Rao M, Reed SG. Adjuvants for human vaccines. Curr Opin 
Immunol. 2012 Jun; 24(3):310-5 
Bauza, A et al., Pemphigus-like lesions induced by imiquimod. Clin Exp Dermatol 2009, 
34, e60-62 

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Bissett SL, Draper E, Myers RE, Godi A, Beddows S. Cross-neutralizing antibodies 
elicited by the Cervarix® human papillomavirus vaccine display a range of Alpha-9 
intertype specificities. Vaccine. 2014 Feb 26; 32(10):1139-46 
Campanelli, A et al., Topical application of imiquimod and associated fever in children. J 
Am Acad Dermatol 2005,52, E1. 
Code of Federal Regulations (1997): Food and Drug Administration, U.S. Department of 
Health and Human Services: Title 21, Part 11: Electronic Records Electronic Signatures. 
Federal Register 62: 13464 
Connolly M and Noah N, Is group C meningococcal disease increasing in Europe? A 
report of surveillance of meningococcal infection in Europe 1993-6. Epidemiol. Infect. 
1999; 122: 41-49. 
Del Giudice G, Fragapane E, Della Cioppa G, et al. Aflunov®: a vaccine tailored for 
prepandemic and pandemic approaches against influenza. Expert Opin Biol Ther. 2013; 
13: 121-35. 
European Centre for Disease Prevention and Control. Surveillance of invasive bacterial 
diseases in Europe 2008/2009. Stockholm: ECDC 2011 
European Parliament (1995): Directive 95/46/EC of the European Parliament and of the 
Council of 4 April 2001. Official Journal of the European Communities. L 281/31-39 
European Parliament (2001): Directive 2001/20/EC of the European Parliament and of the 
Council of 4 April 2001. Official Journal of the European Communities. L 121/34-44 
Hellenbrand W, Elias J, Wichmann O et al. Epidemiology of invasive meningococcal 
disease in Germany, 2002-2010, and impact of vaccination with meningococcal C 
conjugate vaccine. Journal of Infection 2013; 66: 48-56. 
ICH (1997) ICH Harmonised Tripartite ICH Guideline for Good Clinical Practices E6  
(R1). Federal Register, 62 (90): 25691-25709 
ICH (1998) ICH Harmonised Tripartite ICH Guideline for Statistical Principles for 
Clinical Trials E9. Federal Register, 63 (179): 49583 
Ilyinskii, PO, et al., Adjuvant-carrying synthetic vaccine particles augment the immune 
response to encapsulated antigen and exhibit strong local immune activation without 
inducing systemic cytokine release. Vaccine, available online 1 March 2014. 

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Khurana, S., W. Chearwae, F. Castellino, J. Manischewitz, L.R. King, A. Honorkiewicz, 
M.T. Rock, K.M. Edwards, G. Del Giudice, R. Rappuoli, and H. Golding. 2010. 
MF59adjuvanted vaccines expand antibody repertoires targeting protective sites of 
pandemic H5N1 influenza virus. Science Transl. Med. 2: 15ra5: 1-8. 
Khurana, S., N. Verma, J.W. Yewdell, A.K. Hilbert, F. Castellino, M. Lattanzi, G. Del 
Giudice, R. Rappuoli, and H. Golding. 2011. MF59 adjuvant affects human epitope 
repertoire, augments affinity maturation, and neutralization titers to pandemic influenza in 
all age groups. Science Transl. Med. 3: 85ra48. 
Levine RJ. (1988) Ethics and Regulations of Clinical Research. New Haven: Yale 
University Press. 
Meyer, T et al., Clinical investigations of Toll-like receptor agonists. Expert Opin Investig 
Drugs 2008, 17:1051-1065. 
Recommendations of the Standing Committee on Vaccination (STIKO) at the Robert  
Koch Institute / Effective: August 2013; Robert Koch Institut Epidemiologisches Bulletin 
34, 26 August 2013 
Reed SG, Orr MT, Fox CB. Key roles of adjuvants in modern vaccines. Nat Med. 
2013;19 :1597-608. 
Regules JA, Cummings, JF and Ockenhouse CF. The RTS, S vaccine candidate for 
malaria. Expert Rev Vaccines 2011; 10:589-599. 
Rosenstein N, Perkins B, Stephens DS, et al. N. Engl. J. Med. 2001; 344: 1378-1388. 
Tacken, PJ et al., Targeted delivery of TLR ligands to human and mouse dendritic cells 
strongly enhances adjuvanticity. Blood 2011, 118:6836-6844. 
Takeda K, Kaisho T, Akira S Toll-like receptors. Annu.Rev.Immunol. 2003; 21: 335-76. 
U.S. Department of Health and Human Services, Food and Drug Administration, CBER 
(2009): Guidance for Industry Patient-Reported Outcome Measures: Use in Medical  
Product Development to Support Labeling Claims 
Vasilakos JP, and Tomai MA. The use of Toll-like receptor 7/8 agonists as vaccine 
adjuvants." Expert Rev Vaccines 2013; 12: 809-819. 
World Medical Association General Assembly Declaration of Helsinki - Ethical  
Principles for Medical Research Involving Human Subjects (1996) 
 

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APPENDIX A: GRADING SCALES FOR SOLICITED LOCAL ADVERSE  
EVENTS* 
(Adapted from CBER 2007b) 
Adverse event Following  
Administration of  
Injectable Product  
Mild (Grade 
1)  
Moderate 
(Grade 2)  
Severe 
(Grade 3)  
Pain 
present but does not 
interfere with activity 
interferes with activity 
prevents daily activity 
Induration / Swelling /  
Erythema 
25 – 50 mm 
51 – 100 mm  
> 100 mm  
*This toxicity grading scale is adapted from CBER 2007 to enable ease of reporting by Subjects in the 
source documents for ‘patient reported’ solicited adverse events.. ‘Grade 4’ is not listed here but will be 
defined in the Statistical Analysis Plan as necessary. 
 

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APPENDIX B: GRADING SCALES FOR SOLICITED SYSTEMIC ADVERSE  
EVENTS* 
(Adapted from CBER 2007b) 
Systemic  
Adverse event 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Fever 
°C 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 - 102 
39.0 – 40 
102.1 - 104 
°F 
Chills 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Loss of Appetite 
Loss of appetite without 
decreased oral intake  
decreased oral intake  
without weight loss 
decreased oral intake with 
weight loss 
Nausea 
Nausea present but not 
interfering with oral intake 
Nausea leading to decreased 
oral intake 
Nausea leading to minimal to 
no oral intake 
Vomiting 
1-2 episodes/24 hours 
>2 episodes/24 hours 
requires outpatient 
hydratation 
Diarrhea 
2-3 loose stools /24 hours 
4-5 loose stools /24 hours 
6 or more watery stools /24 
hours or requires outpatient 
IV hydration 
Generalized  
Myalgia 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Generalized  
Arthralgia 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Headache 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Fatigue 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Generalized  
Rash 
localized area of the skin (1 
extremity only) 
moderate area of the skin 
(2 or more body regions 
without whole body 
involvement) 
most of the skin 
Urticaria 
localized area of the skin (1 
extremity only) 
moderate area of the skin 
(2 or more body regions 
without whole body 
involvement) 
most of the skin 

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*This toxicity grading scale is adapted from CBER 2007b to enable ease of reporting by Subjects in the 
source documents for ‘patient reported’ solicited adverse events. ‘Grade 4’ is not listed here but will be 
defined in the statistical analysis plan as necessary 

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TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
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APPENDIX C:  
(SERUM CLINICAL CHEMISTRY)  
Serum*,** 
Mild (Grade 1)  
Moderate 
(Grade 2)  
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)*** 
Sodium – Hyponatremia 
mEq/L  
132 – 134  
130 – 131  
125 – 129  
< 125  
Sodium – Hypernatremia 
mEq/L  
144 – 145  
146 – 147  
148 – 150  
> 150  
Potassium – Hypokalemia 
mEq/L  
3.5 – 3.6  
3.3 – 3.4  
3.1 – 3.2  
< 3.1  
Potassium – Hyperkalemia 
mEq/L  
5.1 – 5.2  
5.3 – 5.4  
5.5 – 5.6  
> 5.6  
Blood Urea Nitrogen  
BUN mg/dL  
23 – 26  
27 – 31  
> 31  
Requires dialysis  
Creatinine – mg/dL  
1.5 – 1.7  
1.8 – 2.0  
2.1 – 2.5  
> 2.5 or requires 
dialysis  
Liver Function Tests –ALT,  
AST  
increase by factor  
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN  
5.1 – 10 x ULN  
> 10 x ULN  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 
**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 

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***The clinical signs or symptoms associated with laboratory abnormalities might result in characterization 
of the laboratory abnormalities as Potentially Life Threatening (Grade 4). For example. a low sodium value 
that falls within a grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia event if 
the subject had a new seizure associated with the low sodium value. “ULN” = the upper limit of the normal 
range. 
APPENDIX D:  
(HEMATOLOGY) 
Hematology*,** 
Mild (Grade 
1)  
Moderate  
(Grade 2)  
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)  
Hemoglobin (Female) 
gm/dL  
11.0 – 12.0  
9.5 – 10.9  
8.0 – 9.4  
< 8.0  
Hemoglobin (Female) 
change from baseline 
value - gm/dL  
Any decrease – 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
Hemoglobin (Male) 
gm/dL  
12.5 – 13.5  
10.5 – 12.4  
8.5 – 10.4  
< 8.5  
Hemoglobin (Male) 
change from baseline 
value – gm/dL  
Any decrease – 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
WBC Increase - cell/mm3 
10,800 – 15,000  
15,001 – 20,000  
20,001 – 25, 000  
> 25,000  
WBC Decrease cell/mm3 
2,500 – 3,500 
1,500 – 2,499  
1,000 – 1,499  
< 1,000  

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Platelets Decreased 
cell/mm3 
125,000 – 140,000 
100,000 – 124,000 
25,000 – 99,000  
< 25,000  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate.  
**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 
APPENDIX E:  
(URINE) 
Urine*,** 
Mild (Grade 
1)  
Moderate  
(Grade 2)  
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)  
Protein  
Trace  
1+  
2+  
Hospitalization or 
dialysis  
Glucose  
Trace  
1+  
2+  
Hospitalization for 
hyperglycemia  
Blood (microscopic) – 
red blood cells per high 
power field (rbc/hpf)  
1 - 10  
11 – 50  
> 50 and/or gross 
blood  
Hospitalization or 
packed red blood 
cells (PRBC) 
transfusion  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 
**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 

 
 
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      Document Approval Certificate /  
     
  
  
The individuals listed have approved this document for implementation using an electronic signature in 
the  
Atlas EDMS. PPD 
   
UserName: PPD 
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GlaxoSmithKline Biologicals  
Clinical Study Protocol V132_01EXP Amendment 5 
19 JAN 16 
Confidential 
Page 1 of 2 
 
CLINICAL STUDY PROTOCOL AMENDMENT 
Study Number: V132_01EXP 
Protocol Title:  A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study to 
Evaluate the Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R 
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium  
Hydroxide Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy 
Adults (18-45 years of age) 
Amendment Number 5 
Revised Protocol version 6.0 issued on 19 Jan 2016 
The present amendment reflects changes to the Protocol version 5.0 issued on 
11SEP15   
Property of GlaxoSmithKline 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of GlaxoSmithKline 

  
Confidential 
 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 
GlaxoSmithKline Biologicals 
Clinical Study Protocol V132_01EXP Amendment 5 
19 JAN 16 
Page 2 of 2 
 
DESCRIPTION OF CHANGE(S) AND RATIONALE: 
CHANGE 
LOCATION(S) OF  
CHANGE 
RATIONALE FOR  
CHANGE 
Added under pausing 
guidelines that in case 
criteria for pausing are met, 
vaccination will be 
suspended and a full safety 
review by the DMC and  
EC/IRB will be performed. 
Section 3.6  
‘Stopping/Pausing  
Guidelines’ (page 38-39)   
The Ethics Committee 
approval was received 
under the condition that the 
Ethics Committee is 
consulted in case pausing 
criteria are met.  
Added that the names of the 
independent DMC members 
are mentioned in the DMC 
charter 
Section 3.7 ‘Data  
Monitoring Committee’ 
(page 39) 
Ethics Committee provided 
comment that members of 
the DMC should be 
mentioned and be 
independent  
Added Appendix F with 
grading scales for Vital 
Signs. 
Appendix F (page 105) 
For clarification of the 
grading scales for vital signs  
Added description of the 
procedure for emergency 
unblinding. 
Section 3.3 ‘Blinding  
Procedures’ (page 33-34) 
The Paul-Ehrlich Institute 
requested to describe the 
procedure for emergency 
unblinding. 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 

 
 
Novartis  
  
      Document Approval Certificate /  
     
  
  
The individuals listed have approved this document for implementation using an electronic signature in 
the  
Atlas EDMS PPD 
   
UserName: PPD 
 Title:  Cluster Physician Date: Wednesday, 20 January 2016, 19:36   GMT  
Meaning: As an approver, I agree with the content and format of this document.  
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PRO-01 TEMP 06 / Atlas No. 293620 
Version No. 2 / Version Date: December 2, 2013 
CLINICAL STUDY PROTOCOL V132_01EXP Version 6 
A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study to Evaluate the 
Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R Adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium Hydroxide  
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy Adults (18-45 
years of age) 
EUDRACT No. 2014-002430-31 
Property of GlaxoSmithKline Biologicals S.A. (hereafter referred to as GSK) 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of GSK. 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................ 2 
PROTOCOL SYNOPSIS V132_01EXP.......................................................................... 7 
LIST OF ABBREVIATIONS........................................................................................ 23 
1.0  
BACKGROUND AND RATIONALE............................................................... 25 

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1.1  
Background.................................................................................................... 25 
 
1.2  
Rationale........................................................................................................ 28 
2.0  
OBJECTIVES.................................................................................................... 29 
 
2.1  
Primary Objectives......................................................................................... 29 
 
2.2  
Secondary Objectives..................................................................................... 29 
 
2.3  
Exploratory Objectives................................................................................... 29 
3.0  
STUDY DESIGN .............................................................................................. 31 
 
3.1  
Overview of Study Design............................................................................. 31 
 
3.2  
Study Period .................................................................................................. 32 
 
3.3  
Blinding Procedures....................................................................................... 33 
 
3.4  
Data Collection.............................................................................................. 34 
 
3.4.1  
Data Collected from Subjects ................................................................. 34 
 
3.4.2  
Tools Used for Data Collection .............................................................. 34 
 
3.5  
Collection of Clinical Specimens ................................................................... 35 
 
3.6  
Stopping/Pausing Guidelines.......................................................................... 38 
 
3.7  
Data Monitoring Committee........................................................................... 39 
 
3.8  
Premature Withdrawal from Study................................................................. 39 
 
3.9  
End of Study.................................................................................................. 42 
4.0  
SELECTION OF STUDY POPULATION......................................................... 43 
 
4.1  
Inclusion Criteria ........................................................................................... 43 
 
4.2  
Exclusion Criteria .......................................................................................... 43 
 
4.3  
Criteria for Delay of Vaccination or Blood Draw........................................... 45 
5.0  
STUDY PROCEDURES ................................................................................... 46 
 
5.1  
Pre-vaccination Clinic Visit(s) ....................................................................... 46 
 
5.1.1  
Informed Consent................................................................................... 46 
 
5.1.2  
Screening ............................................................................................... 47 
 
5.2  
Vaccination Clinic Visit(s)............................................................................. 48 

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5.2.1  
Pre-vaccination Procedures..................................................................... 48 
 
5.2.2  
Enrolment .............................................................................................. 49 
 
5.2.3  
Randomization ....................................................................................... 49 
 
5.2.4  
Vaccination............................................................................................ 50 
 
5.2.5  
Post-vaccination Procedures................................................................... 50 
 
5.3  
Post-vaccination Visit(s) ................................................................................ 51 
 
5.3.1  
Subject Diary Reminder, Safety Follow-up and/or Post-vaccination Blood  
Draw Clinic Visits ................................................................................................. 51 
 
5.3.2  
Safety Follow-up Calls........................................................................... 55 
 
5.4  
Unscheduled Visits ........................................................................................ 55 
 
5.5  
Study Termination Visit................................................................................. 56 
 
5.5.1  
Early Termination Visit.......................................................................... 56 
6.0  
TREATMENT OF SUBJECTS.......................................................................... 58 
 
6.1  
Study Vaccine(s)............................................................................................ 58 
 
6.2  
Non-Study Vaccines ...................................................................................... 61 
 
6.3  
Vaccine Preparation and Administration ........................................................ 61 
 
6.4  
Vaccine Administration Error or Overdose of Vaccine................................... 62 
 
6.5  
Prior and Concomitant Medications and Vaccines.......................................... 62 
 
6.6  
Vaccine Supply, Labeling, Storage and Tracking ........................................... 62 
7.0  
ASSESSMENTS................................................................................................ 65 
 
7.1  
Safety Assessment ......................................................................................... 65 
 
7.1.1  
Solicited Adverse Events........................................................................ 65 
 
7.1.2  
Unsolicited Adverse Events.................................................................... 67 
 
7.1.3  
Evaluation of Adverse Events................................................................. 67 
 
7.1.4  
Serious Adverse Events.......................................................................... 68 
 
7.1.4.1  
Adverse Events of Special Interest...................................................... 70 
 
7.1.5  
Methods for Recording Adverse Events and Serious Adverse Events ..... 71 

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7.1.5.1  
Post-Study Events .............................................................................. 72 
 
7.1.6  
Pregnancies............................................................................................ 72 
 
7.1.7  
Safety Laboratory Measurements ........................................................... 72 
 
7.2  
Efficacy Assessment ...................................................................................... 73 
 
7.3  
Immunogenicity Assessment.......................................................................... 73 
 
7.4  
Exploratory Measurements............................................................................. 74 
8.0  
STATISTICAL CONSIDERATIONS................................................................ 76 
 
8.1  
Endpoints....................................................................................................... 76 
 
8.1.1  
Primary Endpoint(s)............................................................................... 76 
 
8.1.1.1  
Primary Safety Endpoint(s) ................................................................ 76 
 
8.1.1.2  
Primary Efficacy Endpoint(s) ............................................................. 76 
 
8.1.1.3  
Primary Immunogenicity Endpoint(s)................................................. 76 
 
8.1.2  
Secondary Endpoint(s) ........................................................................... 76 
 
8.1.2.1  
Secondary Safety Endpoint(s)............................................................. 76 
 
8.1.2.2  
Secondary Efficacy Endpoint(s) ......................................................... 77 
 
8.1.2.3  
Secondary Immunogenicity Endpoint(s)............................................. 77 
 
8.1.3  
Exploratory Endpoint(s)......................................................................... 77 
 
8.2  
Success Criteria ............................................................................................. 78 
 
8.2.1  
Success Criteria for Primary Objective(s)............................................... 78 
 
8.2.2  
Success Criteria for Secondary Objective(s) ........................................... 78 
 
8.3  
Analysis Sets ................................................................................................. 78 
 
8.3.1  
All Enrolled Set...................................................................................... 78 
 
8.3.2  
All Exposed Set...................................................................................... 78 
 
8.3.3  
Safety Set............................................................................................... 78 
 
8.3.4  
Full Analysis Set (FAS) Efficacy/Immunogenicity Set ........................... 79 
 
8.3.5  
Per Protocol (PP) Set Efficacy/Immunogenicity Set................................ 79 
 
8.3.6  
Other Analysis Sets................................................................................ 79 

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8.3.7  
Subgroups.............................................................................................. 80 
 
8.3.8  
Protocol Deviations................................................................................ 80 
 
8.4  
Statistical Analysis Plan................................................................................. 80 
 
8.4.1  
Analysis of Demographic and Baseline Characteristics........................... 80 
 
8.4.2  
Analysis of Primary Objective(s)............................................................ 80 
 
8.4.2.1  
Analysis of Primary Safety Objective(s)............................................. 80 
 
8.4.2.1.1  
Analysis of Extent of Exposure.................................................... 80 
 
8.4.2.1.2  Analysis of Solicited Local, Systemic and Other Adverse Events. 81 
 
8.4.2.1.3  
Analysis of Unsolicited Adverse Events....................................... 81 
 
8.4.2.1.4  
Analysis of Safety Laboratory Values .......................................... 82 
 
8.4.2.2  
Analysis of Primary Efficacy Objective(s).......................................... 83 
 
8.4.2.3  
Analysis of Primary Immunogenicity Objective(s) ............................. 83 
 
8.4.2.3.1  
Statistical Hypotheses .................................................................. 83 
 
8.4.2.3.2  
Analysis Sets................................................................................ 83 
 
8.4.2.3.3 
Statistical Methods....................................................................... 83 
 
8.4.3  
Analysis of Secondary Objective(s)........................................................ 84 
 
8.4.3.1  
Analysis of Secondary Safety Objective(s) ......................................... 84 
 
8.4.3.2  
Analysis of Secondary Efficacy Objective(s)...................................... 84 
 
8.4.3.3  
Analysis of Secondary Immunogenicity Objective(s).......................... 84 
 
8.4.3.3.1  
Statistical Hypotheses .................................................................. 84 
 
8.4.3.3.2  
Analysis Sets................................................................................ 84 
 
8.4.3.3.3  
Statistical Methods....................................................................... 85 
 
8.4.4  
Analysis of Exploratory Objectives ........................................................ 85 
 
8.5  
Sample Size and Power Considerations of Primary Objectives....................... 85 
 
8.6  
Interim Analysis............................................................................................. 86 
9.0  
SOURCE DOCUMENTATION, STUDY MONITORING AND AUDITING... 88 
 
9.1  
Source Documentation................................................................................... 88 

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9.2  
Study Monitoring, Auditing and Source Data Verification ............................. 89 
10.0  
DATA MANAGEMENT................................................................................... 90 
 
10.1  
Data Entry and Management.......................................................................... 90 
 
10.2  
Data Clarification........................................................................................... 90 
 
10.3  
Data Protection .............................................................................................. 90 
11.0  
RECORD RETENTION.................................................................................... 92 
12.0  
USE OF INFORMATION AND PUBLICATION ............................................. 93 
13.0  
ETHICS............................................................................................................. 94 
 
13.1  
Regulatory and Ethical Compliance ............................................................... 94 
 
13.2  
Informed Consent Procedures ........................................................................ 94 
 
13.3  
Responsibilities of the Investigator and IRB/EC............................................. 95 
 
13.4  
Protocol Amendments.................................................................................... 96 
14.0  
REFERENCE LIST........................................................................................... 97 
APPENDIX A:  
GRADING SCALES FOR SOLICITED LOCAL ADVERSE  
EVENTS* 
100 
APPENDIX B:  
GRADING SCALES FOR SOLICITED SYSTEMIC ADVERSE  
EVENTS* 
101 
APPENDIX C:  
TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(SERUM CLINICAL CHEMISTRY).......................................................................... 102 
APPENDIX D: TOXICITY SCALES FOR LABORATORY ABNORMALITIES 
(HEMATOLOGY) 103 
APPENDIX E:  
TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(URINE) 
104 
APPENDIX F:  
TOXICITY SCALES FOR VITAL SIGNS................................... 105 
PROTOCOL SYNOPSIS V132_01EXP 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Title of Study: A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study to  
Evaluate the Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R 
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium  
Hydroxide Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy Adults 
(18-45 years of age) 
Study Period: Approximately 12 months for 
each subject 
Clinical Phase: Phase 1 
Background and Rationale: 
Neisseria meningitidis (N. meningitides)serogroup C (MenC) is one of the major 
serogroups causing invasive meningocococcal disease. Case fatality in Germany has 
ranged between 6% and 8% between 1999 and 2006, and has remained generally 
consistent across the different European countries, varying between 6-11%, with the case 
fatality rate being notably higher for serogroup C disease than for serogroup B. The 
safety and immunogenicity of the GSK Meningococcal C-CRM197 Conjugate Vaccine 
(Menjugate®) has been confirmed through years of commercial use. For children over 
the age of 12 months, for adolescents and for adults a single dose is recommended. For 
infants between 2 and 12 months of age, the recommended schedule for primary 
immunization with the Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) is 
two doses given with an interval of at least 2 months A more potent Meningococcal 
CCRM197 Conjugate Vaccine formulation might enable a reduction of the antigen dosage 
and/or a reduction in the number of doses needed in infants. One approach to achieve 
more potent well-characterized sub-unit vaccines - like the Meningococcal C-CRM197 
Conjugate Vaccine - is the use of new adjuvants that activate the Toll-like receptor 
(TLR) pathway. 
GSK is developing a small molecule immune potentiator (SMIP) LHD153 that is an 
agonist for TLR7. The objective driving the development of LHD153 is to achieve a 
vaccine adjuvant with strong immunopotentiating properties and minimal side effects. In 
line with this objective, it has been postulated that the ideal SMIP should remain local 

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and target innate immune cells at the injection site. To this end, LHD153 contains a 
functional phosphonate group to allow for adsorption to aluminium hydroxide. The  
 
Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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arginine salt derivative of this compound is LHD153R. Preclinical results from animal 
models for bacterial and viral antigens, including MenC, MenB, rabies, HIV and 
respiratory syncytial virus (RSV) showed increased functional antibodies and 
antigenspecific T-cells with LHD153R adsorbed to aluminium hydroxide (Aluminium  
Hydroxide/LHD153R) when compared to aluminium hydroxide adjuvanted controls. In 
vitro toxicity screens confirmed that LHD153R is not phototoxic, genotoxic or 
mutagenic. Furthermore, toxicology studies in dog and rats showed that intramuscular 
(IM) injection of Aluminium Hydroxide/LHD153R was well tolerated. Importantly, in 
contrast to free LHD153R, toxicokinetic analysis in rats and dogs confirmed very 
limited exposure of LHD153 when LHD153R was adsorbed to aluminium hydroxide 
after IM injection. 
The aim of this Phase 1 clinical study is to assess the safety of Aluminium  
Hydroxide/LHD153R adjuvanted MenC-CRM197 conjugate vaccine 
(MenCCRM197/Aluminium Hydroxide/LHD153R) and to compare the antibody-
mediated immune response elicited by MenC-CRM197/Aluminium Hydroxide/LHD153R 
with the licensed aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate 
Vaccine (Menjugate®). Furthermore, a comprehensive set of exploratory objectives has 
been selected to assess the systemic exposure of LHD153 after intramuscular injection of 
MenC-CRM197/Aluminium Hydroxide/LHD153R, to evaluate the quality of the specific 
immune response against MenC-CRM197 in detail and to evaluate biomarkers that may 
be predictive of safety and/or innate immune activation. 
The licensed Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) has been 
selected as the primary vaccine candidate to assess the safety and immunopotentiating 
properties of Aluminium Hydroxide/LHD153R for several reasons. Firstly, the safety 
and immunogenicity profiles of the Meningococcal C-CRM197 Conjugate Vaccine 
(Menjugate®) have been well established through years of commercial use. Secondly, a 
more potent MenC-CRM197 conjugate vaccine might enable a reduction of the antigen 
dosage or the number of doses needed in infants. Finally, MenC-CRM197 is a 
wellcharacterized, single conjugate antigen preparation which provides an ideal setting 
to evaluate the potential of this new Aluminium Hydroxide/LHD153R adjuvant. 
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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Study Objectives: 
Primary Safety Objective: 
To assess the safety of MenC-CRM197/Aluminium Hydroxide/LHD153R as compared to 
that of aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
Primary Immunogenicity Objective: 
To compare the antibody responses of MenC-CRM197/Aluminium Hydroxide/LHD153R 
and aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at 
Day 29, as measured by human complement serum bactericidal assay (hSBA) directed 
against MenC. 
Secondary Immunogenicity Objectives: 
1. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine, at Day 8 and Day 181 after vaccination, as measured 
by hSBA directed against MenC. Baseline antibody titers will also be measured by 
hSBA. 
2. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine at Day 8, Day 29 and Day 181 after vaccination, as 
measured by an enzyme-linked immunosorbent assay (ELISA) to MenC. Baseline 
antibody concentrations will also be measured by ELISA. 
Exploratory Objectives: 
1. To evaluate the systemic exposure of LHD153 at several early time-points after IM 
injection of MenC-CRM197/Aluminium Hydroxide/LHD153R or aluminium 
hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
2. To explore the frequency of B cells specific for MenC polysaccharide and CRM197 
protein at baseline (Day 1) and at Day 8, Day 29 and Day 181 after vaccination with  
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
MenC-CRM197/Aluminium Hydroxide/LHD153R or the aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. Subsequently, the B cell 
repertoire of the antigen specific B cells will be analyzed in a selected subset of 
subjects. 
3. To explore the baseline T cell mediated immunity to CRM197 and to evaluate the 
frequency and quality of CRM197 specific T cells induced by MenC- 
CRM197/Aluminium Hydroxide/ LHD153R compared to aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at Day 8 and Day 29. 
4. To evaluate biomarkers that may be predictive for safety and/or innate immune 
activation. 

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Study Design: 
This Phase 1, randomized, observer-blind, dosage-escalation study will be performed at 
a single center. In total, approximately 80 healthy male and healthy non-pregnant female 
adults (18-45 years of age) will be enrolled in the study. Subjects will be randomized to 
receive a single IM vaccination of either the licensed aluminium hydroxide adjuvanted 
Meningococcal C-CRM197 Conjugate Vaccine (i.e. 10 µg MenC conjugated to CRM197,  
adjuvanted with 1 mg aluminium hydroxide) or one of four dosages of the 
investigational vaccine, MenC-CRM197/Aluminium Hydroxide/LHD153R (i.e. 10 µg 
MenC conjugated to CRM197, adjuvanted with 1 mg aluminium hydroxide and one of 
four dosages [12.5, 25, 50 or 100 µg] of LHD153R). 
For the dosage-escalation of LHD153R, the subjects will be enrolled into 1 of 4 cohorts, 
in a stepwise manner with 20 subjects per cohort. Subjects in all cohorts will be 
randomized in a 1:4 ratio, to receive either aluminium hydroxide adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine (control) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R with increasing doses of LHD153R.Cohort 1 will receive 12.5 μg 
of LHD153R; Cohort 2 will receive 25 μg of LHD153R; Cohort 3 will receive 50 μg of 
LHD 153; and Cohort 4 will receive 100 μg of LHD153R (Table 1). 
 
Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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 Table 1: 
Subjects Randomized per Cohort and Treatment Dosage Group 
Cohort 
Group 
Subjects/ 
Group 
MenC  
Dosage*  
(µg) 
Adjuvant Dosages  
Total 
Volume/Dose 
Total 
Subjects/Cohort 
Aluminium  
Hydroxide  
(mg) 
LHD153R  
(µg) 
1 
A 
4 
10 
1 
0 
0.5 mL 
20 
 
 
 
 
 
 
 
B 
16 
10 
1 
12.5 
0.5 mL 
 
2 
A 
4 
10 
1 
0 
0.5 mL 
20 
C 
16 
10 
1 
25 
0.5 mL 
3 
A 
4 
10 
1 
0 
0.5 mL 
20 
D 
16 
10 
1 
50 
0.5 mL 
4 
A 
4 
10 
1 
0 
0.5 mL 
20 
E 
16 
10 
1 
100 
0.5 mL 
*Conjugated to 12.5-25 µg CRM197 
After vaccination, all subjects will be confined to the clinical site for 24 hours for clinical 
observation, including but not limited to observations for solicited and unsolicited 
adverse events, body temperature measurements and blood sampling for exploratory 
endpoint measurements. 
Importantly, all cohorts will have a staggered entry based on Data Monitoring 
Committee (DMC) reviews. 
▫ For each cohort, the first 5 subjects (i.e. the first 1:4 randomization block) to receive 
either aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate 
Vaccine (n=1) or MenC-CRM197/Aluminium Hydroxide/LHD153R (n=4) will be 
treated at a vaccination rate of 1 subject each day. 
▫ After entry of the first 5 subjects in each cohort, the enrollment will be paused. The 
remaining 15 subjects for each cohort will be enrolled only after DMC review of the 
safety results obtained through Day 14 has been finalized (Table 2). 
▫ In addition, enrollment of the first 5 subjects in the next cohort will only proceed after 
the Day 14 safety results of the first 5 subjects of the previous cohort have been 
reviewed by the DMC (Table 2). 
▫ Furthermore, all available Day 14 and Day 29 safety results will be included in DMC 
reviews between the different enrollment stages. 
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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 Table 2: 
Overview of staggered entry of subjects based on DMC reviews 
Stage 
Dosage Cohort 
MenC-CRM197/ 
Aluminium Hydroxide (n) 
MenC-CRM197/ 
Aluminium Hydroxide 
/LHD153R (n) 
1   
1  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 14 Safety Results 
2 
1  
3 
12 
2  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 29 and Stage 2 Day 14 Safety Results 
3 
2  
3 
12 
3  
1 
4 
Enrollment pause until DMC review of Stage 2 Day 29 and Stage 3 Day 14 Safety Results 
4 
3  
3 
12 
4  
1 
4 
Enrollment pause until DMC review of Stage 3 Day 29 and Stage 4 Day 14 Safety Results 
5 
4  
3 
12 
The DMC review will be performed according to predefined stopping/pausing guidelines 
used to ensure the safety of study subjects. These stopping/pausing guidelines are based 
on FDA guidance and with grading scales from the CBER Guidance for Industry 
“Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials”. See protocol section 3.6 for further details. 
Safety Measurements 
Schedule of safety data collection: 
▫ Solicited local and systemic adverse events (AEs), body temperature and all 
unsolicited AEs will be collected until Day 14. 
▫ All serious adverse events (SAEs), medically attended AEs, AEs leading to study 
withdrawal, new onset of chronic disease (NOCDs), and adverse events of special 
interest (AESIs) will be collected from the date of signed informed consent to study 
completion at Day 366. 
▫ All concomitant medications administered in relation to the reported AEs will be  
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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collected from vaccination to study completion at Day 366. 
Solicited local AEs include injection site erythema, injection site induration, injection 
site pain and injection site swelling. Solicited systemic AEs include body temperature ≥ 
38.0°C (as measured orally), loss of appetite, nausea, fatigue, generalized myalgia, 
generalized arthralgia, headache, chills, vomiting, diarrhea, generalized rash and 
urticaria. 
All AESIs will be reported in the same manner as SAEs. All AEs will be monitored until 
resolution or, if the AE becomes chronic, a cause is identified. If an AE is unresolved at 
the conclusion of the study, a clinical assessment will be made by the investigator and 
the medical monitor to determine whether or not continued follow-up of the AE is 
warranted. 
The relationship of the study treatment to any AE will be determined by the investigator 
as probably related, possibly related, or not related; the relationship of the study 
treatment to any SAE will be determined by the investigator as probably 
related/suspected, or not related. 
Safety Laboratory Parameters 
To assess laboratory AEs, blood and urine samples will be collected from each subject as 
outlined in Table 3 to perform blood chemistry, hematology, and urine analyses. 
Safety laboratory samples will be drawn from all subjects at pre-vaccination screening 
(between Day -28 and Day -3) at Day 1 (pre-vaccination and 24h after vaccination), at 
Day 8 and at Day 29. Safety laboratory assessments will include sodium, potassium, 
chloride, bicarbonate, blood urea nitrogen, creatinine, liver function tests (ALT, AST), a 
complete blood count and C-reactive protein. A urine sample will be collected at the 
same time-points and will be assessed for the presence of protein, glucose and red blood 
cells. 
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Primary and Secondary Immunogenicity Measurements 
Four blood samples per subject (i.e. at Day 1, Day 8, Day 29 and Day 181) will be 
collected for serum preparation and determination of antibody-mediated immune 
responses to MenC-CRM197 as outlined in Table 3 and Table 4. See section 7.3 for 
further details. 
Exploratory Measurements 
In all subjects who agree by signing a separate Informed Consent, additional blood 
samples will be collected at Day 1, Day 4, Day 8, Day 29 and Day 181 for exploratory 
assays as outlined in Table 3 and Table 4. The purpose of these assays is to assess the 
systemic exposure of LHD153, to determine the frequency and quality of B- and T-cells 
specific for MenC polysaccharide and/or CRM197 and to evaluate biomarkers that may 
be predictive of safety and/or innate immune activation. Subsequently, MenC-CRM197 
specific B-cell repertoires will be analyzed in a selected subset of subjects, dependent on 
the results from primary and secondary immunogenicity measurements and the volume 
of  blood  remaining for additional testing. See section 7.4 for further details. All 
exploratory analyses may be performed after the Clinical Study Report (CSR) has been 
completed, in which case these data will be submitted as an addendum to the CSR. 
Number of Subjects planned: 
Approximately 80 adult subjects will be randomized, with anticipated dropout rates of 
5% by Day 181 (last serology time point), and 10%, by Day 366 (last safety time point). 
Sample size is not driven by statistical assumptions for formal hypothesis testing, but the 
proposed number of subjects will be sufficient to provide a descriptive summary of the 
safety and immunogenicity of the study vaccine. 
Study Population and Subject Characteristics: 
Healthy adult male and female volunteers between 18-45 years of age, inclusive. 
The list of inclusion and exclusion criteria is included in protocol section 4.0. 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Study Vaccines: 
The MenC-CRM197 conjugate is a lyophilized powder consisting of 10 µg of MenC 
polysaccharide conjugated to 12.5-25 µg CRM197 carrier protein. The MenC-CRM197 
lyophilized powder will be reconstituted with adjuvant by the unblinded designated site 
staff member who is to follow the procedure as described in the vaccine preparation 
instructions in the Investigator Site File (i.e. the vaccine will be prepared in the clinic 
prior to administration). 
The lyophilized MenC-CRM197 powder will be reconstituted with either: 
(a) aluminium hydroxide adjuvant 
(b) Aluminium Hydroxide/LHD153R adjuvant with specified dosages of LHD153R 
(12.5, 25, 50 or 100 µg) 
The components for each formulation of MenC-CRM197 will be provided in a separate 
kit. 
Aluminium Hydroxide/LHD153R with specified dosages of LHD153R will be prepared  
by dilution of the highest Aluminium Hydroxide/LHD153R dosage (100 µg of 
LHD153R) with aluminium hydroxide. 
In each cohort, subjects will be randomized to receive one injection of MenC- 
CRM197/Aluminium Hydroxide/LHD153R adjuvant or aluminium hydroxide adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine. The 0.5 mL of vaccine will be injected 
IM in the deltoid muscle, with preference that the injection is administered in the 
nondominant arm. 

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Primary Safety Endpoint: 
Safety will be assessed by measuring the frequency of local and systemic solicited AEs, 
unsolicited AEs, SAEs, AESIs, NOCDs, and safety laboratory data for all subjects.  
Specifically, 
▫ The frequency and percentage of subjects with solicited local and systemic AEs 
through Day 14. Time intervals after vaccination that will be summarized are: 30  
 
Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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min post-vaccination, Days 1-4 (without 30 min), Days 5-8, Days 8-14, Days 1-8 
(without 30 min) and Days 1-14 (without 30 min). 
▫ The frequency and percentage of subjects with any unsolicited AEs from the day of 
vaccination (Day 1) to Day 14. 
▫ The frequency and percentage of subjects with SAEs, medically attended AEs,  AEs 
leading to study withdrawal, NOCDs, AESIs for the following time periods: day of 
signed informed consent until study completion (Day 366), day of vaccination (Day 
1) to Day 29 and Day 29 to study completion (Day 366). 
▫ The absolute values and changes in hematology, chemistry, and urinalysis parameters. 
▫ The frequency and percentage of subjects with abnormal laboratory parameter values 
as classified by investigator normal ranges (low, normal, high) and as classified by 
CBER toxicity grading scales, when available. 
Primary Immunogenicity Endpoint: 
Geometric mean titers (GMTs) measured by hSBA directed against MenC from samples 
collected on Day 1 (baseline, before vaccination) and Day 29 as well as the GMR of the 
titers (Day 29 / Day 1). 
Secondary Immunogenicity Endpoints: 
▫ GMTs and corresponding GMRs measured by hSBA directed against MenC for samples 
collected at Day 8 and Day181. 
▫ Percentage of subjects with hSBA seroresponse at Day 8, Day 29, and Day 181. 
seroresponse is defined as a post vaccination hSBA ≥8 for subjects with a baseline 
hSBA <4 or have an increase of at least 4 times the baseline hSBA level for subjects 
with pre-vaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against MenC measured by ELISA 
for samples collected on Day 1 (baseline, prior to vaccination), Day 8, Day 29, and 
Day 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations  
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
to MenC measured by ELISA on Day 8, Day 29, and Day 181 relative to baseline (Day 
1). 
Exploratory Endpoints: 
Testing and analyses of exploratory endpoints may be performed after the Clinical Study 
Report (CSR) has been completed, in which case these data will be submitted as an 
addendum to the CSR. 
1. Serum concentration of LHD153 at Day 1 baseline (prior to vaccination), Day 1 (1h , 
2h, 4h, 8h, and 24h after vaccination) and Day 4 by LC-MS/MS. 
2. Frequency of MenC polysaccharide-specific and CRM197-specific B cells at Day 1 
(baseline), Day 8, Day 29, and Day 181 by ELISPOT. 
3. Diversity of the MenC polysaccharide-specific B-cell repertoire at Day 1 (baseline), 
Day 8, Day 29, and Day 181 by immunoglobulin cDNA sequencing. 
4. Frequency and quality of T cells specific for CRM197 at Day 1 (baseline), Day 8, and 
Day 29 by flow cytometry using intracellular staining with a panel of cytokines and 
staining of surface markers to identify cell populations. 
5. Serum concentrations of a panel of 30 chemokines and cytokines at Day 1 baseline 
(prior to vaccination), Day 1 (6h and 24h after vaccination), Day 4, and Day 8 by 
electrochemo-luminescence based assay. 
6. Gene expression profile in whole blood at Day 1 baseline (prior to vaccination), Day 
1 (6h and 24h after vaccination), Day 4, and Day 8 by RNA micro array analysis. 
7. Number and activation status of myeloid and lymphoid cell populations at Day 1 
baseline (prior to vaccination), Day 1 (24h after vaccination), Day 4 and Day 8 by 
flow cytometry. 
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Statistical Analyses: 
The study is exploratory in nature, thus analyses will be descriptive and no 
formal hypothesis testing will be performed. Primary Safety Analyses 
The primary safety analyses will be based on the safety set for solicited and unsolicited 
adverse events. There is no statistical null hypothesis associated with the safety 
objective, which will be analyzed descriptively. 
Immunogenicity Analyses 
The primary immunogenicity analyses will be based on the per-protocol set (PPS) on 
Day 29. The primary analyses will also be performed using the Full Analysis Set (FAS) 
as a measure of the sensitivity/robustness of the results. All other immunogenicity 
assessments will be performed using the PPS or the appropriate subset of subjects. The 
antibody concentrations/titers will be summarized using GMC/GMTs and two-sided 
95% confidence intervals (CIs) constructed by exponentiation (base 10) of the least 
square means of the logarithmically transformed (base 10) antibody titer. The 95% CIs 
will be obtained from an analysis of covariance (ANCOVA) with baseline 
concentration/titer as a covariate. Additional details will be further described in the 
Statistical Analysis Plan. 
The immunogenicity endpoints based on subjects meeting criteria for seroconversion or 
achieving a certain threshold value will be summarized using frequencies and 
percentages and associated two-sided 95% Clopper-Pearson CIs. For analyses of 
seroconversion, separate summaries may be provided based on seropositivity status at 
baseline. 
Interim Analysis: 
An Interim Analysis will be performed on the immunogenicity and safety data collected 
from all subjects until Day 29, after all cohorts have been enrolled. Further details 
regarding the interim analysis are contained in section 8.6. 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Data Monitoring Committee: 
An independent DMC will be implemented to review safety data during scheduled 
periodic reviews. The DMC will review safety data collected until Day 14, as described 
in the DMC charter and in the Statistical Analysis Plan, after enrollment of the first 5 
subjects in each cohort, before proceeding with enrollment of the remaining 15 subjects 
in each cohort. In addition, enrollment of the first 5 subjects of the next cohort will only 
proceed after the Day 14 safety results of the first 5 subjects of the previous cohort have 
been reviewed. Furthermore, all available Day 14 and Day 29 safety results will be 
included in DMC reviews between the different enrollment stages. Further information 
regarding the DMC is discussed in more detail in the protocol, section 3.7. 

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Table 3: 
Time and Events Table – Treatment Period (until Day 29) 
 
Visit Type 
Clinic Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
 
Study Day 
-28 to -3 
1 
4 
8 
15 
22 
29 
 
Visit Window (Days) 
n/a 
n/a 
n/a 
-1/+1 
+1 
n/a 
-2/+2 
 
Visit Number 
Screening  
1 
2 
3 
4 
5 
6 
Study Event 
References 
 
 
 
 
 
 
 
Study Treatment 
 
 
 
 
 
 
 
 
Vaccination 
Section 5.2 
 
X 
 
 
 
 
 
Screening and Safety 
 
 
 
 
 
 
 
 
Informed Consent  
Section 5.1.1 
X 
 
 
 
 
 
 
Demographic Data & Medical History 
Sections 5.1.2 
X 
 
 
 
 
 
 
Physical Exam 
Sections 5.1.2 and 5.2.1 
X 
Xa 
 
 
 
 
 
Safety Laboratory blood draw (10 ml) 
Section 7.1.7 
X 
Xb 
 
X 
 
 
X 
Urinalysis 
Sections 7.1.7 
X 
Xb 
 
X 
 
 
X 
Pregnancy Test 
Sections 5.1.2 and 5.2.1 
X 
Xa 
 
 
 
 
 
Exclusion/Inclusion Criteria 
Section 4.0 
X 
Xa 
 
 
 
 
 
Randomization 
Section 5.2.3 
 
Xa 
 
 
 
 
 
30 min and 24 hr Post Injection Assessment 
Section 5.2.5 
 
Xc 
 
 
 
 
 
Subject Diary Dispensed with Training 
Section 5.2.5 
 
X 
 
 
 
 
 
Subject Diary Reminder 
Section 5.2.5 
 
 
X 
X 
 
 
 

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Subject Diary Reviewed and Collected 
Section 5.3.1 
 
 
 
 
X 
 
 
Assess all solicited AEs 
Section 7.1.1 and 7.1.3 
 
 
 
 
X 
 
 
Assess all unsolicited AEs 
Sections 7.1.2 and 7.1.3 
X 
X 
X 
X 
X 
 
 
PRO-01 TEMP 06 / Atlas No. 293620 
Visit Type 
Clinic Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Study Day 
-28 to -3 
1 
4 
8 
15 
22 
29 
Visit Window (Days) 
n/a 
n/a 
n/a 
-1/+1 
+1 
n/a 
-2/+2 
Visit Number 
Screening  
1 
2 
3 
4 
5 
6 
Study Event 
References 
 
Assess SAEs 
Section 7.1.4 
X 
X 
X 
X 
X 
X 
X 
Assess AESIs 
Section 7.1.4.1 
X 
X 
X 
X 
X 
X 
X 
Assess NOCDs, medically attended AEs, AEs 
leading to withdrawal  
Sections 7.1.3 
X 
X 
X 
X 
X 
X 
X 
Assess relevant medications 
Sections 5.1.2 and 6.5 
X 
X 
X 
X 
X 
X 
X 
Blood draws for Immunogenicity and Exploratory Objectives 
Serum Blood Draws (Primary/Secondary Objectives; 10 mL)  
Section 3.5 
 
Xa 
 
X 
 
 
X 
Serum Blood Draws (Exploratory Objectives; 5 mL)  
Section 3.5 
 
Xd 
X 
X 
 
 
 
Whole Blood Draws (Exploratory Objectives; 3 mL) 
Section 3.5 
 
Xe 
X 
 
 
 
 
Whole Blood Draws (Exploratory Objectives; 5 mL) 
Section 3.5 
 
Xf 
X 
X 
 
 
 
Whole Blood Draws (Exploratory Objectives; 20 mL) 
Section 3.5 
 
Xg 
X 
 
 
 
 
Whole Blood Draws (Exploratory Objectives; 50 mL) 
Section 3.5 
 
 
 
 
 
 
X 

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Whole Blood Draws (Exploratory Objectives; 70 mL) 
Section 3.5 
 
Xa 
 
X 
 
 
 
Notes: 
a. 
Procedure must be performed prior to vaccination. 
b. 
Two blood draws (2 x 10 ml) and two urine samples must be taken at Study Day 1, i.e. at baseline (prior to vaccination) and at 24h after vaccination. 
c. 
Vital signs will be measured at 30 min and 24h. Additional body temperature measurement must be performed at 2, 4, 6, 8, 10, 12 and 18h after 
vaccination. 
d. 
Three Serum Blood Draws (3 x 5ml) must be taken at Study Day 1, i.e. at baseline (prior to vaccination), at 6h and at 24h after vaccination. 
e. 
Six Whole Blood Draws (6 x 3 mL) must be taken at Study Day 1, i.e. at baseline (prior to vaccination) and at 1, 2, 4, 8 and 24h after vaccination. 
f. 
Three Whole Blood Draws (3 x 5 mL) must be taken at Study Day 1, i.e. at baseline (prior to vaccination), at 6h and at 24h after vaccination. g. Whole 
Blood Draw (20 mL) at Study Day 1 must be taken at 24h after vaccination. 
PRO-01 TEMP 06 / Atlas No. 293620 
Table 4: 
Time and Events Table – Follow-up Period (until Day 366) 
Visit Type 
Clinic Visit 
Clinic Visit 
Clinic Visit 
Phone Call 
Phone Call 
Clinic Visit 
Study Day 
85 
113 
181 
209 
271 
366 
Visit Window (Days) 
-7 to +7 
-7 to +7 
-7 to +7 
-14 to +14 
-14 to +14 
-14 to +14 
Visit Number 
7 
8 
9 
10 
11 
12 
Study Event 
References 
 
 
Safety 
 
Assess SAEs 
Section 7.1.4 
X 
X 
X 
X 
X 
X 
Assess AESI 
Section 7.1.4.1 
X 
X 
X 
X 
X 
X 
Assess NOCDs, medically attended 
AEs, AEs leading to withdrawal 
Sections 7.1.3 
X 
X 
X 
X 
X 
X 
Assess relevant medications 
Sections 5.1.2 and 6.5 
X 
X 
X 
X 
X 
X 
Blood draws for Immunogenicity and Exploratory Objectives 
 

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Serum Blood Draw (Secondary 
Objective; 10 mL) 
Section 3.5 
 
 
X 
 
 
 
Whole Blood Draw  
(Exploratory Objectives; 50 mL) 
Section 3.5 
 
 
X 
 
 
 
Study Completion Procedures 
 
Study Terminationa 
Section 5.5 
 
 
 
 
 
X 
Notes: 
a. Subjects who terminate the study early are recommended to complete certain study-related procedures. See section 5.5 for further details. 
 
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LIST OF ABBREVIATIONS 
ADCC 
Antibody-dependent cell mediated cytotoxicity 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BZN 
Benzonaphthyridines 
CBER 
Center for Biologics Evaluation and Research 
cDNA 
Complementary deoxyribonucleic acid   
CI 
Confidence interval 
CRF 
Case report form 
CRM197 
Cross Reacting Material 197 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
EC 
Ethics committee 
EDC 
Electronic data capture 
ELISA 
Enzyme-linked immunosorbent assay 
ELISPOT 
Enzyme-Linked ImmunoSpot 
EMA 
European Medicines Agency 
FACS 
Fluorescence-activated cell sorting 
FAS 
Full analysis set 
FDA 
Federal Drug Agency 
GCP 
Good clinical practice 
GMC 
Geometric mean concentration 
GMP 
Good manufacturing practice 

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GMT 
Geometric mean titer 
GMR 
Geometric mean ratio 
HEENT  
Head, ears, eyes, nose and throat 
HIV 
Human immunodeficiency virus 
 
HPV 
Human papillomavirus 
hSBA 
Human complement serum bactericidal assay 
ICF 
Informed consent form 
ICH 
International Committee for Harmonization 
IM 
Intramuscular 
IRB 
Institutional review board 
IV 
Intravenous 
LLQ 
Lower limit of quantification 
MenC 
Meningococcal type C 
MPL 
Monophosphoryl lipid A 
NCR 
No carbon required 
NOCD 
New Onset of Chronic Disease 
PEG 
Polyethylene glycol 
PO 
Per oral 
PP 
Per protocol 
RNA 
Ribonucleic acid (RNA 
SAE 
Serious Adverse Event 
SMIP 
Small molecule immune potentiator 
TLR 
Toll-like receptor 
VSAE 
Vaccine serious adverse event 
1.0  
BACKGROUND AND RATIONALE 
1.1  
Background 

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MenC-CRM197 Conjugate Vaccine 
Meningococcal disease worldwide is predominantly a disease of infants and young 
children. N. meningitidis serogroup B and C remain the most prevalent strains in North 
America and Europe, (Rosenstein, N. et al., 2001) and together cause more than 95% of 
reported cases of meningococcal disease in Europe (Connolly, M, et al., 1999). In Europe, 
N. meningitidis serogroup C (MenC) is one of the major serogroups causing invasive 
disease. Case fatality in Germany has ranged between 6% and 8% between 1999 and 
2006, and has remained generally consistent across the different European countries, 
varying between 6-11%, with the case fatality rate being notably higher for serogroup C 
disease than for serogroup B (European Centre for Disease Prevention and Control, 
2011). Since MenC vaccination was added to Germany’s routine schedule for children in 
2006, there has been a reported decline in MenC incidence. However, the decline was not 
as rapid when compared to other European countries (Hellenbrand, W. et al., 2013). 
The GSK Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) comprises MenC 
oligosaccharides conjugated to the protein carrier, CRM197, a nontoxic mutant of 
diphtheria toxin. The vaccine has been shown to be safe and immunogenic and able to 
prime infants, toddlers and young children for immunological memory (see 
Meningococcal C-CRM197 Conjugate Vaccine Summary of Product Characteristics).  
In Germany, the Standing Committee on Vaccination (STIKO) of the Robert Koch  
Institute recommends a single dose of MenC conjugate vaccine in children over the age of  
12 months as part of the routine vaccination campaign (Robert Koch Institute 
Epidemiologisches Bulletin, August 2013). For specific indications, e.g. in case of 
postexposure prophylaxis, the recommended schedule for primary immunization of 
infants between 2 to 12 months of age with a MenC conjugate vaccine is two dosages 
given with an interval of at least 2 months. 
Although the Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) represents an 
example of how vaccination with a well characterized, purified polysaccharide antigen 
can yield pivotal public health triumphs, there remains a need for further improvement of 
the MenC vaccine. A more potent MenC vaccine formulation might yield an increase in 
the magnitude of the antigen-specific immune response enabling a reduction of the 
antigen dosage. Furthermore, induction of a more rapid antigen-specific immune response 
may enable a reduction in the number of doses needed for post-exposure prophylaxis in 
infants. 

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Vaccine Adjuvants 
Immunization with purified protein or polysaccharide antigens typically results in the 
induction of a modest antibody response with little or no T cell response when compared 
to vaccines comprised of whole or killed bacteria or viruses that have inherent 
immunepotentiating activity. The need to increase the immunogenic response of 
wellcharacterized and purified antigens that display suboptimal immunogenicity when 
used alone affirms the essential role for the use of adjuvants. Vaccine adjuvants may 
significantly reduce the amount of antigen needed (Del Giudice, G, et al., 2013) and may 
induce a more rapid immune response enabling a reduction in the number of doses in a 
regimen. 
Besides reducing the antigen dosage or number of doses in the vaccine regimen, there is 
now an increased appreciation of the capacity of adjuvants to increase not just overall 
antibody titer but also to increase the number of functional antibodies and/or antibodies 
with higher affinity for vaccine antigens. Many pathogens, such as influenza viruses, 
HIV, human papilloma virus (HPV) and the malaria parasite, display substantial antigenic 
drift, subtype and/or strain variations. Therefore, the ability of adjuvants to broaden an 
immune response profile could be crucial to the success of vaccines against such targets. 
Previous studies have shown that the broadening effect of adjuvants may be mediated via 
expansion of B cell diversity, not merely through increased titers (Khurana, et al., 2010, 
2011). Clinically, antibody response broadening by adjuvants such as AS04 or oil-inwater 
emulsions has been demonstrated in HPV vaccines and influenza, respectively (Bissett, 
SL et al., 2014; Del Giudice, G et al., 2013). 
One unmet need is the development of vaccines for effective T cell responses. Several 
vaccines in development are aimed at eliciting T cell responses, which historically have 
not been induced by the most commonly used adjuvants in vaccines for human use, such 
as aluminium hydroxide. Therefore, an objective of many adjuvant discovery and 
development programs is to elicit more effective engagement of T-helper cells for 
optimizing the quality, breadth and durability of antibody responses, or, to induce effector 
CD4+ or CD8+ T cells to kill intracellular pathogens. One approach for new generation 
vaccines is the use of agonists for Toll-like receptors (TLRs) that activate innate immune 
receptors, mainly on antigen presenting cells, and facilitate the generation of T helper cell 
responses. 
Adjuvants that are currently employed in human vaccines licensed for use in the USA 
and/or Europe include aluminium salts, oil-in-water emulsions (MF59, AS03 and AF03), 
virosomes, and AS04 (Alving, CR, et al., 2012). Among the most advanced adjuvants 
systems is AS04 which is used in the Cervarix® HPV vaccine and consist of the TLR4 
ligand monophosphoryl lipid A (MPL) combined with aluminium salt. MPL, along with 

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QS21, is also part of the adjuvant system (AS01) in the RTS, S malaria vaccine which has 
been evaluated in a Phase 3 clinical trial (Regules, JA, et al., 2011). Another clinically 
advanced adjuvant is CpG oligodeoxynucleotide (ODN), a TLR9 ligand contained in the 
Heplisav® vaccine candidate for hepatitis B from Dynavax, that has completed a Phase 3 
clinical trial (Reed, SG, et al., 2013). 
Small molecule immune potentiators as a new class of vaccine adjuvants 
A new class of adjuvants, small molecule immune potentiators (SMIPs), has been 
identified that activate immune cells by targeting TLR7 and TLR8. Imiquimod and 
Resiquimod (R848) are clinically advanced TLR7 and/or TLR8 SMIPs that are used as 
immunotherapeutics. Although Imiquimod and Resiquimod have been studied 
extensively as vaccine adjuvants in preclinical models (Vasilakos et al. 2013), they were 
never optimized for this use and, in general, compare poorly to other pre-clinical and 
clinical adjuvant candidates. Furthermore, when Imiquimod is applied topically (it is a 
licensed topical treatment for viral and malignant skin lesions) it induces strong local and 
systemic inflammatory reactions, and is poorly tolerated (Bauza, et al. 2009; Campanelli, 
et al. 2005; Meyer, et al. 2008). 
Unlike traditional drugs, TLR7 SMIPs activate innate immunity and initiate a cascade of 
immune responses that can have systemic impact and endure after the compound has been 
cleared from the organism. For SMIPs as vaccine adjuvants this difference is highlighted 
further by the fact that 2-3 local IM injections drive antigen-specific B and T cell 
responses at distal sites and these can provide protection in the form of immunologic 
memory (Tacken,  et al. 2011; Ilyinskii, et al., 2014). Therefore, limiting the systemic 
exposure of the SMIP adjuvants has been postulated as an approach to both increase 
vaccine efficacy and minimize side effects associated with systemic and generalized 
inflammation. GSK is currently developing a novel adjuvant, containing a SMIP from the 
benzonaphthryridines (BZN) series, LHD153, which targets TLR7. The objective driving 
the discovery of this new TLR7 ligand was to develop a vaccine adjuvant with high 
efficacy in increasing the vaccine specific immune response and with minimal side 
effects. To obtain this objective it was postulated that the ideal compound would remain 
localized at the site of injection to help trigger the immune reaction to vaccine antigens, 
yet maintain a low systemic distribution. At the same time this compound had to be 
soluble to make industrial scale-up and manufacturing feasible. Soluble BZN were 
engineered so that they could be formulated with aluminium salts with the aim of limiting 
their systemic exposure and keeping them localized in the muscle for short time after 
immunization. The strongest adsorption to aluminium hydroxide particles is obtained 
through ligand exchange of hydroxyl and/or phosphate groups on the surface of 
aluminium hydroxide or phosphate with soft anionic moieties such as phosphates, 
phosphonates, phosphites, sulfates and carboxylates. To drive the adsorption to 

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aluminium hydroxide through ligand exchange, LHD153 was functionalized with a 
polyethylene glycol (PEG) linker and a terminal phosphonate. Furthermore, LHD153 was 
stabilized with arginine salt to allow scale up for GMP manufacturing, yielding 
LHD153R. As predicted, unformulated LHD153R exhibited high levels of systemic 
exposure when injected IM in mice, rats and dogs, whereas the serum concentrations of 
LHD153R adsorbed to aluminium hydroxide (Aluminium Hydroxide/LHD153R) was 
dramatically reduced. Moreover, Aluminium Hydroxide/LHD153R remained localized to 
the injection site. 
Preclinical studies using Aluminium Hydroxide/LHD153R to date confirm the activation 
of the TLR7 pathway and subsequent boost of both the humoral and cellular immune 
response. Moreover, Aluminium Hydroxide/LHD153R displays a unique 
pharmacokinetic profile as demonstrated by its minimal systemic exposure, potentially 
minimizing any systemic inflammatory response associated with tolerability issues. 
Aluminium hydroxide/LHD153R has achieved proof of concept in animal models using 
several vaccine antigens including MenC, MenB, rabies, HIV and respiratory syncytial 
virus (RSV). In vitro toxicity of LDH153R has been assessed, and in vivo nonclinical 
tolerability and safety of LHD153R and Aluminium Hydroxide/LHD153R have been 
evaluated in rats, dogs and non-human primates. LHD153R was not phototoxic, 
genotoxic or mutagenic (Ames and chromosomal aberration tests), and did not cause local 
or systemic toxicity in dogs or rats. Furthermore, Aluminium Hydroxide/LHD153R was 
well tolerated in rhesus monkeys. 
1.2  
Rationale 
The aim of this study is to assess the safety of Aluminium Hydroxide/LHD153R 
adjuvanted MenC-CRM197 conjugate vaccine (MenC-CRM197/Aluminium  
Hydroxide/LHD153R) and to compare the antibody-mediated immune response elicited 
by MenC-CRM197/Aluminium Hydroxide/LHD153R with the licensed aluminium 
hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®). 
Furthermore, a comprehensive set of exploratory objectives has been selected to assess 
the systemic exposure of LHD153 after intramuscular injection and to evaluate the quality 
of the specific immune response against MenC-CRM197 in detail and to evaluate 
biomarkers that may be predictive of safety and/or innate immune activation. 
The licensed Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) has been 
chosen as the primary vaccine candidate to assess the safety and immunopotentiating 
properties of Aluminium Hydroxide/LHD153R for several reasons. Firstly, the safety and 
immunogenicity profiles of the Meningococcal C-CRM197 Conjugate Vaccine have been 
well established through years of commercial use. Secondly, a more potent 

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Meningococcal C-CRM197 Conjugate Vaccine might enable a reduction of the antigen 
dosage or the number of doses needed in infants between 2 and 12 months of age. Finally, 
Meningococcal C-CRM197 is a well-characterized, single conjugate antigen preparation 
which provides an ideal setting to explore the potential of this new Aluminium 
Hydroxide/LHD153R adjuvant. 
2.0  
OBJECTIVES 
2.1  
Primary Objectives 
Primary Safety Objective 
To assess the safety of MenC-CRM197/Aluminium Hydroxide/LHD153R as compared to 
that of aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
Primary Immunogenicity Objective 
To compare the antibody responses of MenC-CRM197/Aluminium Hydroxide/LHD153R 
and aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at 
Day 29, as measured by human complement serum bactericidal assay (hSBA) directed 
against MenC. 
2.2  
Secondary Objectives 
Secondary Immunogenicity Objective(s) 
1. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine at Day 8 and Day 181 after vaccination, as measured by 
hSBA directed against MenC. Baseline antibody titers will also be measured by 
hSBA. 
2. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine, at Day 8, Day 29 and Day 181 after vaccination, as 
measured by an enzyme-linked immunosorbent assay (ELISA) to MenC. Baseline 
antibody concentrations will also be measured by ELISA. 
2.3  
Exploratory Objectives 

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1. To evaluate the systemic exposure of LHD153 at several early time-points after IM 
injection of MenC-CRM197/Aluminium Hydroxide/LHD153R or Meningococcal 
CCRM197 Conjugate Vaccine. 
2. To explore the frequency of B cells specific for MenC polysaccharide and CRM197 
protein at baseline (Day 1) and at Day 8, Day 29 and Day 181 after vaccination with 
MenC-CRM197/Aluminium Hydroxide/LHD153R or the aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. Subsequently, the B cell 
repertoire of the antigen specific B cells will be analyzed in a selected subset of 
subjects. 
3. To explore the baseline T cell mediated immunity to CRM197 and to evaluate the 
frequency and quality of CRM197 specific T cells induced by 
MenCCRM197/Aluminium Hydroxide/ LHD153R compared to aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at Day 8 and Day 29. 
4. To evaluate biomarkers that may be predictive for safety and/or innate immune 
activation. 
 

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3.0 
STUDY DESIGN 
3.1 
Overview of Study Design 
This is a Phase 1, randomized, observer blind, adjuvant dosage-escalation study. It will be 
performed at a single center. In total, approximately 80 healthy male and healthy 
nonpregnant female adults (18-45 years of age) will be enrolled in the study. 
Subjects will be randomized to receive a single IM vaccination of either the licensed 
aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine 
(Menjugate®) or the investigational vaccine, MenC-CRM197/Aluminium 
Hydroxide/LHD153R. 
The dosage of LHD153R will be escalated from 12.5 µg to 100 µg.  For the 
dosageescalation of LHD153R, the subjects will be enrolled into 1 of 4 cohorts, in a 
stepwise manner with 20 subjects per cohort. Subjects in all cohorts will be randomized 
in a 1:4 ratio, to receive either aluminium hydroxide adjuvanted Meningococcal C-
CRM197 Conjugate Vaccine (control) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R with increasing doses of LHD153R. Subjects assigned to MenC-
CRM197/Aluminium Hydroxide/LHD153R in Cohort 1 will receive 12.5 μg of LHD153R; 
Subjects in Cohort 2 will receive 25 μg of LHD153R; Subjects in Cohort 3 will receive 
50 μg of LHD153R; Subjects in Cohort 4 will receive 100 μg of LHD153R (Table 3.1-1). 
Table 3.1-1: Subjects Randomized per Cohort and Treatment Dosage Group 
Cohort 
Group 
Subjects/ 
Group 
MenC 
Dosage* 
(µg) 
Adjuvant Dosages 
Total 
Volume/Dose 
Total 
Subjects/Cohort 
Aluminium  
Hydroxide  
(mg) 
LHD153R  
(µg) 
1 
A 
4 
10 
1 
0 
0.5 mL 
20 
 
 
 
 
 
 
 
B 
16 
10 
1 
12.5 
0.5 mL 
 
2 
A 
4 
10 
1 
0 
0.5 mL 
20 
C 
16 
10 
1 
25 
0.5 mL 
3 
A 
4 
10 
1 
0 
0.5 mL 
20 
D 
16 
10 
1 
50 
0.5 mL 
4 
A 
4 
10 
1 
0 
0.5 mL 
20 
E 
16 
10 
1 
100 
0.5 mL 
*Conjugated to 12.5-25 µg CRM197 
All cohorts will have a staggered entry. For each cohort, the first 5 subjects (i.e. the first  
1:4 randomization block) to receive either aluminium hydroxide adjuvanted  

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Meningococcal C-CRM197 Conjugate Vaccine (n=1) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R (n=4) will be vaccinated at rate of 1 subject each day. 
After entry of the first 5 subjects in each cohort, the enrollment will be paused. The 
remaining 15 subjects for each cohort will be enrolled only after DMC review of the 
safety results obtained through Day 14 has been finalized (Table 3.1-2). In addition, 
enrollment of the first 5 subjects of the next cohort will only proceed after the Day 14 
safety results of the first 5 subjects of the previous cohort have been reviewed by the 
DMC. Furthermore, all available Day 14 and Day 29 safety results will be included in 
DMC review between the different enrollment stages. 
Table 3.1-2: Overview of staggered entry of subjects based on DMC reviews 
Stage 
Dosage Cohort 
MenC-CRM197/ 
Aluminium Hydroxide (n) 
MenC-CRM197/ 
Aluminium Hydroxide 
/LHD153R (n) 
1   
1  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 14 Safety Results 
2 
1  
3 
12 
2  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 29 and Stage 2 Day 14 Safety Results 
3 
2  
3 
12 
3  
1 
4 
Enrollment pause until DMC review of Stage 2 Day 29 and Stage 3 Day 14 Safety Results 
4 
3  
3 
12 
4  
1 
4 
Enrollment pause until DMC review of Stage 3 Day 29 and Stage 4 Day 14 Safety Results 
5 
4  
3 
12 
Post-vaccination procedures include collection of urine specimens at Day 1, Day 8 and 
Day 29 for safety assessment and blood specimens at Day 1, Day 8, Day 29 and Day 181 
for safety assessment and evaluation of the primary and secondary immunogenicity 
endpoints. Furthermore, additional blood specimens will be collected for assessment of 
exploratory endpoints at Day 1, Day 4, Day 8, Day 29 and Day 181 from those subjects 
that signed an additional informed consent concerning blood collection for exploratory 
assessment. 
3.2  
Study Period 
Each subject should expect to participate in the study for approximately 12 months, from 
the time of enrolment through the last study visit. 

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3.3  
Blinding Procedures 
This study is designed as an observer-blind study. For each dosage cohort, subjects, 
investigators, laboratories and the sponsor will be blinded to vaccine assignments. 
To maintain the blindness within each cohort, designated nurse(s) or physician(s) will be 
responsible for administering the study vaccines to the subjects, and will be instructed not 
to reveal the identity of the study vaccines neither to the subject nor to the investigative 
site personnel (investigator, study nurse, monitor) involved in the conduct or monitoring 
of the trial. This (these) designated individual(s) will have no contact with the subjects 
after the administration of the study vaccine. Furthermore, unblinded monitors are 
assigned to reconcile actual vaccine treatment. 
Study unblinding, at the group level, is planned for an Interim Analysis of the safety and 
immunogenicity data obtained up to Day 29 after all cohorts are enrolled and for full 
unblinding at the End of Study. 
Except in the case of medical necessity, a subject’s treatment should not be unblinded 
without the approval of the Sponsor. In such instance of medical emergency, every effort 
should be made to contact the Sponsor prior to unblinding. If unblinding should occur (by 
either accidental unblinding or emergency unblinding for a serious adverse event) prior to 
completion of the study, the investigator must promptly contact the Sponsor and 
document the circumstances on the appropriate forms. 
Emergency unblinding 
Emergency unblinding should only be undertaken when it is essential for effective 
treatment of the subject. The investigator will receive a blinded code break envelope for 
each subject, with the details of drug treatment included. Emergency code break 
envelopes must be stored in a secure place but be accessible in case of emergency. In an 
emergency, the envelope can be opened to determine the treatment. The envelope is not to 
be opened for any reason other than an emergency. When the investigator opens the 
envelope he/she must note the date, time, and reason for opening it and retain this 
information with the case report form documentation. The unblinded treatment code 
should not be recorded in the case report form. 
It is the investigator’s responsibility to ensure that there is a procedure in place to allow 
access to the code break envelope in case of emergency. The investigator must provide 
the subject with an emergency card to contact the clinical unit in cases of emergency and 
will inform the subject how to contact his/her backup in cases of emergency when he/she 
is unavailable. Subjects may continue the study after unblinding for safety follow-up. 

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For emergency unblinding, the corresponding Parexel standard operating procedure 
should be followed: 
 Annotate, sign and date the code break envelope. 
 Immediately inform Sponsor. 
 Complete the Randomization Code Break Form. 
 File the Randomization Code Break Form and the annotated envelope with the 
participant’s source documents. 
 Provide the Sponsor as soon as feasible, with a copy of the completed Randomization 
Code Break Form. 
3.4  
Data Collection 
3.4.1 
Data Collected from Subjects 
The following data will be collected from each subject over the duration of their study 
participation: 
▫ Demographic Information 
▫ Adverse Events 
▫ Medical History 
▫ Concomitant Medications 
▫ Vital signs 
All data collected must only be identified using the Subject ID, as described in section 
5.2.3. 
3.4.2 
Tools Used for Data Collection 
Data will be recorded in the Subject Diary and collected on Case Report Forms (CRFs). 
Subject Diary 
Subject Diaries will be the only source document allowed for solicited local and systemic 
adverse events (including body temperature measurements), starting after the initial 24 
hours post-vaccination observation period at the clinic. The following additional rules 
apply to documentation of safety information collected in the Subject Diary: 

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1. No corrections or additions to the Subject Diary will be allowed after it is delivered to 
the site. 
2. Any blank or illegible fields on the Subject Diary must be described as missing in the 
CRF. 
3. Any corrections to the Subject Diary must be performed by the person completing the 
Subject Diary and should include a single strike through line through the incorrect 
value or text with a brief explanation for each change, the initials of that person, and 
date of correction. 
Case Report Forms 
This study utilizes CRFs to collect study-related data from each subject. A qualified site 
staff member(s) is required to enter subject data in the CRFs based on the medical 
information available in each subject’s record. The following additional rules apply to 
documentation of Subject Diary information collected in the CRFs: 
1. The site must enter all readable entries in the Subject Diary into the CRF, including 
those values that may be biologically implausible (e.g. body temperature: 400°C). 
2. Any illegible or implausible data should be reviewed with the subject. If an 
underlying solicited or unsolicited adverse event is described on review with the 
subject, this should be described in the source document and reported as an 
unsolicited adverse event in the appropriate CRF (e.g., if the subject above confirms 
body temperature of 40°C on the day in which body temperature: 400°C was written 
into his/her Subject Diary, this fever of 40°C should be recorded in the appropriate 
CRF). 
3. Any newly described safety information (including a solicited adverse event) must not 
be written into the Subject Diary and must be described in the study file as a verbally 
reported adverse event. Any adverse event reported in this fashion must be described 
as an unsolicited adverse event and therefore, entered in the appropriate CRF. 
Data should be entered into the CRF in a timely fashion following each subject’s clinic 
visit, study procedure, or phone call. Each subject’s CRF casebook will be compared with 
the subject’s source records by a GSK-approved study monitor (or designee) over the 
duration of the study in order to ensure data collection accuracy. 
3.5  
Collection of Clinical Specimens 
The following clinical specimens are required to be collected from each subject in this 
study: 

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▫ Blood 
▫ Urine 
Processing of each specimen should be completed by a qualified site member. Testing of 
clinical specimens will be performed by a GSK or designated laboratory. 
Blood Specimens 
Before Vaccination 
▫ At the Pre-vaccination Screening Visit (between Day -28 to -3) one sample of 
approximately 10 ml blood will be drawn from all subjects. 
▫ At Visit 1 (Day 1) - prior to vaccination – two samples of approximately 10 ml blood 
will be drawn from all subjects. 
▫ At Visit 1 (Day 1) - prior to vaccination - the following blood samples will be drawn 
from subjects that gave additional informed consent for blood collection for 
exploratory assays: 
- 
One sample of approximately 3 ml 
- 
Two samples of approximately 5 ml 
- 
One sample of approximately 70 ml 
After Vaccination 
▫ At Visit 1 (Day 1) - 1 hour after vaccination - one sample of approximately 3 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 2 hours after vaccination - one sample of approximately 3 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 4 hours after vaccination - one sample of approximately 3 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 6 hours after vaccination – two samples of approximately 5 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 

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▫ At Visit 1 (Day 1) - 8 hours after vaccination - one sample of approximately 3 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 24 hours after vaccination - one sample of approximately 10 ml 
blood will be drawn from all subjects. 
▫ At Visit 1 (Day 1) - 24 hours after vaccination - the following blood samples will be 
drawn from subjects that gave additional informed consent for blood collection for 
exploratory assays: 
- 
One sample of approximately 3 ml 
- 
Two samples of  approximately 5 ml 
- 
One sample of approximately 20 ml 
▫ At Visit 2 (Day 4) the following blood samples will be drawn from subjects that gave 
additional informed consent for blood collection for exploratory assays: 
- 
One sample of  approximately 3 ml 
- 
Two samples of  approximately 5 ml 
- 
One sample of approximately 20 ml 
▫ At Visit 3 (Day 8) two samples of approximately 10 ml blood will be drawn from all 
subjects. 
▫ At Visit 3 (Day 8) the following blood samples will be drawn from subjects that gave 
additional informed consent for blood collection for exploratory assays 
- 
Two samples of approximately 5 ml 
- 
One sample of approximately 70 ml 
▫ At Visit 6 (Day 29) two samples of approximately 10 ml blood will be drawn from all 
subjects. 
▫ At Visit 6 (Day 29) one sample of approximately 50 ml blood will be drawn from 
subjects that gave additional informed consent for blood collection for exploratory 
assays. 
▫ At Visit 9 (Day 181) one sample of approximately 10 ml blood will be drawn from all 
subjects. 

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▫ At Visit 9 (Day 181) one sample of approximately 50 ml blood will be drawn from 
subjects that gave additional informed consent for blood collection for exploratory 
assays. 
The blood will be used for screening and safety laboratory assessments, immunological 
serology assays, pharmacokinetic analysis, cell mediated immunity assays and gene 
expression and protein production assays. See section 5.1.2, section 5.2.1 and section 7.0 
for additional details. 
Processing of each blood specimen should be completed in accordance with the study 
specific Clinical Specimen Laboratory Manual. 
The total amount of blood collected over the study period for all subjects will be 
approximately 90 ml. 
For subjects that signed an additional informed consent for blood collection for 
exploratory assays the total amount of blood collected over the study period will be 
approximately 441 ml. 
Urine Specimens 
Urine will be collected at the Pre-vaccination Screening Visit (between Day -28- to -3), at 
Visit 1 (Day 1; before vaccination and 24 hours after vaccination), at Visit 3 (Day 8) and 
at Visit 6 (Day 29). Results will be recorded in the source document and CRF. 
Urine will be collected from all subjects for safety laboratory assessments and drugs-
ofabuse testing. Furthermore, urine will be collected for pregnancy testing in all females. 
3.6  
Stopping/Pausing Guidelines 
Stopping/pausing guidelines are predefined criteria that halt the conduct of a study (either 
a vaccine group or the entire study). These guidelines are used to ensure the safety of study 
subjects.  
The following criteria, based on FDA guidance and with grading scales adapted from the 
CBER Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive vaccine Clinical Trials”, will be used for this study: 
1. The study will be halted (no new enrollments and no further investigational product 
administered) and a full safety review by the DMC and the IRB/EC will be performed 
if one of the following occurs. 

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a. One subject experiences a serious adverse event (SAE) assessed as possibly or 
probably related to investigational product or, 
b. There is a subject death assessed as possibly or probably related to the 
investigational product. 
2. The safety data will also be provided to the health authorities and potential restart of 
the study will require authorization from IRB/EC and health authorities.If one or more 
subjects experience a Grade 4 AE (see Appendix C, D, E and F for grading scales), 
vital sign or clinically significant laboratory abnormality that cannot be clearly 
attributed to another cause, vaccination will be suspended and a full safety review by 
the DMC and the IRB/EC will be performed. Potential continuation of the study will 
require authorization from IRB/EC. 
3. If six or more subjects experience a Grade 3 AE (see Appendix A, B, C, D, E and F 
for grading scales), vital sign or clinically significant laboratory abnormality, dosage 
escalation will be suspended for that vaccine and  a full safety review by the DMC 
and the IRB/EC will be performed. Potential continuation of the study will require 
authorization from IRB/EC. 
The sponsor or the investigator (following consultation with the sponsor) has the right to 
discontinue the study at any time. If the clinical study is prematurely terminated, the 
investigator must promptly inform the study subjects and must assure appropriate therapy 
and follow-up for the subjects. All procedures and requirements pertaining to the 
archiving of the documents must be followed.  All other study materials (such as study 
vaccines) must be returned to the sponsor or destroyed after sponsor approval. 
3.7  
Data Monitoring Committee 
An independent DMC will be formed to review safety data during scheduled periodic 
reviews. The DMC may also perform reviews on an ad hoc basis as needed. DMC 
membership will consist of at least 3 individuals who are external to the site and sponsor, 
and will include 1 statistician who is independent from the study team. The names of the 
independent DMC members are mentioned in the DMC charter. 
Subjects will be enrolled in a stepwise manner in each of the four vaccine dosage cohorts 
(Cohort 1: 12.5 μg LHD153R, Cohort 2: 25 μg of LHD153R, Cohort 3: 50 μg of  
LHD153R and Cohort 4: 100 μg of LHD153R). The DMC will review all safety data, as 
described in the DMC charter and in the Statistical Analysis Plan, after the first 5 subjects 
in each cohort have completed Visit 4 and their data are available for analysis, and before 
enrollment of the remaining subjects in the respective cohort and before enrollment of the 
first 5 subjects in the subsequent cohort. In addition, in between the different enrollment 

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stages, the DMC will review all available safety data of subjects that have completed 
Visit 4 and all available safety data of subjects that have completed Visit 6. 
The specific roles and responsibilities of the DMC members and other personnel involved 
will be documented in the DMC charter. The DMC charter will be finalized before the 
start of the study and will outline in detail all pausing and stopping rules according to the 
Clinical Study Protocol. 
3.8  
Premature Withdrawal from Study 
Subjects may withdraw at any time, or be dropped from the study at the discretion of the 
investigator should any untoward effects occur and/or for safety reasons. In addition, a 
subject may be withdrawn by the investigator or the Sponsor if he/she violates the study 
plan or for administrative reasons. The investigator or study coordinator must notify the 
Sponsor immediately when a subject has been withdrawn due to an adverse event. 
The circumstances above are referred to as premature withdrawal from the study, and the 
reason for premature withdrawal should be clearly documented and detailed in the source 
documentation. The investigator should make every attempt to evaluate the subject’s 
safety, including resolution of ongoing AEs, at the time of premature withdrawal. If a 
subject wants to withdraw from the study prior to the last planned study visit, the subject 
will be asked to be followed for safety for the duration of the study. When a subject 
withdraws, or is withdrawn, from the study, the procedures described in section 5.5.1 
should be completed if possible. 
The reasons for premature withdrawal from the study include: Adverse event, death, 
withdrawal of consent, lost to follow-up, administrative reason, and protocol deviation. 
These reasons are described in greater detail below. 
Adverse Event 
For any subject withdrawn from study participation prior to the planned Study  
Termination Visit, it is important to determine if an AE was associated with the reason for 
discontinuing the study. This AE must be identified on the appropriate CRF page by 
indicating “Withdrawn from study due to AE”. Any ongoing AEs at the time of study 
withdrawal must be followed until resolution or stabilization. 
Death 
For any subject withdrawn from study participation due to death, this should be noted on 
the appropriate CRF page and the associated SAE that led to the death must be reported. 

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Withdrawal of consent 
The subject can withdraw consent for participation in the study at any time without 
penalty or loss of benefit to which the subject is otherwise entitled. Reason for early 
termination should be deemed as “withdrawal of consent” if the subject withdraws from 
participation due to a non-medical reason (i.e., reason other than AE). If the subject 
intends to withdraw consent from the study, the investigator should clarify if the subject 
will withdraw completely from the study or if the subject will continue study participation 
for safety, or a subset of other study procedures. If the subject requests complete 
withdrawal from the study, no further study interventions will be performed with the 
subject. 
Lost to Follow-Up 
For subjects who fail to show up for study visits (clinic or telephone contacts), study staff 
is encouraged to make at least three documented attempts to contact the subject by 
telephone and at least one documented written attempt to contact the subject to encourage 
the completion of study termination procedures. These efforts to contact the subject must 
be recorded in the source document. The termination date for the subject to be captured 
on the appropriate CRF page is the date of the last contact (clinic visit or telephone) with 
the subject. 
Administrative Reason 
Examples for subjects withdrawn from the study due to administrative reason can include: 
Sponsor decision to terminate the study, subject meeting a pre-specified withdrawal 
criterion, subject discontinuation for insurance issues, moving, no time, etc. This reason 
should be noted in the appropriate CRF page and any ongoing AEs at the time of study 
withdrawal must be followed until resolution/stabilization. 
If the clinical study is prematurely terminated by the Sponsor, the investigator is to 
promptly inform the study subjects and local EC/IRB and should assure appropriate 
therapy and follow up for the subjects. All procedures and requirements pertaining to the 
archiving of study documents should be followed. All other study materials (study 
medication/vaccines, etc.) must be returned to the Sponsor. 
For subjects who are withdrawn from the study due to receipt of an excluded 
medication/vaccination or due to significant protocol non-compliance, this reason should 
be noted in the appropriate CRF page. 
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A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. In general, subjects associated with protocol deviations 
may remain in the study unless continuation in the study jeopardizes the subject’s health, 
safety, or rights. 
Investigators will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact GSK or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are 
permitted. If the investigator feels a change to the protocol would improve the conduct of 
the study this must be considered a protocol amendment, and unless such an amendment 
is agreed upon by GSK and approved by the IRB/EC and health authorities it cannot be 
implemented. 
Any subject who becomes pregnant during the study should be encouraged to continue 
participating in the study for safety follow-up. The site must complete a Pregnancy 
Report CRF (initial report) as soon as possible after learning of pregnancy occurrence 
(see section 7.1.6 for further details). If the subject withdraws from the study for any of 
the above categories except death, the site will obtain permission from the subject to 
continue to remain in contact with her until the outcome of the pregnancy is known, even 
if the outcome is not known until after the subject reaches the end of the routine study 
period. 
3.9  
End of Study 
Most clinical trials intended to support the efficacy/immunogenicity and safety of an 
Investigational Product proceed to full completion of planned sample size accrual. 
A subject is considered to have completed this study when he/she has: (1) received the 
intended dose of study vaccine and (2) completed 365 days (Visit 12) of safety follow-up 
after receiving the study vaccine. 
Evaluation of the primary and secondary immunogenicity objectives requires the testing 
of biological samples from all study subjects, which can only be completed after all 
samples are collected. The last samples for the analysis of the primary and/or secondary 
objectives will be taken at Visit 9 (Day 181). For the purpose of this protocol, End of 
Study is defined as the completion of the testing of such biological samples, to be 
achieved no later than 8 months after collection of the last biological sample at Visit 9. 

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4.0  
SELECTION OF STUDY POPULATION 
4.1  
Inclusion Criteria 
In order to participate in this study, all subjects must meet all of the inclusion criteria 
described. 
1. Male or female individuals of 18 through 45 years of age on the day of informed 
consent. 
2. Healthy volunteers with good physical and mental health status, determined on the 
basis of the medical history, a physical examination and the results of the screening 
tests as judged by the investigator. 
3. Individuals who have voluntarily given written informed consent after the nature of 
the study has been explained according to local regulatory requirements, prior to 
study entry. 
4. Individuals who can comply with study procedures including follow-up1. 
5. Individuals that are able to understand, read and write German language. 
6. Females of childbearing potential who are using an effective birth control method2 
which they intend to use for at least 30 days after the study vaccination. 
4.2  
Exclusion Criteria 
Each subject must not have or must not be: 
1. Progressive, unstable or uncontrolled clinical conditions. 
2. Hypersensitivity, including allergy, to any component of vaccines, medicinal products 
or medical equipment whose use is foreseen in this study. 
                                                
1 A subject is considered to be compliant if the Investigator judges that the subject will complete the Subject 
Diary, return for all the follow-up visits and be available for telephone calls as scheduled in the study. 
2 The following birth control methods are considered effective: 
- 
Hormonal contraceptive (such as oral, injection, transdermal patch, implant) if used for at least 30 
days prior to informed consent 
- 
Diaphragm with spermicide, tubal occlusion device 
- 
Intrauterine device (IUD) 
- 
Tubal ligation 

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- 
Male partner using condom with spermicide 
- 
Male partner having been vasectomized at least six months prior to informed consent 
3. Clinical conditions representing a contraindication to intramuscular vaccination and 
blood draws. 
4. Abnormal function of the immune system resulting from: 
a. Clinical conditions. 
b. Systemic administration of corticosteroids (PO/IV/IM) for more than 14 
consecutive days within 90 days prior to informed consent. 
c. Administration of antineoplastic and prescription immunomodulating agents or 
radiotherapy within 90 days prior to informed consent. 
5. Received immunoglobulins or any blood products within 180 days prior to informed 
consent. 
6. Received an investigational or non-registered medicinal product within 30 days prior 
to informed consent or intend to participate in another clinical study at any time 
during the conduct of this study. 
7. Vulnerable subjects (e.g. persons kept in detention), study personnel or an immediate 
family or household member of study personnel, subjects with legal incapacity or 
limited legal capacity 
8. Any relevant deviation from the laboratory parameters at screening as judged by the 
investigator. 
9. Previously received any vaccine that included a MenC antigen. 
10. Previously suspected or confirmed disease caused by N. meningitides. 
11. Had household contact with and/or intimate exposure to an individual with culture 
proven MenC. 
12. A positive serum or urine pregnancy test prior to the study vaccine administration or 
are currently lactating. 
13. A positive drugs-of-abuse test prior to the study vaccine administration 
14. Received any other vaccines within 30 days prior to enrolment in this study or who 
are planning to receive any vaccine within 30 days from the administration of study 
vaccines. 

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15. Any other condition that, in the opinion of the investigator, might interfere with the 
results of the study or pose additional risk to the subject due to participation in the 
study. 
4.3  
Criteria for Delay of Vaccination or Blood Draw 
There may be instances when individuals meet all eligibility criteria for vaccination or 
blood draw yet have a transient clinical circumstance which may warrant delay of 
vaccination or blood draw. Under such circumstances, a subject may be considered 
eligible for study enrolment after the appropriate window for delay has passed and 
inclusion/exclusion criteria have been rechecked, and if the subject is confirmed to be 
eligible. 
Reasons for delay of vaccination include: 
▫ Body temperature elevation ≥38.0°C (measured orally) within 3 days prior to intended 
study vaccination. 
▫ Use of antipyretics and/or analgesic medications within 24 hours prior to vaccination. 
Reasons for delay of blood draw include: 
▫ Subject has received a dose of systemic antibiotics less than 6 days before blood 
collection for the hSBA directed against MenC. 
 

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5.0  
STUDY PROCEDURES 
The sections that follow provide an overview of the procedures that are to be followed in 
enrolling, evaluating, and following subjects who participate in this clinical study. Visits 
can be either clinic visits or safety follow-up telephone calls, as specified in the Table 
below and in the Time and Events Tables 3 and 4 of the Study Synopsis. 
Table 5.0-1: Study procedures 
Visit Category 
Procedures 
Pre-vaccination Clinic Visit 
Section 5.1 describes procedures to be followed 
prior to subject enrollment, including: informed 
consent and screening procedures. 
Vaccination Clinic Visit 
Section 5.2 describes procedures to be followed 
during the vaccination clinic visit, including: 
prevaccination procedures, enrolment, 
randomization, vaccination and post-vaccination 
procedures. 
Post-vaccination Visits 
Section 5.3 describes follow-up clinic visits and 
safety follow-up calls. 
Unscheduled Visits 
Section 5.4 describes possible procedures to be 
followed at unscheduled clinic visit. 
Study Termination Visit 
Section 5.5 describes procedures to be followed at 
the last study visit for a subject (may include early 
termination visit). 
5.1 
Pre-vaccination Clinic Visit(s) 
The Pre-vaccination Clinic Visit must be performed in the period between Day -28 and 
Day -3. 
This section describes the procedures that must be performed for each potential subject 
prior to enrollment, including obtaining informed consent and screening. 
5.1.1  
Informed Consent 
"Informed consent" is the voluntary agreement of an individual or his/her legal 
guardian(s) to participate in research. Consent must be given with free will of choice, and 
without undue inducement. The individual must have sufficient knowledge and 
understanding of the nature of the proposed research, the anticipated risks and potential 
benefits, and the requirements of the research to be able to make an informed decision. 

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Informed consent following local IRB/EC guidance must be obtained before conducting 
any study-specific procedure (i.e., all of the procedures described in the protocol). Prior to 
any additional blood sample collection for exploratory objectives, a secondary informed 
consent must be signed by subjects. The process of obtaining informed consent should be 
documented in the subject source document in addition to maintaining a copy of the 
signed and dated informed consent. 
5.1.2  
Screening 
After an individual has consented to participate in the study and informed consent is 
signed, that individual will be given a unique Screening Number. The subject’s unique 
Screening Number will be documented in the Screening and Enrolment log. The 
eligibility of the subject will be determined based on the inclusion and exclusion criteria 
listed in section 4.0 and evaluated during this screening procedure. 
Screening procedures at the Pre-vaccination Clinical Visit (between Day -28 and Day -3) 
will include the following: 
▫ Review of demographic data, including age, gender, race, body weight and height. 
▫ Review of medical history, including but not limited to any medical history, ongoing 
illnesses or injuries that may be relevant to subject eligibility for study participation. 
Relevant medical history can also include any medical history that contributes to the 
understanding of an adverse event that occurs during study participation, if it 
represents an exacerbation of an underlying disease/pre-existing problem. 
▫ Perform physical examination, including but not limited to: 
- 
Assessment of general appearance 
- 
Collection of vital signs, including body temperature, blood pressure, heart rate 
and respiratory rate 
- 
Examination of head, ears, eyes, nose and throat (HEENT) 
- 
Examination of skin 
- 
Auscultation of heart and lungs 
▫ Collection and review of prior and concomitant medications or vaccinations taken 
prior to start of study (refer to section 6.5 for further details). 
▫ Collection of any unsolicited AEs occurring prior to administration of the study 
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▫ Blood draw (approximately 10 ml) for Safety Laboratory assessments, measurement of 
Hepatitis B surface antigen, anti-Hepatitis C virus antibodies, anti-HIV 1 and 2 
antibodies and serum pregnancy test (all women). 
▫ Urine sample for Safety Laboratory assessments and drugs-of-abuse testing. 
NOTE: A general physical examination is to be performed by a qualified health care 
practitioner. “Qualified health care practitioner” refers to any licensed health care 
professional who is permitted by institutional policy to perform physical examinations 
and who is identified within the Study Staff Signature Log. 
Data collected during the Pre-vaccination Screening Clinic Visit must be written in the 
source document (see section 9.1) and will be captured in the screening CRF Forms. In 
the event that the individual is determined ineligible for study participation, he/she is 
considered a screen failure. The reason for screen failure must be documented in the 
Screening and Enrolment log. 
5.2  
Vaccination Clinic Visit(s) 
This section describes the procedures to be performed at the Vaccination Clinic Visit 
(Visit 1, Day 1), including: pre-vaccination procedures, enrolment, randomization, 
prevaccination blood draw, vaccination and post-vaccination procedures. 
5.2.1  
Pre-vaccination Procedures 
During pre-vaccination procedures at Visit 1 (Day 1), the eligibility of the subject will be 
confirmed based on the inclusion and exclusion criteria listed in section 4.0. 
Pre-vaccination procedures at Visit 1 (Day 1) will include the following: 
▫ Review of systems by means of a structured interview that queries the subject as to any 
complaints the subject has experienced across each organ system. 
▫ Perform physical examination, including but not limited to: 
- 
Assessment of general appearance 
- 
Assessment of body weight and collection of vital signs, including body 
temperature, blood pressure, heart rate, and respiratory rate 
- 
Examination of head, ears, eyes, nose and throat (HEENT) 
- 
Examination of skin 
- 
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▫ Collection and review of prior and concomitant medications or vaccinations taken, or 
recalled, since the last visit (refer to section 6.5 for further details). 
▫ Collection of any unsolicited AEs occurring prior to administration of the study 
vaccine. 
▫ One blood sample (approximately 10 ml) will be drawn from all subjects for serology 
testing. 
▫ One blood sample (approximately 10 ml) will be drawn from all subjects for baseline 
Safety Laboratory assessments. 
▫ One urine sample for baseline Safety Laboratory assessments, pregnancy testing (all 
women) and drugs-of-abuse testing. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of blood draws are provided in section 3.5. 
NOTE: A general physical examination is to be performed by a qualified health care 
practitioner. “Qualified health care practitioner” refers to any licensed health care 
professional who is permitted by institutional policy to perform physical examinations 
and who is identified within the Study Staff Signature Log. 
Data collected during pre-vaccination procedures at Visit 1 must be written in the source 
document (see section 9.1). In the event that the individual is determined ineligible for 
study participation, he/she is considered a screen failure. The reason for screen failure 
must be documented in the Screening and Enrolment log. If the individual is determined 
to be eligible for the study, he/she can be enrolled into the study. 
5.2.2 
Enrolment 
After an individual is determined to be eligible for study participation, the investigator 
will enroll the subject into an Electronic Data Capture (EDC) system where the 
randomization to the treatment group will occur. The Screening Number ceases to be used 
and remains in the Screening and Enrolment Log only. 
If for any reason, after signing the informed consent form (ICF), the subject who is 
eligible and enrolled fails to be randomized, this is called a randomization failure. In this 
case the early termination study procedures must be applied. The reason for all 
randomization failures should be recorded in the Screening and Enrolment Log and in the 
source document as specified in the Source Data Agreement. The information on subjects 

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who are randomization failures should be kept distinct from subjects who are screen 
failures, as described in section 5.1.2 and section 5.2.1. 
5.2.3 
Randomization 
Enrolled subjects will be randomized and automatically assigned a unique Subject ID. 
The Subject ID will be the subject’s unique identification number for all CRFs and 
associated study documentation that will be used for the duration of the study. 
If for any reason, after signing the informed consent form (ICF), the eligible subject is 
enrolled and randomized but fails to undergo treatment, this is an Early Termination and 
the reason should be recorded in source document as specified in the Source Data 
Agreement/Source Data Verification Form. The information on these Early Termination 
subjects should be kept distinct in the source documentation from randomization failures, 
which are described in section 5.2.2. 
5.2.4 
Vaccination 
After completing the pre-vaccination procedures at Visit 1 (Day 1), administer the 
vaccine to the subject according to the procedures described in section 6.3. Observe the 
blinding procedures described in section 3.3. 
5.2.5 
Post-vaccination Procedures 
The following post-vaccination procedures will be performed at Visit 1 (Day 1): 
▫ After vaccination, the subject will be observed for at least 30 minutes for any 
immediate solicited and unsolicited AEs, body temperature measurement and vital 
signs at 30 min after vaccination. All safety and body temperature data collected 
during this time are to be recorded in the subject’s source document. 
▫ After vaccination, the subject will be observed for at least 24 hours at the clinic 
including observation for solicited and unsolicited AEs, body temperature 
measurements. Body temperature measurements must be performed at 2, 4, 6, 8, 10, 
12, 18 and 24 hours after vaccination and additional vital signs at 24h after 
vaccination. All safety and body temperature data collected during this time are to be 
recorded in the subject’s source. 
▫ One blood sample (approximately 10 ml) will be drawn from all subjects at 24 hours 
after vaccination for Safety Laboratory assessments. 
▫ One urine sample will be collected from all subjects at 24 hours after vaccination for 
Safety Laboratory assessments. 

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▫ From those subjects that signed an additional Informed Consent for exploratory assays, 
additional blood samples will be drawn in the first 24 hours after vaccination. Details 
regarding the number and volume of post-vaccination blood draws are provided in 
section 3.5. 
After the initial 24 hours inpatient observation period, a Subject Diary will be used in this 
study to document solicited and unsolicited AEs until Day 14. The Subject Diary is the 
only source for collection of solicited AEs after the initial 24 hours inpatient observation 
period. Therefore, it is critical that the subject completes the Subject Diary correctly. 
The following training regarding completion of the Subject Diary must be provided: 
▫ The subject should be trained on how and when to complete each field of the Subject 
Diary. 
▫ The subject should be trained on how to self-measure local solicited adverse events 
and body temperature. The measurement of solicited local adverse events is to be 
performed using the ruler provided by the site. 
▫ The subject should be instructed how to perform body temperature measurement using 
the thermometer provided by the site. If the subject feels unusually hot or cold during 
the day, the subject should check their body temperature. If the subject has fever, the 
highest body temperature observed that day should be recorded in the Subject Diary. 
Subject Diary training should be directed at the individual(s) who will perform the 
measurements of adverse events and who will enter the information into the Subject 
Diary. This individual may not be the subject, but if a person other than the subject enters 
information into the Subject Diary, this person’s identity must be documented in the 
Subject Diary. Any individual that writes in the Subject Diary must receive training on 
completion of the Diary Card at the time of the visit. This training must be documented in 
the subject’s source record. 
The site should schedule the next study activity (clinic visit) with the subject. 
The subject will receive a written reminder of the next planned study activity. The subject 
will be reminded to complete the Subject Diary and to contact the site if there are any 
questions, and to contact the site immediately (or as soon as the subject is medically 
stable) if the subject has a medical condition that leads to a hospitalization or an 
emergency room visit. 
5.3  
Post-vaccination Visit(s) 

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5.3.1 Subject Diary Reminder, Safety Follow-up and/or Post-vaccination Blood 
Draw Clinic Visits 
Subject Diary reminder, Safety follow-up and/or post-vaccination blood draw clinic visits 
will be performed on Day 4 (Visit 2), Day 8 (Visit 3), Day 15 (Visit 4), Day 29 (Visit 6), 
Day 85 (Visit 7), Day 113 (Visit 8) and Day 181 (Visit 9) 
At Day 4 (Visit 2) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. All unsolicited AEs, SAEs, AESIs, 
medically attended AEs, AEs leading to study withdrawal and NOCD must be 
recorded on source documents. Any concomitant medications or vaccinations 
associated with those events must also be recorded on the source documents. 
▫ All subjects will be reminded to complete the Subject Diary and to contact the site if 
there are any questions, and to contact the site immediately (or as soon as the subject 
is medically stable) if the subject has a medical condition that leads to a 
hospitalization or an emergency room visit. No changes to the Subject Diary should 
be done at the clinic visit. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of blood draws are provided in section 3.5. 
▫ The site should schedule the next study activity (clinic visit) with the subject and the 
subject will receive a written reminder of the next planned study activity. 
At Day 8 (Visit 3) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. All unsolicited AEs, SAEs, AESIs, 
medically attended AEs, AEs leading to study withdrawal and NOCD must be 
recorded on source documents. Any concomitant medications or vaccinations 
associated with those events must also be recorded on the source documents. 

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▫ The subject will be reminded to complete the Subject Diary and to contact the site if 
there are any questions, and to contact the site immediately (or as soon as the subject 
is medically stable) if the subject has a medical condition that leads to hospitalization 
or an emergency room visit. No changes to the Subject Diary should be done at the 
clinic visit. 
▫ Blood draw (approximately 10 ml) from all subjects for Safety Laboratory 
assessments. 
▫ Urine sample from all subjects for Safety Laboratory assessments. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 

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volume of blood draws are provided in section 3.5. 
The site should schedule the next study activity (clinic visit) with the subject and the 
subject will receive a written reminder of the next planned study activity. 
At Day 15 (Visit 4) the following procedures will be performed: 
▫ The Subject Diary will be collected and reviewed. No changes to the Subject Diary 
should be done at the clinic visit. For details on the Subject Diary see sections 3.4.2, 
and 5.2.5. The healthcare professional reviewing these data will discuss the symptoms 
(if any) reported by the subject and will determine if any additional diagnoses and/or 
adverse events are present. All unsolicited AEs until Day 14, solicited local and 
systemic AEs persisting at Day 14, SAEs, AESIs, medically attended AEs, AEs 
leading to study withdrawal and NOCD must be recorded on source documents. All 
concomitant medications or vaccinations associated with those events must also be 
recorded on the source documents. 
▫ The site should schedule the next study activity (safety phone call) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 29 (Visit 6) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events 
occurred and if any concomitant medications or vaccines were taken / received in the 
time since the last clinic visit. The healthcare professional reviewing these data will 
discuss the symptoms (if any) reported by the subject and will determine if any 
additional diagnoses and/or adverse events are present. Any solicited local and 
systemic AEs continuing beyond Day 14, SAEs, AESIs, medically attended AEs, 
AEs leading to study withdrawal and NOCD must be recorded on source documents. 
All concomitant medications or vaccinations associated with those events must also 
be recorded on the source documents. 

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▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and  
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▫ Blood draw (approximately 10 ml) from all subjects for Safety Laboratory 
assessments. 
▫ Urine sample from all subjects for Safety Laboratory assessments. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 
volume of post-vaccination blood draws are provided in section 3.5. 
The site should schedule the next study activity (clinic visit) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 85 and Day 113 (Visit 7 and Visit 8), the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events 
occurred and if any concomitant medications or vaccines were taken / received in the 
time since the last clinic visit. The healthcare professional reviewing these data will 
discuss the symptoms (if any) reported by the subject and will determine if any 
additional diagnoses and/or adverse events are present. Any solicited local and 
systemic AEs continuing beyond Day 14, SAEs, AESIs, medically attended AEs, 
AEs leading to study withdrawal and NOCD must be recorded on source documents. 
All concomitant medications or vaccinations associated with those events must also 
be recorded on the source documents. 
▫ The site should schedule the next study activity (clinic visit) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 181 (Visit 9), the following procedures will be performed: 

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▫ The subject will be interviewed to determine if any unsolicited adverse events 
occurred and if any concomitant medications or vaccines were taken / received in the 
time since the last clinic visit. The healthcare professional reviewing these data will 
discuss the symptoms (if any) reported by the subject and will determine if any 
additional diagnoses and/or adverse events are present. Any solicited local and 
systemic AEs continuing beyond Day 14, SAEs, AESIs, medically attended AEs, 
AEs leading to study withdrawal and NOCD must be recorded on source documents. 
All concomitant medications or vaccinations associated with those events must also 
be recorded on the source documents. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 
volume of post-vaccination blood draws are provided in section 3.5. 
The site should schedule the next study activity (safety phone call) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
5.3.2  
Safety Follow-up Calls 
Safety follow-up calls will be performed on Day 22 (Visit 5), Day 209 (Visit 10) and Day 
271 (Visit 11) and include the following procedures: 
▫ Safety follow-up calls are calls made to the subject by a healthcare professional 
designated on the site log. These calls will follow a script which will facilitate the 
collection of relevant safety information. The subject will be interviewed according to 
the script, and information relating to solicited local and systemic AEs persisting 
beyond Day 14 and unsolicited adverse events including SAEs, AESIs, medically 
attended AEs, AEs leading to study withdrawal, and/or NOCD and concomitant 
medications or vaccinations associated with those events. All safety information 
described by the subject must be written down in a designated location within the 
source document and not written on the script used for the telephone call. 

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assays, additional blood samples will be drawn. Details regarding the number and  
▫ 
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▫ The site should schedule the next study activity (clinic visit or study termination visit) 
with the subject. 
▫ The subject will be reminded to contact the site if there are any questions and to 
contact the site immediately (or as soon as the subject is medically stable) if the 
subject has a medical condition that leads to a hospitalization or an emergency room 
visit. 
5.4  
Unscheduled Visits  
An unscheduled visit describes a non-routine study visit triggered by a specific event. 
These could include anticipated or unanticipated adverse events or interventions. 
The following procedures should be carried out for all unscheduled visits: 
1. Evaluate the subject’s vital signs body temperature, heart rate, and blood pressure and 
perform a symptom-directed physical examination. 
2. Record any observed AEs in the source documents. 

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3. Record any concomitant medications or vaccinations associated with AEs in the 
source documents. 
5.5  
Study Termination Visit 
The study termination visit is scheduled on Day 366 (Visit 12). The termination visit is a 
clinic visit. For visit procedures to be performed for a subject whose planned study 
participation ends prematurely, please see section 5.5.1. 
At the Study Termination clinic visit the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. 
▫ The healthcare professional reviewing these data will discuss the symptoms (if any) 
reported by the subject and will determine if any additional diagnoses and/or adverse 
events are present. 
▫ Medically attended AEs, SAEs, NOCDs, or AESIs will be recorded on source 
documents. 
▫ All medications taken or vaccines received will also be recorded on the source 
documents. 
▫ The site will review with the subject the plan of when information relating to the 
subject’s participation in the study may be available (e.g., study results, treatment 
assignments). It will also be discussed how information relating to the subject’s 
participation in the study will be shared with the subject’s healthcare provider, if the 
subject chooses to share this information. 
▫ The site will complete the termination CRF page and this will mark the completion of 
the subject’s participation in the study. 
5.5.1  
Early Termination Visit 
The date of termination is the date of the last contact in which the subject’s health status 
was assessed or, in cases where the subject does not agree to any further safety follow-up, 
it is the date consent is withdrawn. This date should be recorded on the appropriate CRF 
page. 
When a subject is withdrawn from treatment or withdraws from the study, the investigator 
will notify the Sponsor and, when possible, will perform the procedures listed below. 

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The reason(s) for the early termination must be included in the subject’s source 
documentation. If the Early Termination Visit is a telephone call, collect as much 
information as possible. Early Termination Visits include subjects who were randomized 
but not treated. 
At the clinic visit or during the telephone call, the following procedures should be 
performed, when possible: 
▫ Collection and review of Subject Diary (if not already collected). 
▫ Interview of subject to collect unsolicited adverse events, medically attended AEs, 
AEs leading to withdrawal, SAEs, AESIs, and NOCD. 
▫ Interview of subject to collect concomitant medications and/or vaccinations. 
▫ Symptom-directed physical assessment, at least including measurement of vital signs 
(body temperature, respiratory rate, blood pressure, heart rate) and a check of general 
appearance (in case of clinic early termination visit). 
▫ Draw a blood sample (approximately 10 ml) and a urine sample for Safety Laboratory 
assessment (in case of clinic early termination visit). 
▫ The site will review with the subject the plan of when information relating to the 
subject’s participation in the study may be available (e.g., study results, treatment 
assignments). It will also be discussed how information relating to the subject’s 
participation in the study will be shared with the subject’s healthcare provider, if the 
subject chooses to share this information. 
▫ The site will complete the appropriate CRF page and this will mark the completion of 
the subject’s participation in the study. 
6.0  
TREATMENT OF SUBJECTS 
All vaccines associated with this study are to be stored separately from other vaccines and 
medications in a secure location under appropriate storage conditions with temperature 
monitoring. All vaccines associated with this study must be checked for expiration 
date prior to use. Expired vaccines must not be administered to subjects. 
6.1  
Study Vaccine(s) 
The term ‘study vaccine’ refers to those vaccines provided by the Sponsor, which will be 
evaluated as part of the study objectives. The study vaccines specific to this study are 
described in Table 6.1-1. 

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Table 6.1-1: Study Vaccine Composition 
Group A (Control) Meningococcal C-CRM197 Conjugate Vaccine 
 
Vaccine Component 
Quantity per 0.5 ml dose 
 
 
Vial Containing Vaccine Conjugate 
 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
 
Aluminum Hydroxide Solvent Components (for 0.5 mL dose) 
 
Aluminum hydroxide 
1.0 mg 
Sodium Chloride 
3.5 mg 
Sterile water for injection, up to 
0.5 ml 
 
 
Group B (12.5µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
12.5 µg 
Sodium Chloride 
3.4 mg 

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Histidine  
0.1 mg 
Tris 
30 µg 
Sterile water for injection, up to 
0.5 ml 
 
 
Group C (25 µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
25 µg 
Sodium Chloride 
3.4 mg  
Histidine 
0.2 mg 
Tris 
61 µg 
Sterile water for injection, up to 
0.5 ml 
 
 
Group D (50µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 

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Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
50 µg 
Sodium Chloride 
3.2 mg 
Histidine 
0.4 mg 
Tris 
121 µg 
Sterile water for injection, up to 
0.5 ml 
 
Group E (100µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
100 µg 
Sodium Chloride 
2.9 mg 
Histidine 
0.8 mg 
Tris 
243 µg 
Sterile water for injection, up to 
0.5 ml 
6.2  
Non-Study Vaccines 

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The term ‘non-study vaccine’ refers to those vaccines which will be intentionally given to 
study subjects but not formally included in the analysis of study objectives. 
No non-study vaccines are planned for this study. Any non-study vaccines administered 
during the study conduct will be captured in the CRF as concomitant medications and/or 
vaccinations. 
6.3  
Vaccine Preparation and Administration 
The investigator or designee will be responsible for oversight of the administration of 
vaccine to subjects enrolled in the study according to the procedures stipulated in this 
study protocol. All vaccines will be administered only by unblinded personnel who are 
qualified to perform that function under applicable local laws and regulations for the 
specific study site. 
The vaccine components will be provided in 5 separate kits (i.e. one for the control and 
one for each of the 4 dosage groups). The vaccine components must be mixed prior to 
vaccination taking into account the appropriate aseptic procedures. Detailed vaccine 
preparation and administration instructions, including the maximal administration period, 
will be provided to investigators prior to study start and must be filed in the Investigator 
Site File. 
PRECAUTIONS TO BE OBSERVED IN ADMINISTERING STUDY VACCINE: 
- 
Prior to vaccination, subjects must be determined to be eligible for study vaccination 
and it must be clinically appropriate in the judgment of the investigator to vaccinate. 
Eligibility for vaccination prior to first study vaccine administration is determined by 
evaluating the entry criteria outlined in protocol sections 4.0. 
- 
Study vaccines must not be administered to individuals with known hypersensitivity 
to any component of the vaccines. 
- 
Standard immunization practices are to be observed and care should be taken to 
administer the injection intramuscularly. Before administering vaccine, the 
vaccination site is to be disinfected with a skin disinfectant (e.g., 70% alcohol). Allow 
the skin to dry. DO NOT inject intravascularly. 
- 
As with all injectable vaccines, trained medical personnel and appropriate medical 
treatment must be readily available in case of anaphylactic reactions following 
vaccine administration. For example, epinephrine 1:1000, diphenhydramine, and/or 
other medications for treating anaphylaxis should be available. 

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6.4 
Vaccine Administration Error or Overdose of Vaccine 
Vaccine administration error is defined as receiving a dose of study vaccine that was not 
reconstituted as instructed or administered by a different route from the intended route of 
administration. An overdose of study vaccine (whether accidental or intentional) is 
defined when a dosage higher than the recommended dosage is administered in one dose 
of study vaccine. 
Any vaccine administration error or overdose of study vaccine detailed in this protocol 
must be reported as an adverse event, and if the vaccine administration error or overdose 
is associated with a serious adverse event, it must be reported as such within 24 hours to 
the Sponsor. 
6.5 
Prior and Concomitant Medications and Vaccines 
All medications, vaccines and blood products taken or received by the subject within 180 
days prior to the start of the study are to be recorded in the appropriate CRF. 
Medications taken for prophylaxis are those intended to prevent the onset of symptoms. 
Medications taken for treatment are intended to reduce or eliminate the presence of 
symptoms that are present. 
NOTE: Use of antipyretics/analgesics within 24 hours prior to vaccine administration is a 
reason to delay study vaccination (see section 4.3). 
Concomitant medications include all medications (including vaccines) taken 
by/administered to the subject at and after enrolment and must be documented in the 
appropriate CRF. 
When recording concomitant medications/vaccines, they should be checked against the 
study entry criteria in section 4.0, to ensure that the subject should be enrolled in the 
study. 
6.6  
Vaccine Supply, Labeling, Storage and Tracking 
The Sponsor will ensure the following: 
▫ Supply the study vaccines. 
▫ Appropriate labeling of all study vaccines provided that complies with the legal 
requirements of each country where the study is to be performed. 

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The investigator must ensure the following: 
▫ Acknowledge receipt of the study vaccines by a designated staff member at the site, 
including: 
- 
Confirmation that the vaccines were received in good condition 
- 
Confirmation to the Sponsor of the temperature range during shipment from the  
Sponsor to the investigator’s designated storage location 
- 
Confirmation by the Sponsor that the vaccines are authorized for use. 
▫ Proper storage of the study vaccines, including: 
- 
Storage in a secure, locked, temperature-controlled location. 
- 
Proper storage according to the instructions specified on the labels. 
- 
Appropriate record keeping and inventory of the study vaccines, including regular 
documentation of adequate storage temperature. 
▫ Appropriate use of the study vaccines, including: 
- 
No use of vaccines prior to receipt of authorization for use from the Sponsor. 
- 
Use only in accordance with the approved protocol. 
- 
Proper handling, including confirmation that the vaccine has not expired prior to 
administration. 
- 
Appropriate documentation of administration of vaccines to study subjects 
including: 
▪ 
Date, dosage, batch/lot numbers, expiration dates, unique identifying 
numbers assigned to subjects and study vaccines, and time of vaccine 
administration. This information will be maintained in an accountability log 
that will be reviewed by the site monitor. 
▪ 
Reconciliation of all vaccines received from the Sponsor. Reconciliation is 
defined as maintaining records of which and how many vaccines were 
received, which vaccines were administered to subjects, which vaccines 
were destroyed at the site, and which vaccines were returned to the Sponsor, 
as applicable. 
▫ Proper adherence to the local institutional policy with respect to destruction of study 
vaccines. 

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▫ Complete record keeping of vaccine use, wastage, return or destruction, including 
documentation of: 
- 
Copy of the site’s procedure for destruction of hazardous material. 
- 
Number of doses destroyed, date of destruction, destruction code (if available), 
method of destruction, and name of individual performing destruction. 
Vaccines that have been stored differently from the manufacturer’s indications must not 
be used unless the Sponsor provides written authorization for use. In the event that the use 
cannot be authorized, the Sponsor will make every effort to replace the vaccine supply. 
All vaccines used in conjunction with this protocol must be stored separately from normal 
hospital/practice stocks to prevent unintentional use of study vaccines outside of the 
clinical study setting. 
Monitoring of vaccine accountability will be performed by the study monitor during site 
visits and at the completion of the study. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator must ensure that all unused study vaccines, packaging and supplementary 
labels are destroyed locally (upon approval from Sponsor) or returned to the Sponsor. 

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7.0 
ASSESSMENTS 
7.1 
Safety Assessment 
The measures of safety used in this study are based on previous study data and based on 
comparable routine clinical/laboratory procedures. They include a close vigilance for, and 
stringent reporting of selected local and systemic adverse events routinely monitored in 
vaccine studies as indicators of reactogenicity. 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product at any dose that does 
not necessarily have to have a causal relationship with this treatment. Therefore, an AE 
can be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the investigational product. 
This definition includes intercurrent illnesses or injuries and exacerbation of pre-existing 
conditions. 
The period of observation for AEs extends from the time the subject signs informed 
consent until he or she completes the specified safety follow-up period (Day 366) or 
terminates the study early (whichever comes first). AEs occurring after the informed 
consent form is signed but prior to receiving study vaccine/product will be documented as 
an adverse event and recorded within the source documents. However, any AEs occurring 
prior to receipt of any study vaccine will be analyzed separately from “treatment 
emergent” AEs (AEs occurring after administration of the first study vaccine). 
Adverse events are collected as either solicited or unsolicited adverse events. Solicited 
events are derived from organized data collection systems, such as Subject Diaries or 
interview. 
7.1.1 
Solicited Adverse Events 
The term “reactogenicity” refers to solicited signs and symptoms (“solicited adverse 
events”) occurring in the hours and days following a vaccination, to be collected by the 
subject after the first 24 hours inpatient observation period at Day 1until Day 14, using a 
pre-defined Subject Diary. 
The following solicited adverse events are included in the Subject Diary. Each adverse 
event is to be assessed using the scoring system shown in Appendix A (Solicited Local 
AEs) and Appendix B (Solicited Systemic AE): 

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Solicited Local Adverse Events 
Solicited local AEs include: 
- 
injection site erythema 
- 
injection site induration 
- 
injection site pain 
- 
injection site swelling Solicited Systemic Adverse Events 
Solicited systemic AEs include: 
- 
body temperature ≥38.0°C (as measured orally) 
- 
loss of appetite 
- 
nausea 
- 
fatigue 
- 
generalized myalgia 
- 
generalized arthralgia 
- 
headache - 
chills 
- 
vomiting 
- 
diarrhea 
- 
generalized rash 
- 
urticaria 
Other Solicited Data 
Other solicited data collected per Subject Diary include: 
▫ Use of analgesics/antipyretics recorded as “absent” or “present” and summarized by 
“for treatment” or “for prophylaxis” 
▫ Body temperature as recorded daily, ideally at same time, by the oral route 
The study staff must review the data entered into the Subject Diary as described in 
sections 3.4.2 and 5.3.1. 

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NOTE: Any solicited adverse event that meets any of the following criteria must be 
entered into the subjects’ source documents (see section 9.1) and also as an adverse event 
in the appropriate CRF: 
▫ Solicited local or systemic adverse event that continues beyond Day 14 after 
vaccination. 
▫ Solicited local or systemic adverse event that leads to a visit to a healthcare provider 
(medically attended adverse event, see section 7.1.3). 
▫ Solicited local or systemic adverse event leading to the subject withdrawing from the 
study or the subject being withdrawn from the study by the investigator (adverse event 
leading to withdrawal, see section 7.1.3). 
▫ Solicited local or systemic adverse event that otherwise meets the definition of a 
serious adverse event (see section 7.1.4). 
7.1.2  
Unsolicited Adverse Events 
An unsolicited adverse event is an adverse event that was not solicited using a Subject 
Diary and that was spontaneously communicated by a subject who has signed the 
informed consent. 
7.1.3  
Evaluation of Adverse Events 
Every effort should be made by the investigator to evaluate safety information reported by 
a subject for an underlying diagnosis and to capture this diagnosis as the event in the AE 
page. In other words, the practice of reporting only symptoms (e.g., “cough” or “ear 
pain”) are better reported according to the underlying cause (e.g., “asthma exacerbation” 
or “otitis media”). 
The severity of events reported on the appropriate CRF page will be determined by the 
investigator as: 
Mild: 
transient with no limitation in normal daily activity. 
Moderate: 
some limitation in normal daily activity. 
Severe: unable to perform normal daily activity. 
The relationship of the study treatment to an AE will be determined by the investigator 
based on the following definitions: 

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1. Not Related 
The AE is not related to an investigational vaccine if there is evidence that clearly 
indicates an alternative explanation. If the subject has not received the vaccine, the timing 
of the exposure to the vaccine and the onset of the AE are not reasonably related in time, 
or other facts, evidence or arguments exist that reasonably suggest an alternative 
explanation, then the AE is not related. 
2. Possibly Related 
The administration of the investigational vaccine and AE are considered reasonably 
related in time and the AE could be explained by exposure to the investigational vaccine 
or by other causes. 
3. Probably Related 
Exposure to the investigational vaccine and AE are reasonably related in time and no 
alternative explanation has been identified. 
The relationship of the study treatment to an unsolicited AE will be determined by the 
investigator.  
Note: solicited AEs will not be evaluated for relationship to study treatment. Grading for 
severity of solicited local and systemic AEs is described in Appendix A and Appendix B. 
Adverse events will also be evaluated by the investigator for the co-existence of any of 
the other following conditions: 
▫ “Medically attended adverse event”: an adverse event that leads to a visit to a 
healthcare provider. 
▫ “New onset of chronic disease” (NOCD): an adverse event that represents a new 
diagnosis of a chronic medical condition that was not present or suspected in a subject 
prior to study enrolment. 
▫ AEs leading to withdrawal: adverse events leading to study or vaccine withdrawal. 
All AEs, regardless of severity, will be monitored until resolution or until the investigator 
assesses them as chronic or stable. All subjects experiencing AEs - whether considered 
associated with the use of the study vaccine or not - must be monitored until symptoms 
subside and any abnormal laboratory values have returned to baseline, or until there is a 
satisfactory explanation for the changes observed, or until death, in which case a full 
pathologist’s report should be supplied, if possible. 

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7.1.4  
Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose results in one or more of the following: 
▫ Death. 
▫ Is life-threatening (i.e., the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred); it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
▫ Required or prolonged hospitalization. 
▫ Persistent or significant disability/incapacity (i.e., the event causes a substantial 
disruption of a person’s ability to conduct normal life functions). 
▫ Congenital anomaly/or birth defect. 
▫ An important and significant medical event that may not be immediately life 
threatening or resulting in death or hospitalization but, based upon appropriate 
medical judgment, may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed above. 
Adverse events which do not fall into these categories are defined as non-serious. 
It should be noted that a severe adverse event need not be serious in nature and that a 
serious adverse event need not, by definition, be severe. 
Serious adverse events will be captured both on the Vaccines Serious Adverse Event 
(VSAE) form as well as on the appropriate CRF page. All SAEs will be evaluated by the 
investigator for relationship of the event to study vaccine. SAEs that are judged to be 
possibly or probably related to the study vaccine should be reported to the Sponsor as 
related/suspected events. 
The relationship of the study treatment to an SAE will be determined by the investigator 
based on the following definitions: 
1. Related/suspected 
The SAE is judged by the investigator to be possibly or probably related to the study 
vaccine on the appropriate CRF page (see section 7.1.3). 

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2. Not Related 
The SAE is not related if exposure to the study vaccine has not occurred, or the 
occurrence of the SAE is not reasonably related in time, or the SAE is considered 
unlikely to be related to use of the study vaccine, i.e., there are no facts (evidence) or 
arguments to suggest a causal relationship. 
The relationship of the study vaccine to an SAE will be determined by the investigator. 
In addition, SAEs will be evaluated by the Sponsor or designee for “expectedness.” An 
unexpected AE is one that is not listed in the current Summary of Product Characteristics 
or the Investigator’s Brochure or an event that is by nature more specific or more severe 
than a listed event. 
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded on the appropriate CRF. If the onset of an event occurred before the subject 
entered the study (e.g., any pre-planned hospitalization for conditions like cosmetic 
treatments or for non-emergency routine visits for a pre-existing condition), the 
hospitalization would not lead to an AE being classified as serious unless, in the view of 
the investigator, hospitalization was prolonged as a result of participation in the clinical 
study or was necessary due to a worsening of the pre-existing condition. 
7.1.4.1  
Adverse Events of Special Interest 
Certain adverse events of special interest (AESIs) are monitored after the administration 
of immunostimulatory agents. All subjects enrolled in this study will be monitored for 
AESIs for the entire follow-up period. The AESIs will be defined according to MedDRA 
preferred terms. The investigator will be provided with a list of AESIs prior to study start. 
Receipt of this list will be notified and stored, along with the list of AESIs, in the 
Investigator Site File. During the course of the trial the list of AESIs may change. If this 
occurs, the investigators will be advised of the change and confirmation of receipt will be 
documented. The updated list of AESIs and documentation of receipt are also stored in 
the Investigator Site File. The occurrence of any of these adverse events will be treated as 
a serious adverse event (SAE), meeting the criterion of a “medically important event.” 
Subjects will be assessed for diagnosis of an AESI at the following visits: 
- 
Pre-vaccination clinic visit (Day -28 to Day -3)  
- 
Visit 1 (Day 1, pre-vaccination) 
- 
Visit 2 (Day 4) 

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- 
Visit 3 (Day 8) 
- 
Visit 4 (Day 15) 
- 
Visit 5 (Day 22; Safety Follow-Up Call) - Visit 6 (Day 29) 
- 
Visit 7 (Day 85) 
- 
Visit 8 (Day 113) 
- 
Visit 9 (Day 181) 
- 
Visit 10 (Day 209; Safety Follow-Up Call) 
- 
Visit 11 (Day 271; Safety Follow-Up Call) 
- 
Visit 12 (Day 366; Study Termination Visit) 
At these visits a qualified health care practitioner listed on the site’s responsibilities and 
delegation logs will conduct a review of organ systems and a targeted physical exam and 
will evaluate subjects for any new signs or symptoms that could indicate one of the 
AESIs as specified in the list of AESIs stored in the Investigator Site File. They will also 
interview the subject about recent medical history and any new diagnosis that could 
indicate an AESI. Medical records related to any new medical event or diagnosis will be 
requested, reviewed by the site staff, and recorded in the subject’s source documents. 
A diagnosis of an AESI will be reported in the same manner and time frame as an SAE 
using the VSAE form. The investigator must notify GSK within 24 hours. The AESI 
diagnosis, as well as any medications taken to treat the condition, will be recorded in the 
subject’s source documents and on the appropriate CRF. 
7.1.5  
Methods for Recording Adverse Events and Serious Adverse Events 
All findings regarding Adverse Events must be reported on the appropriate CRF page and 
on the VSAE form, if applicable, which is part of the Investigator Site File. All findings 
in subjects experiencing AEs must be reported also in the subject's source document. 
All SAEs which occur during the course of the study, whether considered to be associated 
with the study vaccination or not, must be reported within 24 hours of the site becoming 
aware of the event to GSK or its designee. Specific instructions and contact details for 
collecting and reporting SAEs to GSK will be provided to the investigator. 
All SAEs are also to be documented on the appropriate CRF page. Any medication or 
other therapeutic measures used to treat the AE will be recorded on the appropriate 
CRF(s) in addition to the outcome of the AE. 

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After receipt of the initial report, representatives of GSK or its designee will contact the 
investigator if it is necessary to obtain further information for assessment of the event. 
All SAEs must be reported by the investigator to his/her corresponding EC and applicable 
regulatory authorities in accordance with institutional policy/regulatory requirements and 
adequate documentation of this notification must be provided to the Sponsor. 
GSK or its designee must also comply with the applicable regulatory requirement(s) 
related to the reporting of suspected unexpected serious adverse vaccine reactions (also 
known as SUSARs) to the regulatory authority(ies) and the IRB/EC. If a SUSAR or other 
safety signal relating to use of one of the study vaccines is reported to GSK or its 
designee, the Sponsor will communicate the information to the investigator and the 
investigator will be responsible for submitting this information to the EC and other 
relevant authorities. 
7.1.5.1 
Post-Study Events 
Any suspected SAE that occurs outside of the protocol-specified follow-up period or after 
the end of the study but considered to be caused by the study vaccine must be reported to 
GSK or its designee. These SAEs will be processed by GSK or its designee as during the 
course of the study, until 3 months after the last scheduled study visit. Instructions and 
contact details for collecting and reporting these suspected SAEs will be provided to the 
investigator. 
7.1.6  
Pregnancies 
To ensure subjects’ safety, each pregnancy in a subject after study vaccination must be 
reported to GSK within 72 hours of the site learning of its occurrence. If the subject 
agrees to submit this information, the pregnancy must be followed to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. This follow-up should occur even if intended duration of safety follow-up 
for the study has ended. 
Pregnancy data must be recorded on a Pregnancy Report CRF (initial report) and 
Pregnancy Follow-Up CRF (outcome report). 
Any pregnancy outcome meeting the definition of a SAE (see section 7.1.4) must also be 
reported on the VSAE Report Form. 
7.1.7  
Safety Laboratory Measurements 

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Blood and urine samples will be collected from all subjects at the Pre-vaccination  
Screening, at Visit 1 (pre-vaccination and 24 hours after vaccination), at Visit 3 and at 
Visit 6 as outlined in Time and Events Table 3. The blood safety laboratory assessments 
will include sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, 
liver function tests (ALT, AST), a complete blood count and C-reactive protein. The urine 
safety laboratory assessments will include protein, glucose and red blood cells. An 
additional blood and urine sample will be collected in case of a clinic Early Termination 
Visit as outlined in section 5.5.1. 
All testing will be conducted by qualified and certified laboratories. The Investigator 
must assess all safety laboratory results. Abnormal laboratory values must be classified 
by the Investigator as clinically significant or not. Abnormal laboratory values that are 
considered clinical significant will be defined following the FDA CBER Guidance for 
Industry “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials” dated September 2007, or the institution’s normal 
ranges if they differ from CBER guidance. Please see Appendix C, D and E for further 
details on the Toxicity Grading Scales according to CBER. 
Retesting may be performed in case of abnormal values per guidance of the investigator.  
7.2  
Efficacy Assessment 
Efficacy measurement will not be performed as part of this study. 
7.3  
Immunogenicity Assessment 
The measures to assess the primary and secondary immunogenicity endpoints for this 
study are standard, i.e., widely used and generally recognized as reliable, accurate, and 
relevant (able to describe the quality and extent of the immune response). 
The assay’s used in this study to assess the primary and immunogenicity endpoints are 
human serum bactericidal assay (hSBA) and ELISA specific for MenC 
The hSBA is a functional measure of the ability of specific antibodies, in conjunction 
with human complement, to kill MenC indicator strains, and is widely used and generally 
recognized as the serological correlate of protection. The specific ELISA will be used to 
measure the induction of antibodies directed against MenC following vaccination with the 
study vaccines. 

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Blood samples (approximately 10 ml) to obtain serum for hSBA and ELISA assays will 
be collected at Day 1, Day 8, Day 29 and Day 181 (refer to section 3.5 for detailed 
specimen collection procedures). 
Testing will be conducted by a GSK or designated laboratory in a blinded manner 
towards the treatment group. Laboratory contact details are listed in the Protocol 
Ancillary Document. 
All data will be captured at the laboratory and transferred via Electronic Data Transfer  
(EDT) 
Details on all blood sample handling steps are described in the Clinical Specimen Lab 
Manual provided to the study site. 
7.4 
Exploratory Measurements 
In those subjects who agree to a separate Informed Consent, additional blood samples will 
be collected at Day 1, Day 4, Day 8, Day 29 and Day 181 for exploratory measurements. 
The purpose of these exploratory measurements is to assess the systemic exposure of 
LHD153, to further delineate vaccine induced antigen specific immune responses and to 
evaluate biomarkers that may be predictive for safety and/or innate immune activation. 
All exploratory measurements will be conducted by a GSK or a designated laboratory. 
Laboratory contact details are listed in the Protocol Ancillary Document. 
Exploratory measurements may be performed after the Clinical Study Report (CSR) has 
been completed, in which case these data will be submitted as an addendum to the CSR. 
Systemic exposure of LHD153 
Systemic exposure of LHD153 will be assessed by analyzing LHD153 blood plasma 
levels at Day 1 (baseline, 1, 2, 4, 8 and 24h after vaccination) and Day 4 using 
LC/MS/MS. Time-points for assessment of clinical exposure of LHD153 have been 
selected based on non-clinical data in dogs and rats. 
Vaccine-induced antigen-specific immune responses 
The frequency of B cells specific for MenC polysaccharide and CRM197 will be 
determined by enzyme-linked immunosorbent spot (ELISPOT) at Day 1, Day 8, Day 29 
and Day 181 in order to evaluate the baseline specific B-cell frequency (Day 1), the peak 
of plasmablast responses (Day 8), the peak of B cell memory responses (Day 29), and the 
persistence of memory B cell responses (Day 181). 

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Subsequently, the diversity of the antigen specific B-cell repertoire will be analyzed in a 
selected subset of subjects. The selection of the subset will be based on the most 
pronounced response to the study vaccines when compared to baseline as determined by 
the primary and secondary immunogenicity assessment. 
The diversity of the elicited B-cell receptors will be assessed through sequence analysis of 
complementary DNA (cDNA) generated from immunoglobulin (Ig) messenger RNA 
(mRNA). The Ig cDNAs will be analyzed from antigen-specific B cells obtained at Day 
1, Day 29 and/or Day 181 and plasmablasts isolated at Day 8. The analysis of the B-cell 
receptor diversity does not have the intent nor the capability to identify or rule out any 
genetic modifications in the RNA or DNA that are presumably linked to disease or 
predisposition to disease. 
The frequency of T cells specific for the CRM197 protein at baseline (Day 1), at Day 8 and 
at Day 29 after vaccination with the study vaccines will be determined by FACS analysis 
using intracellular staining with a panel of cytokines and surface markers to identify cell 
populations. 
Early Markers for Safety and Innate immune activation 
The evaluation of potential biomarkers of safety and innate immune activation will be 
performed on blood specimens collected at Day 1 (baseline, 6h and 24h after vaccination) 
and Day 4. 
The vaccine-induced production of inflammatory cytokines and chemokines will be 
monitored on serum samples using a commercially available electrochemoluminescence 
assay for a panel of pro-inflammatory cytokines and chemokines, including Eotaxin, 
Eotaxin-3, GM-CSF, IFN-g, IL-1a, IL-1b, IL-10, IL-12 p70, IL-12/IL-23p40, IL-13, 
IL15, IL-16, IL-17A, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IP-10, MCP-1, MCP-
4, MDC, MIP-1a, MIP-1b, TARC, TNF-a, TNF-b, VEGF. 
The vaccine-induced expression of genes and gene families will be monitored on whole 
blood samples using of RNA microarrays by existing technologies. The RNA micro array 
analysis does not have the intent nor the capability to identify or rule out any genetic 
modifications in the RNA or DNA that are presumably linked to disease or predisposition 
to disease. 
The vaccine-induced changes in myeloid (e.g. monocytes and dendritic cells) and 
lymphoid (e.g. NK cells, NKT cells) cell numbers and their activation status will be 
assessed using flow cytometry. 
8.0  
STATISTICAL CONSIDERATIONS 

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8.1  
Endpoints 
8.1.1 
Primary Endpoint(s) 
8.1.1.1  
Primary Safety Endpoint(s) 
The measures for assessing safety and tolerability (by vaccine group within each cohort 
and by LHD153R adjuvant dosage group overall) are as follows: 
▫ The frequency and percentage of subjects with solicited local and systemic  AEs 
through Day 14. Time intervals after vaccination that will be summarized are:30 
minutes post-vaccination, Days 1-4 (without 30 minutes), Days 5-8, Days 8-14, Days 
1-8 (without 30 minutes) and Days 1-14 (without 30 minutes). 
▫ The frequency and percentage of subjects with any unsolicited AEs from the day of 
vaccination (Day 1) to Day 14. 
▫ The frequency and percentage of subjects with SAEs, medically attended AEs,  AEs 
leading to study withdrawal, NOCDs, AESIs for the following time periods: day of 
signed informed consent until study completion (Day 366), day of vaccination (Day 1) 
to Day 29, and Day 29 to study completion (Day 366). 
▫ The absolute values and changes in hematology, chemistry, and urinalysis parameters 
(see section 7.1.7). 
▫ The frequency and percentage of subjects with abnormal laboratory parameter values 
as classified by investigator normal ranges (low, normal, high) and as classified by 
CBER toxicity grading scales, when available. 8.1.1.2  
Primary Efficacy 
Endpoint(s) 
Not applicable. 
8.1.1.3  
Primary Immunogenicity Endpoint(s) 
The primary immunogenicity endpoints are the GMTs measured by hSBA directed 
against MenC from samples collected on Day 1 (baseline, before vaccination) and Day 29 
as well as the GMR of the titers (Day 29 / Day 1). 
8.1.2 
Secondary Endpoint(s) 8.1.2.1 
 Secondary Safety Endpoint(s) 

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Not applicable. 
8.1.2.2  
Secondary Efficacy Endpoint(s) 
Not applicable. 
8.1.2.3  
Secondary Immunogenicity Endpoint(s) 
The secondary immunogenicity endpoints are: 
▫ GMTs and corresponding GMRs measured by hSBA directed against MenC for 
samples collected at Day 8 and Day181. 
▫ Percentage of subjects with hSBA seroresponse at Days 8, 29, and 181. Seroresponse 
is defined as a post vaccination hSBA ≥8 for subjects with a baseline hSBA <4 or 
have an increase of at least 4 times the baseline hSBA level for subjects with 
prevaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against MenC measured by ELISA 
for samples collected on Days 1 (baseline, prior to vaccination), 8, 29, and 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations to 
MenC as measured by ELISA on Day 8, 29, and 181 relative to baseline (Day 1). 
8.1.3  
Exploratory Endpoint(s) 
The exploratory  endpoints are based on results of testing which may not be performed 
until after the study report has been finalized and will be further refined prior to testing. 
They include the following: 
▫ Serum concentration of LHD153 at Day 1 baseline (prior to vaccination), Day 1 (1h , 
2h, 4h, 8h, and 24h after vaccination), Day 4 by LC-MS/MS. 
▫ Frequency of MenC polysaccharide-specific and CRM197-specific B cells at Day 1 
(baseline), Day 8, Day 29, and Day 181 by ELISPOT. 
▫ Diversity of MenC polysaccharide-specific B-cell repertoire at Day 1 (baseline), Day 
8, Day 29, and Day 181 by immunoglobulin cDNA sequencing. 
▫ Frequency and quality of T cells specific for CRM197 at Day 1 (baseline), Day 8, and 
Day 29 by flow cytometry analysis using intracellular staining with a wide panel of 
cytokines and surface markers to identify cell populations. 

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▫ Serum concentrations of a panel of 30 chemokines and cytokines at Day 1 baseline 
(prior to vaccination), Day 1 (6h and 24h after vaccination), Day 4, and Day 8 by 
multiplex Electro-chemo-luminescence based assay. 
▫ Gene expression profile in whole blood at Day 1 baseline (prior to vaccination), Day 1 
(6h and 24h after vaccination), Day 4, and Day 8 by RNA micro array analysis. 
▫ Number and activation status of myeloid and lymphoid cell populations at Day 1 
baseline (prior to vaccination), Day 1 (24h after vaccination), Day 4 and Day 8 by 
flow cytometry. 
8.2  
Success Criteria 
The study has no formal statistical hypotheses and will not be declared positive or 
negative according to given rules. The selection of an appropriate LHD153R adjuvant 
dosage for future studies will be determined by the joint evaluation of the 
immunogenicity and safety profiles of each dosage group. 8.2.1  
Success Criteria 
for Primary Objective(s) Not applicable. 
8.2.2  
Success Criteria for Secondary Objective(s) 
Not applicable. 
8.3  
Analysis Sets 
8.3.1  
All Enrolled Set 
All screened subjects who provide informed consent and provide demographic and/or 
baseline screening assessments, regardless of the subject’s randomization and treatment 
status in the study and received a Subject ID. 
8.3.2  
All Exposed Set 
All subjects in the enrolled set who receive a study vaccination. 
8.3.3  
Safety Set 
Safety Set (solicited adverse events and other solicited reactions) 
All subjects in the Exposed Set who: 

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▫ Provide post vaccination reactogenicity data. 
Safety Set (unsolicited adverse events) 
All subjects in the Exposed Set who: 
▫ Have post-vaccination unsolicited adverse event records. 
Safety Set (overall) 
All subjects in the Exposed Set who: 
▫ Have either post-vaccination adverse event or reactogenicity records. 
Subjects will be analyzed as “treated” (i.e., according to the vaccine a subject received, 
rather than the vaccine to which the subject may have been randomized). 
8.3.4  
Full Analysis Set (FAS) Efficacy/Immunogenicity Set 
All subjects in the Enrolled Set who: 
▫ Receive a study vaccination AND provide efficacy/immunogenicity data at relevant 
time points. 
FAS sets will be analyzed “as randomized” (i.e., according to the vaccine a subject was 
designated to receive, which may be different from the vaccine the subject actually 
received). 
8.3.5  
Per Protocol (PP) Set Efficacy/Immunogenicity Set 
All subjects in the FAS efficacy/immunogenicity set who: 
▫ Are not excluded due to reasons (see section 8.3.8) defined prior to unblinding or 
analysis. 
PPS are subsets of FAS and should always be defined even if the objectives do not 
require it. 
Examples for subjects excluded due to other reasons than protocol deviations are: 
- 
Subjects who withdrew informed consent. 
- 
Premature withdrawal due to an adverse event. 

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Exclusions need to be considered by objective/time point, i.e., sometimes not all data of a 
subject but only part of the subject's data will be removed from the PPS analysis. 
8.3.6  
Other Analysis Sets  
All subjects in the Enrolled Set who consent to additional blood draws, receive a study 
vaccination AND provide exploratory assay data at relevant time points will be included 
in an exploratory assay subset. 
8.3.7  
Subgroups 
Selected immunogenicity analyses may be provided based on seropositivity status at 
baseline. 
8.3.8  
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. A protocol deviation may be a reason to remove data from 
an analysis set at the time of analysis. Reportable protocol deviations will be defined as 
exclusionary from the analysis according to protocol objectives and endpoints, which will 
be specified in the Statistical Analysis Plan. In some cases exclusion of data may be due 
to a reason other than a protocol deviation, e.g. early termination. 
8.4  
Statistical Analysis Plan 
This section provides a summary of the statistical methodology to be used. A more 
detailed description of analysis methods will be provided in a separate Statistical Analysis 
Plan which may also include additional exploratory analyses not explicitly mentioned in 
the following sections. 
8.4.1  
Analysis of Demographic and Baseline Characteristics 
Descriptive statistics (number of non-missing observations, mean, standard deviation, 
median, minimum and maximum) for age, height and weight at enrolment will be 
calculated overall and by vaccine group and LHD153R adjuvant dosage. 
Distributions of subjects by sex and ethnic origin will be summarized overall and by 
vaccine group and LHD153R adjuvant dosage. 
8.4.2  
Analysis of Primary Objective(s) 
8.4.2.1  
Analysis of Primary Safety Objective(s) 

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Safety of the study vaccines will be assessed in all subjects in terms of the frequency and 
percentage of reported AEs as well as by changes in clinical laboratory values.  
8.4.2.1.1  
Analysis of Extent of Exposure 
The frequency and percentage of subjects with vaccinations will be summarized by 
vaccine group and LHD153R adjuvant dosage, by cohort and overall, for the Enrolled 
Set. 
8.4.2.1.2  
Analysis of Solicited Local, Systemic and Other Adverse Events 
All solicited adverse events will be summarized according to defined severity grading 
scales. Use of medication to prevent/treat fever will be summarized according to 
frequencies and percentages reporting “Yes” and “No”. 
Frequencies and percentages of subjects experiencing each adverse event will be 
presented for each symptom severity. Summary tables showing the occurrence of any 
local or systemic adverse event overall and at each time point will also be presented. 
Post-vaccination solicited adverse events reported from Day 1 to Day 14 will be 
summarized for the intervals Day 1-4 (without 30 minutes), Day 5-8, Day 1-8 (without 30 
minutes), Day 8-14 and Day 1-14 (without 30 minutes) by maximal severity and by 
vaccine group and LHD153R adjuvant. The severity of solicited local adverse events, 
including injection-site erythema, swelling and induration will be summarized according 
to categories based on linear measurement: 25-50 mm, 51-100 mm, > 100 mm. 
Injection site pain and systemic reactions (except fever) occurring up to Day 14 will be 
summarized according to “mild”, “moderate” or “severe”. 
Each solicited local and systemic adverse event will also be further summarized as “none” 
versus “any”. 
Implausible measurements (for further definition see Statistical Analysis Plan) will be left 
out of the analysis. 
Use of antipyretics and analgesics will be summarized by frequency by type of use 
(prophylactic versus treatment) and percentage of subjects reporting use. The influence of 
antipyretics and analgesics use on the occurrence of specific adverse events (e.g., fever, 
pain) will be assessed. 
Body temperature will be summarized by 0.5 °C and 1.0 °C increments from 36.0 °C up 
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8.4.2.1.3  
Analysis of Unsolicited Adverse Events 
This analysis applies to all adverse events occurring during the study, judged either as 
probably related, possibly related, or not related to vaccination by the investigator, 
recorded in the CRF, with a start date on or after the date of first vaccination. AE starting 
prior to the first vaccination will only be listed. The original verbatim terms used by 
investigators to identify adverse events in the CRFs will be mapped to preferred terms 
using the MedDRA dictionary. The adverse events will then be grouped by MedDRA 
preferred terms into frequency tables according to system organ class. 
All reported adverse events, as well as adverse events judged by the investigator as at 
least possibly related to study vaccine, will be summarized according to system organ 
class and preferred term within system organ class. These summaries will be presented by 
vaccination group and LHD153R adjuvant dosage for each cohort and by interval of 
study observation. When an adverse event occurs more than once for a subject, the 
maximal severity and strongest relationship to the vaccine group will be counted. 
Separate summaries will be produced for the following categories: 
▫ Serious adverse events. 
▫ Adverse events that are possibly or probably related to vaccine. 
▫ Adverse events of special interest. 
▫ New onset of chronic disease. 
▫ Adverse event leading to withdrawal. 
▫ Adverse events leading to a medically attended visit. 
▫ Adverse event by data source. 
Data listings of all adverse events will be provided by subject. In addition, adverse events 
in the categories above will be provided as listed data. 
8.4.2.1.4  
Analysis of Safety Laboratory Values 
The investigator must review all safety laboratory results (see Section 7.1.7). Abnormal 
laboratory values and clinically significant changes in values from pre-vaccination 
(Screening Visit) will be assessed, using medical judgment, based on the FDA CBER  
Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” dated September 2007, or the 

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institution’s normal ranges if they differ from CBER guidance. Please see Appendix C, D 
and E for further details. 
The following information will be provided: 
▫ Change in absolute laboratory value from pre-vaccination (Screening Visit) and Day 1 
(Visit 1) baseline to Day 1 (24 hours after vaccination), Day 8 (Visit 3) and Day 29 
(Visit 6) after vaccination. 
▫ The classification of laboratory values and/or their changes from pre-vaccination 
according to the CBER toxicity grading scale. 
▫ 3 x 3 shift tables by visit using the categorization of laboratory values according to 
institutional normal reference ranges (below, within, above). 
8.4.2.2  
Analysis of Primary Efficacy Objective(s) 
Not applicable. 
8.4.2.3  
Analysis of Primary Immunogenicity Objective(s) 
8.4.2.3.1  
Statistical Hypotheses 
There are no statistical hypotheses associated with the primary immunogenicity 
objectives. All analyses are descriptive. 
8.4.2.3.2  
Analysis Sets 
The primary immunogenicity analyses will be based on the per-protocol set (PPS) at Day 
29. The primary analyses will be repeated using the Full Analysis Set (FAS) as a measure 
of the sensitivity/robustness of the results (further details are given in section 8.3). 
8.4.2.3.3  
Statistical Methods 
Before any statistical analysis that assumes normally distributed observations, antibody 
titers will be log10-transformed. Individual titers below the limit of quantitation (LLQ) 
will be set to half that limit. 
Geometric Mean Titers 
The logarithmically (base 10) transformed antibody titers will be modeled using an 
analysis of covariance (ANCOVA) model with a qualitative factor for LHD153R 
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pre-vaccination titer as a covariate. The adjusted GMT and the two-sided, 95%, 
confidence intervals (CIs) of the GMT will be calculated based on this model as will the 
ratio of GMTs and corresponding CIs. The adjusted GMT and two-sided 95% CIs will be 
constructed by exponentiation (base 10) of the least square means of the logarithmically 
transformed (base 10) antibody titer. The ratio of GMTs (LHD153R adjuvant dosage 
minus MenC), and corresponding two-sided 95% CIs, will be constructed by 
exponentiation (base 10) of the least square differences obtained from this model. The 
model can be written as:  
log10 (yik) = µ + αi + βxik + εik 
where µ represents a common overall mean, αi represents the adjuvant dose group i effect, 
β represents the common slope for the log10 pre-vaccination titer, xik for subject k in 
adjuvant dose group I, and εik represents random error for subject k in adjuvant dose 
group i. 
Geometric Mean Ratios 
The logarithmically (base 10) transformed within subject ratio of antibody titers (Day 29 / 
pre-vaccination) will be modeled using an analysis of variance model with a qualitative 
factor for LHD153R adjuvant dosage (0 [for non-LHD153R adjuvanted MenC], 12.5, 25, 
50 or 100 µg). The adjusted GMR and the two-sided, 95% CIs of the GMR will be 
calculated based on this model. The model can be written as: 
log10 (yik) = µ + αi + εik 
where µ represents a common overall mean, αi represents the adjuvant dose group i effect 
and εik represents random error for subject k in adjuvant dose group i. 
Handling of missing values 
For immunogenicity data, it may be reasonable to consider missing immunogenicity 
values as missing completely at random (MCAR), i.e., not informative. Therefore, the 
primary analysis will comprise a complete case analysis only, without introducing any 
bias. Imputation methods will not be used. 
8.4.3  Analysis of Secondary Objective(s) 8.4.3.1 
 Analysis of Secondary Safety Objective(s) Not 
applicable. 
8.4.3.2  
Analysis of Secondary Efficacy Objective(s) 

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Not applicable. 
8.4.3.3  
Analysis of Secondary Immunogenicity Objective(s) 
8.4.3.3.1  
Statistical Hypotheses 
There are no statistical hypotheses associated with the secondary immunogenicity 
objectives. All analyses are descriptive. 
8.4.3.3.2  
Analysis Sets 
The secondary immunogenicity analyses will be based on the PPS (further details are 
given in section 8.3) or the appropriate subset of subjects. 
8.4.3.3.3  
Statistical Methods 
The secondary immunogenicity endpoints are: 
▫ GMTs and corresponding GMRs measured by hSBA directed against MenC for 
samples collected at Day 8 and Day181. 
▫ Percentage of subjects with hSBA seroresponse at Days 8, 29, and 181. seroresponse is 
defined as a post vaccination hSBA ≥8 for subjects with a baseline hSBA <4 or have 
an increase of at least 4 times the baseline hSBA level for subjects with 
prevaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against MenC measured by ELISA 
for samples collected on Days 1 (baseline, prior to vaccination), 8, 29, and 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations to 
MenC as measured by ELISA on Day 8, 29, and 181 relative to baseline (Day 1). 
The GMTs for samples collected at Day 8 and Day 181 as well as the GMCs for samples 
collected at Day 1, Day 8, Day 29, and Day 181 will be analyzed using the same approach 
as for the primary immunogenicity endpoint. 
The remaining immunogenicity endpoints are based on subjects meeting criteria for 
seroconversion or achieving a certain threshold value. These endpoints will be 
summarized using frequencies and percentages by LHD153R adjuvant dosage (0 [for 
non-LHD153R adjuvanted MenC], 12.5, 25, 50 or 100 µg). Two-sided 95% 
ClopperPearson CIs will also be provided for percentages. For analyses of 
seroconversion, separate summaries may be provided based on seropositivity status at 
baseline. 

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8.4.4  
Analysis of Exploratory Objectives 
Testing and analyses of exploratory endpoints may be performed after the Clinical Study 
Report (CSR) has been completed, in which case these data will be submitted as an 
addendum to the CSR. 
In general, concentration and titer results will be summarized for each LHD153R 
adjuvant dosage group using geometric means and associated 2-sided 95% confidence 
intervals; and, categorical data will be summarized using frequencies and percentages, 
with corresponding two-sided, 95% confidence intervals. 
8.5  
Sample Size and Power Considerations of Primary Objectives 
Sample size is not driven by statistical assumptions for formal hypothesis testing, but was 
based on the safety objective for the study. The table below provides the probability for 
various combinations of sample size (N) and presumed true frequency of a given event 
within an individual vaccine group  
Frequency 
of Event 
Probability to Observe at Least 1 Subject with a Given Event For  
Various Choices of N 
4 
8 
12 
16 
0.05 
0.1855 
0.3366 
0.4596 
0.5599 
0.10 
0.3439 
0.5695 
0.7176 
0.8147 
0.15 
0.4780 
0.7275 
0.8577 
0.9257 
0.20 
0.5904 
0.8322 
0.9313 
0.9718 
0.30 
0.8250 
0.9423 
0.9862 
0.9967 
0.40 
0.8704 
0.9832 
0.9978 
0.9997 
The proposed combinations of sample sizes within each cohort are 4 aluminium 
hydroxide adjuvanted MenC-CRM197 and 16 MenC-CRM197 plus an assigned-level of 
LHD153R adsorbed to aluminium hydroxide. If all four cohorts are fully enrolled, there 
will be 16 subjects receiving aluminium hydroxide adjuvanted MenC-CRM197. 
With 16 subjects, events which occur at a frequency of 15% or more will be detected with 
at least 90% probability; and, events which occur at a frequency of 10% or more will be 
detected with 81% probability. With 4 subjects, events which occur at a frequency of 30% 
or more will be detected with at least 80% probability. Intermediate values of 8 and 12 

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are provided to correspond to sample sizes in the MenC-CRM197 after cohort 2 and cohort 
3 are fully enrolled. 
8.6  
Interim Analysis 
The DMC will be reviewing the accumulating safety data from the study in order to 
continue enrollment of subjects within a cohort and whether to enroll subjects into the 
next cohort. 
In addition to these periodic reviews, there will be a safety and immunogenicity interim 
analysis for the selection of an LHD153R adjuvant dosage based on the data collected 
through Day 29 from subjects enrolled in all cohorts. This analysis will be performed by 
personnel not involved in study decisions. The results will be unblinded at the group level 
thereby preserving the blind for individual subjects. No adjustment to the overall alpha 
will be performed as the data collected subsequent to this analysis involve secondary and 
exploratory endpoints. 
 

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9.0  
SOURCE DOCUMENTATION, STUDY MONITORING AND 
AUDITING 
Study monitoring and auditing will be standardized and performed in accordance with the 
Sponsor’s or delegated contract research organization’s (CRO) standard operating 
procedures and applicable regulatory requirements (e.g., FDA, EMA, and ICH 
guidelines). 
Prior to enrolment of the first study subject, GSK or delegate will train investigators 
and/or their study staff on the study protocol, all applicable study procedures, 
documentation practices and all electronic systems. CRFs must be completed for each 
enrolled subject (see section 8.3.1 for definition of enrolled subject). Documentation of 
screened but not enrolled subjects must be maintained at the site and made available for 
review by the site monitor. 
9.1  
Source Documentation 
Prior to the start of the study, the site staff participating in the study conduct will be 
instructed on what documents will be required for review as source documents. The kinds 
of documents that will serve as source documents will be agreed between Sponsor or 
delegate and investigator and designees and specified in the SDA/Source Data 
Verification Form prior to subject enrolment. 
In addition, source documentation must include all of the following: subject identification 
(on each page), eligibility and participation, proper informed consent procedures, dates of 
visits, adherence to protocol procedures, adequate reporting and follow-up of adverse 
events, documentation of prior/concomitant medication/vaccines, study vaccine 
receipt/dispensing/return records, study vaccine administration information, any data 
collected by a telephone conversation with the subject and date of completion and reason. 
The subject must also allow access to the subject’s medical records. Each subject must be 
informed of this prior to the start of the study and consent for access to medical records 
may be required in accordance with local regulations. 
All safety data reported by subjects must be written down in source documents. If there 
are multiple sources of information (e.g., Subject Diary, verbal report of the subject, 
telephone contact details, medical chart) supporting the diagnosis of an adverse event, 
these sources must be identified in the source documents, discrepancies between sources 
clarified, the ultimate diagnosis must be justified and written in the source documents, 
and this diagnosis must be captured in the appropriate CRF page. The CRF must also 

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capture which source(s) of information were used to determine the adverse event (e.g., 
subject recall, medical chart, Subject Diary). 
9.2  
Study Monitoring, Auditing and Source Data Verification 
Prior to enrolment of the first study subject, GSK or its designee (e.g., a CRO) will 
develop a Monitoring Plan to specify how centralized and/or on-site monitoring, 
including clinical specimens reconciliation, will be performed for the study. Study 
progress will be monitored as frequently as necessary to ensure: 
▫ that the rights and well-being of human subjects are protected, 
▫ the reported study data are accurate, complete, and verifiable from the source 
documents and 
▫ the conduct of the study is in compliance with the current approved 
protocol/amendment(s), GCP and applicable regulatory requirements. 
Contact details for the team involved in study monitoring will be provided to the 
investigator. Study data recorded on CRFs will be verified by checking the CRF entries 
against source documents in order to ensure data completeness and accuracy as required 
by study protocol. 
Additional documents such as the investigator site file, pharmacy records, and informed 
consent documentation must also be available for review if requested. Arrangements for 
monitoring visits will be made in advance in accordance with the monitoring plan, except 
in case of emergency. 
The investigator and/or site staff must make source documents of subjects enrolled in this 
study available for inspection at the time of each monitoring visit and Sponsor audits, 
when applicable. These documents must also be available for inspection, verification and 
copying, as required by regulations, by officials of the regulatory health authorities (e.g., 
FDA, EMA and others) and/or ECs/IRBs. The investigator and study site staff must 
comply with applicable privacy, data protection and medical confidentiality laws for use 
and disclosure of information related to the study and enrolled subjects. 
10.0  
DATA MANAGEMENT 
10.1 
Data Entry and Management 
In this study, all clinical data (including, but not limited to, AE/SAEs, concomitant 
medications, medical history, and physical assessments), safety data, and immunogenicity 
data will be entered into an EDC system, which is compliant with Title 21 Part 11 

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policies of the Code of Federal Regulations (FDA, 1997). The data system includes 
password protection and internal quality checks. The EDC system will be designed and 
validated by the Sponsor prior to activation for data entry by sites. The investigator or 
designated delegate must review data entered and electronically sign the CRFs to verify 
their accuracy. 
Access to the EDC system for data entry or review will require training and distinct 
individual access code assignments to those site staff members who will be entering study 
data and those involved in study oversight who may review study data. Data are collected 
within the EDC system, to which the Sponsor and site monitors have exclusively “read 
only” access. 
Paper CRFs will be provided for each pregnant subject by the Sponsor. All appropriate 
pregnant subject data collected will be recorded on this form. One copy must be retained 
by the investigator, and all other copies (including the original copy) will be returned as 
directed by the Sponsor. Instructions on how to complete this form will be provided to the 
investigator. 
10.2  
Data Clarification 
As part of the conduct of the trial, the Sponsor may have questions about the data entered 
by the site, referred to as queries. The monitors and the Sponsor are the only parties that 
can generate a query. All corrections and clarifications will be entered into the EDC 
system and will be identified by the person entering the information, the reason for the 
change, as well as the time of the changes made. If changes are made to a previously and 
electronically signed CRF, the investigator must confirm and endorse the changes 
10.3  
Data Protection 
GSK respects the subjects’ rights to privacy and will ensure the confidentiality of their 
medical information in accordance with all applicable laws and regulations. 
The Sponsor as Data Controller according to the European Directive on the protection of 
individuals with regard to the processing of personal data and on the free movement of 
such data (95/46/EC) confirms herewith compliance to Directive 95/46/EC in all stages of 
Data Management. 
 

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11.0  
RECORD RETENTION 
Investigators must retain all study records required by GSK and by the applicable 
regulations in a secure and safe facility. The investigator must consult a GSK 
representative before disposal of any study records, and must notify the Sponsor of any 
change in the location, disposition, or custody of the study files. Essential documents 
must be retained for 15 years. “Essential documents” are defined as documents that 
individually and collectively permit evaluation of the conduct of a study and the quality 
of the data produced. These documents should be retained for a longer period, however, if 
required by the applicable national regulatory or institutional requirements.  
These principles of record retention will also be applied to the storage of laboratory 
samples, provided that the integrity of the stored sample permits testing. 
 

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12.0  
USE OF INFORMATION AND PUBLICATION 
GSK assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov, and in compliance with current regulations. 
GSK also assures that key results of this clinical study will be posted in a publicly 
accessible database within the required time-frame from the End of Study as defined in 
section 3.9. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
GSK must be notified of any intent to publish data collected from the study and prior 
approval from GSK must be obtained prior to submission for publication. 
 

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13.0  
ETHICS 
13.1  
Regulatory and Ethical Compliance 
The study will be conducted in compliance with the protocol, GCP and applicable 
regulatory requirement(s). 
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, European 
Directive 2001/20/EC, GSK codes on protection of human rights, and with the ethical 
principles laid down in the Declaration of Helsinki (European Council 2001, US Code of 
Federal Regulations, ICH 1997). 
13.2  
Informed Consent Procedures 
Eligible subjects may only be included in the study after providing written informed 
consent or assent, as described in section 5.1.1. Before the start of the study, the 
investigator will have the informed consent and any other materials that will be provided 
to the subjects reviewed and approved by the IRB/EC. This review and approval will be 
documented and stored with other study documents. The investigator or designee must 
fully inform the subject or legal guardian of all pertinent aspects of the study. A copy of 
the written informed consent will be given to the subject or the designee. The 
subject/designee must be allowed ample time to ask about the details of the study and to 
make a decision as to whether or not to participate in the study. The subject and/or legal 
guardian(s) must sign the consent form indicating their agreement to participate in the 
study before any study-related procedures are conducted. The informed consent process 
may be conducted up to 28 days prior to vaccination on Day 1. If the subject is unable to 
read and write, a witness must be present during the informed consent discussion and at 
the time of informed consent signature. 
Prior to the start of the study, GSK will provide to investigators a proposed informed 
consent form that complies with the ICH GCP guideline and regulatory requirements and 
is considered appropriate for this study. Any changes to the proposed consent form 
suggested by the investigator must be agreed to by GSK before submission to the IRB/EC 
and a copy of the approved version must be provided to GSK after IRB/EC approval. 
Women of childbearing potential should be informed that taking the study medication 
may involve unknown risks to the fetus if pregnancy were to occur during the study and 
agree that in order to participate in the study they must adhere to the contraception 
requirements indicated in the protocol for the duration of the study. In case of doubt on 

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the ability of a subject to adhere to these requirements, that subject should not be allowed 
in the study 
13.3  
Responsibilities of the Investigator and IRB/EC 
The protocol and the proposed informed consent form must be reviewed and approved by 
a properly constituted IRB/EC before study start. Properly constituted IRB/EC is defined 
in ICH Guideline for Good Clinical Practice E6 (R1), Section 3 (ICH, 1997). A signed 
and dated statement that the protocol and informed consent have been approved by the 
IRB/EC must be given to GSK before study initiation. Prior to study start and at any time 
the protocol is amended during study conduct, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance 
with these documents and all of the instructions and procedures found in this protocol and 
to give access to all relevant data and records to GSK monitors, auditors, GSK Clinical 
Quality Assurance representatives, designated agents of GSK, IRBs/ECs, and regulatory 
authorities as required. If an inspection of the clinical site is requested by a regulatory 
authority, the investigator must inform GSK immediately that this request has been made. 
The investigator also responsible for the following: 
▫ Maintaining a list of appropriately qualified persons to whom the investigator has 
delegated significant study-related duties. 
▫ Demonstrating the capability of recruiting the required number of suitable subjects 
within the recruitment period. 
▫ Demonstrating sufficient time and staffing to properly conduct and complete the study 
within the agreed study period. 
▫ Ensuring that all persons assisting with the study are adequately informed about the 
protocol, the investigational product(s), and their study-related duties and functions 
▫ Ensuring that appropriately trained health care professionals are responsible for all 
study-related medical decisions and for ensuring appropriate medical care of subjects 
experiencing any adverse event related to the study. 
▫ If permission to do so is given by the subject, ensuring that the subject’s primary 
healthcare provider is informed of the subject’s participation in the study. 
The investigator should not implement any deviation from, or changes of the protocol 
without agreement by the Sponsor and prior review and documented approval/favourable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an 
immediate hazard(s) to study subjects, or when the change(s) involves only logistical or 
administrative aspects of the study (e.g., change in monitor(s), change of telephone 

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number(s)). In addition, the investigator, or person designated by the investigator, should 
document and explain any deviation from the approved protocol. 
The investigator may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior IRB/IEC 
approval/favourable opinion. As soon as possible, the implemented deviation or change, 
the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be 
submitted: 
(a) to the IRB/IEC for review and approval/favourable opinion, 
(b) to the Sponsor for agreement and, if required, 
(c) to the regulatory authority(ies). 
13.4  
Protocol Amendments 
An amendment is a written description of change(s) to or formal clarification of a study 
protocol which may impact on the conduct of the clinical study, potential benefit of the 
clinical study, or may affect subject safety, including changes of study objectives, study 
design, subject population, sample sizes, study procedures, or significant administrative 
aspects. An administrative change of a study protocol is a minor correction or 
clarification that has no significant impact on the way the clinical study is to be conducted 
and no effect on subject safety (e.g., change of telephone number(s), logistical changes). 
Protocol amendments must be approved by GSK, health authorities where required, and 
the IRB/EC. In cases when the amendment is required in order to protect the subject 
safety, the amendment can be implemented prior to IRB/EC approval. Notwithstanding, 
the need for formal approval of a protocol amendment, the investigator is expected to take 
any immediate action required for the safety of any subject included in this study, even if 
this action represents a deviation from the protocol. In such cases, GSK should be notified 
of this action, the IRB/EC at the study site, and, if required by local regulations, the 
relevant health authority should be informed within 10 working days. 
14.0  
REFERENCE LIST 
Alving CR, Peachman KK, Rao M, Reed SG. Adjuvants for human vaccines. Curr Opin 
Immunol. 2012 Jun; 24(3):310-5 
Bauza, A et al., Pemphigus-like lesions induced by imiquimod. Clin Exp Dermatol 2009, 
34, e60-62 

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Bissett SL, Draper E, Myers RE, Godi A, Beddows S. Cross-neutralizing antibodies 
elicited by the Cervarix® human papillomavirus vaccine display a range of Alpha-9 
intertype specificities. Vaccine. 2014 Feb 26; 32(10):1139-46 
Campanelli, A et al., Topical application of imiquimod and associated fever in children. J 
Am Acad Dermatol 2005,52, E1. 
Code of Federal Regulations (1997): Food and Drug Administration, U.S. Department of 
Health and Human Services: Title 21, Part 11: Electronic Records Electronic Signatures. 
Federal Register 62: 13464 
Connolly M and Noah N, Is group C meningococcal disease increasing in Europe? A 
report of surveillance of meningococcal infection in Europe 1993-6. Epidemiol. Infect. 
1999; 122: 41-49. 
Del Giudice G, Fragapane E, Della Cioppa G, et al. Aflunov®: a vaccine tailored for 
prepandemic and pandemic approaches against influenza. Expert Opin Biol Ther. 2013; 
13: 121-35. 
European Centre for Disease Prevention and Control. Surveillance of invasive bacterial 
diseases in Europe 2008/2009. Stockholm: ECDC 2011 
European Parliament (1995): Directive 95/46/EC of the European Parliament and of the 
Council of 4 April 2001. Official Journal of the European Communities. L 281/31-39 
European Parliament (2001): Directive 2001/20/EC of the European Parliament and of the 
Council of 4 April 2001. Official Journal of the European Communities. L 121/34-44 
Hellenbrand W, Elias J, Wichmann O et al. Epidemiology of invasive meningococcal 
disease in Germany, 2002-2010, and impact of vaccination with meningococcal C 
conjugate vaccine. Journal of Infection 2013; 66: 48-56. 
ICH (1997) ICH Harmonised Tripartite ICH Guideline for Good Clinical Practices E6  
(R1). Federal Register, 62 (90): 25691-25709 
ICH (1998) ICH Harmonised Tripartite ICH Guideline for Statistical Principles for 
Clinical Trials E9. Federal Register, 63 (179): 49583 
Ilyinskii, PO, et al., Adjuvant-carrying synthetic vaccine particles augment the immune 
response to encapsulated antigen and exhibit strong local immune activation without 
inducing systemic cytokine release. Vaccine, available online 1 March 2014. 

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Khurana, S., W. Chearwae, F. Castellino, J. Manischewitz, L.R. King, A. Honorkiewicz, 
M.T. Rock, K.M. Edwards, G. Del Giudice, R. Rappuoli, and H. Golding. 2010. 
MF59adjuvanted vaccines expand antibody repertoires targeting protective sites of 
pandemic H5N1 influenza virus. Science Transl. Med. 2: 15ra5: 1-8. 
Khurana, S., N. Verma, J.W. Yewdell, A.K. Hilbert, F. Castellino, M. Lattanzi, G. Del 
Giudice, R. Rappuoli, and H. Golding. 2011. MF59 adjuvant affects human epitope 
repertoire, augments affinity maturation, and neutralization titers to pandemic influenza in 
all age groups. Science Transl. Med. 3: 85ra48. 
Levine RJ. (1988) Ethics and Regulations of Clinical Research. New Haven: Yale 
University Press. 
Meyer, T et al., Clinical investigations of Toll-like receptor agonists. Expert Opin Investig 
Drugs 2008, 17:1051-1065. 
Recommendations of the Standing Committee on Vaccination (STIKO) at the Robert  
Koch Institute / Effective: August 2013; Robert Koch Institut Epidemiologisches Bulletin 
34, 26 August 2013 
Reed SG, Orr MT, Fox CB. Key roles of adjuvants in modern vaccines. Nat Med. 
2013;19 :1597-608. 
Regules JA, Cummings, JF and Ockenhouse CF. The RTS, S vaccine candidate for 
malaria. Expert Rev Vaccines 2011; 10:589-599. 
Rosenstein N, Perkins B, Stephens DS, et al. N. Engl. J. Med. 2001; 344: 1378-1388. 
Tacken, PJ et al., Targeted delivery of TLR ligands to human and mouse dendritic cells 
strongly enhances adjuvanticity. Blood 2011, 118:6836-6844. 
Takeda K, Kaisho T, Akira S Toll-like receptors. Annu.Rev.Immunol. 2003; 21: 335-76. 
U.S. Department of Health and Human Services, Food and Drug Administration, CBER  
(2009): Guidance for Industry Patient-Reported Outcome Measures: Use in Medical  
Product Development to Support Labeling Claims 
Vasilakos JP, and Tomai MA. The use of Toll-like receptor 7/8 agonists as vaccine 
adjuvants." Expert Rev Vaccines 2013; 12: 809-819. 
World Medical Association General Assembly Declaration of Helsinki - Ethical  
Principles for Medical Research Involving Human Subjects (1996) 
 

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APPENDIX A: GRADING SCALES FOR SOLICITED LOCAL ADVERSE  
EVENTS* 
(Adapted from CBER 2007b) 
Adverse event Following  
Administration of  
Injectable Product  
Mild (Grade 
1)  
Moderate 
(Grade 2)  
Severe 
(Grade 3)  
Pain 
present but does not 
interfere with activity 
interferes with activity 
prevents daily activity 
Induration / Swelling /  
Erythema 
25 – 50 mm 
51 – 100 mm 
> 100 mm  
*This toxicity grading scale is adapted from CBER 2007 to enable ease of reporting by Subjects in the 
source documents for ‘patient reported’ solicited adverse events.. ‘Grade 4’ is not listed here but will be 
defined in the Statistical Analysis Plan as necessary. 
 

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APPENDIX B: GRADING SCALES FOR SOLICITED SYSTEMIC ADVERSE  
EVENTS* 
(Adapted from CBER 2007b) 
Systemic  
Adverse event 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Fever 
°C 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 - 102 
39.0 – 40 
102.1 - 104 
°F 
Chills 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Loss of Appetite 
Loss of appetite without 
decreased oral intake  
decreased oral intake  
without weight loss 
decreased oral intake with 
weight loss 
Nausea 
Nausea present but not 
interfering with oral intake 
Nausea leading to decreased 
oral intake 
Nausea leading to minimal to 
no oral intake 
Vomiting 
1-2 episodes/24 hours 
>2 episodes/24 hours 
requires outpatient 
hydratation 
Diarrhea 
2-3 loose stools /24 hours 
4-5 loose stools /24 hours 
6 or more watery stools /24 
hours or requires outpatient 
IV hydration 
Generalized  
Myalgia 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Generalized  
Arthralgia 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Headache 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Fatigue 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Generalized  
Rash 
localized area of the skin (1 
extremity only) 
moderate area of the skin 
(2 or more body regions 
without whole body 
involvement) 
most of the skin 
Urticaria 
localized area of the skin (1 
extremity only) 
moderate area of the skin 
(2 or more body regions 
without whole body 
involvement) 
most of the skin 

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*This toxicity grading scale is adapted from CBER 2007b to enable ease of reporting by Subjects in the 
source documents for ‘patient reported’ solicited adverse events. ‘Grade 4’ is not listed here but will be 
defined in the statistical analysis plan as necessary 

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APPENDIX C:  
(SERUM CLINICAL CHEMISTRY)  
Serum*,** 
Mild (Grade 1)  
Moderate 
(Grade 2)  
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)*** 
Sodium – Hyponatremia 
mEq/L  
132 – 134  
130 – 131  
125 – 129  
< 125  
Sodium – Hypernatremia 
mEq/L  
144 – 145  
146 – 147  
148 – 150  
> 150  
Potassium – Hypokalemia 
mEq/L  
3.5 – 3.6  
3.3 – 3.4  
3.1 – 3.2  
< 3.1  
Potassium – Hyperkalemia 
mEq/L  
5.1 – 5.2  
5.3 – 5.4  
5.5 – 5.6  
> 5.6  
Blood Urea Nitrogen  
BUN mg/dL  
23 – 26  
27 – 31  
> 31  
Requires dialysis  
Creatinine – mg/dL  
1.5 – 1.7  
1.8 – 2.0  
2.1 – 2.5  
> 2.5 or requires 
dialysis  
Liver Function Tests –ALT,  
AST  
increase by factor  
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN  
5.1 – 10 x ULN  
> 10 x ULN  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 
**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 

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***The clinical signs or symptoms associated with laboratory abnormalities might result in characterization 
of the laboratory abnormalities as Potentially Life Threatening (Grade 4). For example. a low sodium value 
that falls within a grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia event if 
the subject had a new seizure associated with the low sodium value. “ULN” = the upper limit of the normal 
range. 
APPENDIX D:  
(HEMATOLOGY) 
Hematology*,** 
Mild (Grade 
1)  
Moderate  
(Grade 2)  
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)  
Hemoglobin (Female) 
gm/dL  
11.0 – 12.0  
9.5 – 10.9  
8.0 – 9.4  
< 8.0  
Hemoglobin (Female) 
change from baseline 
value - gm/dL  
Any decrease – 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
Hemoglobin (Male) 
gm/dL  
12.5 – 13.5  
10.5 – 12.4  
8.5 – 10.4  
< 8.5  
Hemoglobin (Male) 
change from baseline 
value – gm/dL  
Any decrease – 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
WBC Increase - cell/mm3 
10,800 – 15,000  
15,001 – 20,000  
20,001 – 25, 000  
> 25,000  
WBC Decrease cell/mm3 
2,500 – 3,500  
1,500 – 2,499  
1,000 – 1,499  
< 1,000  

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TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
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Platelets Decreased 
cell/mm3 
125,000 – 140,000 
100,000 – 124,000 
25,000 – 99,000  
< 25,000  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate.  
**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 
APPENDIX E:  
(URINE) 
Urine*,** 
Mild (Grade 
1)  
Moderate  
(Grade 2)  
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)  
Protein  
Trace  
1+  
2+  
Hospitalization or 
dialysis  
Glucose  
Trace  
1+  
2+  
Hospitalization for 
hyperglycemia  
Blood (microscopic) – 
red blood cells per high 
power field (rbc/hpf)  
1 - 10  
11 – 50  
> 50 and/or gross 
blood  
Hospitalization or 
packed red blood 
cells (PRBC) 
transfusion  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 
**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 

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APPENDIX F: TOXICITY SCALES FOR VITAL SIGNS 
Vital Signs* 
Mild (Grade 
1)  
Moderate  
(Grade 2)  
Severe (Grade 
3)  
Potentially Life  
Threatening  
(Grade 4)  
Tachycardia - beats per 
minute 
101-115 
116-130 
>130 
ER visit or 
hospitalization for 
arrhythmia 
Bradycardia - beats per 
minute** 
40-44 
35-39 
<35 
ER visit or 
hospitalization for 
arrhythmia 
Hypertension (systolic) - 
mm Hg 
141-150 
151-155 
>155 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypertension (diastolic) - 
mm Hg 
91-95 
96-100 
>100 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypotension 
(systolic) 
mm Hg  
85-89 
80-84 
<80 
ER visit or 
hospitalization for 
hypotensive shock 
Respiratory Rate – 
breaths per minute*** 
21-23 
24-27 
>27 
Intubation 
*Subject should be at rest for all vital signs measurements 
**Resting heart rate for young healthy subject population is between 45-90 per minute 
***Respiratory rate for young healthy subject population is between 12-20 breaths per minute 

 
 
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PRO-01 TEMP 06 / Atlas No. 293620 
Version No. 2 / Version Date: December 2, 2013 
CLINICAL STUDY PROTOCOL V132_01EXP Version 7 
A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study to Evaluate the 
Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R Adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium Hydroxide  
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy Adults (18-45 
years of age) 
EUDRACT No. 2014-002430-31 
Property of GlaxoSmithKline Biologicals S.A. (hereafter referred to as GSK) 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of GSK. 
TABLE OF CONTENTS 
TABLE OF CONTENTS.....................................................................................................2 
PROTOCOL SYNOPSIS V132_01EXP.............................................................................7 
LIST OF ABBREVIATIONS............................................................................................23 
1.0  
BACKGROUND AND RATIONALE..................................................................25 

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1.1  
Background........................................................................................................25 
 
1.2  
Rationale............................................................................................................28 
2.0  
OBJECTIVES........................................................................................................29 
 
2.1  
Primary Objectives ............................................................................................29 
 
2.2  
Secondary Objectives ........................................................................................29 
 
2.3  
Exploratory Objectives ......................................................................................29 
3.0  
STUDY DESIGN...................................................................................................31 
 
3.1  
Overview of Study Design.................................................................................31 
 
3.2  
Study Period.......................................................................................................32 
 
3.3  
Blinding Procedures...........................................................................................33 
 
3.4  
Data Collection ..................................................................................................34 
 
3.4.1  
Data Collected from Subjects ....................................................................34 
 
3.4.2  
Tools Used for Data Collection .................................................................34 
 
3.5  
Collection of Clinical Specimens ......................................................................35 
 
3.6  
Stopping/Pausing Guidelines.............................................................................38 
 
3.7  
Data Monitoring Committee..............................................................................39 
 
3.8  
Premature Withdrawal from Study....................................................................39 
 
3.9  
End of Study ......................................................................................................42 
4.0  
SELECTION OF STUDY POPULATION ...........................................................43 
 
4.1  
Inclusion Criteria ...............................................................................................43 
 
4.2  
Exclusion Criteria ..............................................................................................43 
 
4.3  
Criteria for Delay of Vaccination or Blood Draw .............................................45 
5.0  
STUDY PROCEDURES .......................................................................................46 
 
5.1  
Pre-vaccination Clinic Visit(s)...........................................................................46 
 
5.1.1  
Informed Consent.......................................................................................46 
 
5.1.2  
Screening....................................................................................................47 
 
5.2  
Vaccination Clinic Visit(s) ................................................................................48 

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5.2.1  
Pre-vaccination Procedures........................................................................48 
 
5.2.2  
Enrolment...................................................................................................49 
 
5.2.3  
Randomization...........................................................................................49 
 
5.2.4  
Vaccination ................................................................................................50 
 
5.2.5  
Post-vaccination Procedures......................................................................50 
 
5.3  
Post-vaccination Visit(s)....................................................................................51 
 
5.3.1  
Subject Diary Reminder, Safety Follow-up and/or Post-vaccination Blood  
Draw Clinic Visits......................................................................................................51 
 
5.3.2  
Safety Follow-up Calls ..............................................................................55 
 
5.4  
Unscheduled Visits ............................................................................................55 
 
5.5  
Study Termination Visit.....................................................................................56 
 
5.5.1  
Early Termination Visit .............................................................................56 
6.0  
TREATMENT OF SUBJECTS.............................................................................58 
 
6.1  
Study Vaccine(s)................................................................................................58 
 
6.2  
Non-Study Vaccines ..........................................................................................61 
 
6.3  
Vaccine Preparation and Administration...........................................................61 
 
6.4  
Vaccine Administration Error or Overdose of Vaccine.....................................62 
 
6.5  
Prior and Concomitant Medications and Vaccines............................................62 
 
6.6  
Vaccine Supply, Labeling, Storage and Tracking .............................................62 
7.0  
ASSESSMENTS....................................................................................................65 
 
7.1  
Safety Assessment .............................................................................................65 
 
7.1.1  
Solicited Adverse Events...........................................................................65 
 
7.1.2  
Unsolicited Adverse Events.......................................................................67 
 
7.1.3  
Evaluation of Adverse Events....................................................................67 
 
7.1.4  
Serious Adverse Events .............................................................................68 
 
7.1.4.1  
Adverse Events of Special Interest........................................................70 
 
7.1.5  
Methods for Recording Adverse Events and Serious Adverse Events......71 

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7.1.5.1  
Post-Study Events..................................................................................72 
 
7.1.6  
Pregnancies ................................................................................................72 
 
7.1.7  
Safety Laboratory Measurements ..............................................................72 
 
7.2  
Efficacy Assessment..........................................................................................73 
 
7.3  
Immunogenicity Assessment.............................................................................73 
 
7.4  
Exploratory Measurements................................................................................74 
8.0  
STATISTICAL CONSIDERATIONS...................................................................76 
 
8.1  
Endpoints ...........................................................................................................76 
 
8.1.1  
Primary Endpoint(s)...................................................................................76 
 
8.1.1.1  
Primary Safety Endpoint(s) ...................................................................76 
 
8.1.1.2  
Primary Efficacy Endpoint(s)................................................................76 
 
8.1.1.3  Primary Immunogenicity Endpoint(s) ...................................................76 
 
8.1.2  
Secondary Endpoint(s)...............................................................................76 
 
8.1.2.1  
Secondary Safety Endpoint(s)................................................................76 
 
8.1.2.2  
Secondary Efficacy Endpoint(s)............................................................77 
 
8.1.2.3  Secondary Immunogenicity Endpoint(s) ...............................................77 
 
8.1.3  
Exploratory Endpoint(s).............................................................................77 
 
8.2  
Success Criteria..................................................................................................78 
 
8.2.1  
Success Criteria for Primary Objective(s) .................................................78 
 
8.2.2  
Success Criteria for Secondary Objective(s) .............................................78 
 
8.3  
Analysis Sets......................................................................................................78 
 
8.3.1  
All Enrolled Set..........................................................................................78 
 
8.3.2  
All Exposed Set..........................................................................................78 
 
8.3.3  
Safety Set ...................................................................................................79 
 
8.3.4  
Full Analysis Set (FAS) Efficacy/Immunogenicity Set.............................79 
 
8.3.5  
Per Protocol (PP) Set Efficacy/Immunogenicity Set .................................79 
 
8.3.6  
Other Analysis Sets....................................................................................80 

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8.3.7  
Subgroups ..................................................................................................80 
 
8.3.8  
Protocol Deviations....................................................................................80 
 
8.4  
Statistical Analysis Plan.....................................................................................80 
 
8.4.1  
Analysis of Demographic and Baseline Characteristics............................80 
 
8.4.2  
Analysis of Primary Objective(s)...............................................................81 
 
8.4.2.1  Analysis of Primary Safety Objective(s) ...............................................81 
 
8.4.2.1.1  Analysis of Extent of Exposure.......................................................81 
 
8.4.2.1.2  Analysis of Solicited Local, Systemic and Other Adverse Events .81 
 
8.4.2.1.3  
Analysis of Unsolicited Adverse Events.........................................82 
 
8.4.2.1.4  Analysis of Safety Laboratory Values ............................................82 
 
8.4.2.2  
Analysis of Primary Efficacy Objective(s)............................................83 
 
8.4.2.3  
Analysis of Primary Immunogenicity Objective(s)...............................83 
 
8.4.2.3.1  Statistical Hypotheses .....................................................................83 
 
8.4.2.3.2  
Analysis Sets...................................................................................83 
 
8.4.2.3.3 
Statistical Methods..........................................................................83 
 
8.4.3  
Analysis of Secondary Objective(s)...........................................................84 
 
8.4.3.1  Analysis of Secondary Safety Objective(s) ...........................................84 
 
8.4.3.2  
Analysis of Secondary Efficacy Objective(s)........................................84 
 
8.4.3.3  
Analysis of Secondary Immunogenicity Objective(s)...........................85 
 
8.4.3.3.1  Statistical Hypotheses .....................................................................85 
 
8.4.3.3.2  
Analysis Sets...................................................................................85 
 
8.4.3.3.3  
Statistical Methods..........................................................................85 
 
8.4.4  
Analysis of Exploratory Objectives...........................................................86 
 
8.5  
Sample Size and Power Considerations of Primary Objectives ........................86 
 
8.6  
Interim Analysis.................................................................................................87 
9.0  
SOURCE DOCUMENTATION, STUDY MONITORING AND AUDITING ...88 
 
9.1  
Source Documentation.......................................................................................88 

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9.2  
Study Monitoring, Auditing and Source Data Verification...............................89 
10.0  
DATA MANAGEMENT.......................................................................................90 
 
10.1  Data Entry and Management .............................................................................90 
 
10.2  
Data Clarification...............................................................................................90 
 
10.3  
Data Protection ..................................................................................................90 
11.0  
RECORD RETENTION........................................................................................92 
12.0  
USE OF INFORMATION AND PUBLICATION................................................93 
13.0  
ETHICS..................................................................................................................94 
 
13.1  Regulatory and Ethical Compliance ..................................................................94 
 
13.2  
Informed Consent Procedures............................................................................94 
 
13.3  
Responsibilities of the Investigator and IRB/EC...............................................95 
 
13.4  
Protocol Amendments........................................................................................96 
14.0  REFERENCE LIST ...............................................................................................97 
APPENDIX A:  
GRADING SCALES FOR SOLICITED LOCAL ADVERSE  
EVENTS* 
100 
APPENDIX B:  
GRADING SCALES FOR SOLICITED SYSTEMIC ADVERSE  
EVENTS* 
101 
APPENDIX C:  
TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(SERUM CLINICAL CHEMISTRY) .............................................................................102 
APPENDIX D: TOXICITY SCALES FOR LABORATORY ABNORMALITIES 
(HEMATOLOGY) 103 
APPENDIX E:  
TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
(URINE) 
104 
APPENDIX F:  
TOXICITY SCALES FOR VITAL SIGNS.....................................105 
APPENDIX G:  
PROTOCOL AMENDMENTS SUMMARY OF CHANGES........106 
PROTOCOL SYNOPSIS V132_01EXP 

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Version No. 2 / Version Date: December 2, 2013 
Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Title of Study: A Phase 1, Randomized, Observer-Blind, Dosage-Escalation Study to  
Evaluate the Safety and Immunogenicity of an Aluminium Hydroxide/LHD153R 
Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine Compared to Aluminium  
Hydroxide Adjuvanted Meningococcal C-CRM197 Conjugate Vaccine in Healthy Adults 
(18-45 years of age) 
Study Period: Approximately 12 months for 
each subject 
Clinical Phase: Phase 1 
Background and Rationale: 
Neisseria meningitidis (N. meningitides) serogroup C (MenC) is one of the major 
serogroups causing invasive meningocococcal disease. Case fatality in Germany has 
ranged between 6% and 8% between 1999 and 2006, and has remained generally 
consistent across the different European countries, varying between 6-11%, with the case 
fatality rate being notably higher for serogroup C disease than for serogroup B. The 
safety and immunogenicity of the GSK Meningococcal C-CRM197 Conjugate Vaccine 
(Menjugate®) has been confirmed through years of commercial use. For children over 
the age of 12 months, for adolescents and for adults a single dose is recommended. For 
infants between 2 and 12 months of age, the recommended schedule for primary 
immunization with the Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) is 
two doses given with an interval of at least 2 months A more potent Meningococcal 
CCRM197 Conjugate Vaccine formulation might enable a reduction of the antigen dosage 
and/or a reduction in the number of doses needed in infants. One approach to achieve 
more potent well-characterized sub-unit vaccines - like the Meningococcal C-CRM197 
Conjugate Vaccine - is the use of new adjuvants that activate the Toll-like receptor 
(TLR) pathway. 
GSK is developing a small molecule immune potentiator (SMIP) LHD153 that is an 
agonist for TLR7. The objective driving the development of LHD153 is to achieve a 
vaccine adjuvant with strong immunopotentiating properties and minimal side effects. In 
line with this objective, it has been postulated that the ideal SMIP should remain local 

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and target innate immune cells at the injection site. To this end, LHD153 contains a 
functional phosphonate group to allow for adsorption to aluminium hydroxide. The  
 
Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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arginine salt derivative of this compound is LHD153R. Preclinical results from animal 
models for bacterial and viral antigens, including MenC, MenB, rabies, HIV and 
respiratory syncytial virus (RSV) showed increased functional antibodies and 
antigenspecific T-cells with LHD153R adsorbed to aluminium hydroxide (Aluminium 
Hydroxide/LHD153R) when compared to aluminium hydroxide adjuvanted controls. In 
vitro toxicity screens confirmed that LHD153R is not phototoxic, genotoxic or 
mutagenic. Furthermore, toxicology studies in dog and rats showed that intramuscular 
(IM) injection of Aluminium Hydroxide/LHD153R was well tolerated. Importantly, in 
contrast to free LHD153R, toxicokinetic analysis in rats and dogs confirmed very 
limited exposure of LHD153 when LHD153R was adsorbed to aluminium hydroxide 
after IM injection. 
The aim of this Phase 1 clinical study is to assess the safety of Aluminium  
Hydroxide/LHD153R adjuvanted MenC-CRM197 conjugate vaccine 
(MenCCRM197/Aluminium Hydroxide/LHD153R) and to compare the antibody-
mediated immune response elicited by MenC-CRM197/Aluminium Hydroxide/LHD153R 
with the licensed aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate 
Vaccine (Menjugate®). Furthermore, a comprehensive set of exploratory objectives has 
been selected to assess the systemic exposure of LHD153 after intramuscular injection of 
MenC-CRM197/Aluminium Hydroxide/LHD153R, to evaluate the quality of the specific 
immune response against MenC-CRM197 in detail and to evaluate biomarkers that may 
be predictive of safety and/or innate immune activation. 
The licensed Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) has been 
selected as the primary vaccine candidate to assess the safety and immunopotentiating 
properties of Aluminium Hydroxide/LHD153R for several reasons. Firstly, the safety 
and immunogenicity profiles of the Meningococcal C-CRM197 Conjugate Vaccine 
(Menjugate®) have been well established through years of commercial use. Secondly, a 
more potent MenC-CRM197 conjugate vaccine might enable a reduction of the antigen 
dosage or the number of doses needed in infants. Finally, MenC-CRM197 is a 
wellcharacterized, single conjugate antigen preparation which provides an ideal setting to 
evaluate the potential of this new Aluminium Hydroxide/LHD153R adjuvant. 
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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Study Objectives: 
Primary Safety Objective: 
To assess the safety of MenC-CRM197/Aluminium Hydroxide/LHD153R as compared to 
that of aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
Primary Immunogenicity Objective: 
To compare the antibody responses of MenC-CRM197/Aluminium Hydroxide/LHD153R 
and aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at 
Day 29, as measured by human complement serum bactericidal assay (hSBA) directed 
against MenC. 
Secondary Immunogenicity Objectives: 
1. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine, at Day 8 and Day 181 after vaccination, as measured 
by hSBA directed against MenC. Baseline antibody titers will also be measured by 
hSBA. 
2. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine at Day 8, Day 29 and Day 181 after vaccination, as 
measured by an enzyme-linked immunosorbent assay (ELISA) to MenC. Baseline 
antibody concentrations will also be measured by ELISA. 
Exploratory Objectives: 
1. To evaluate the systemic exposure of LHD153 at several early time-points after IM 
injection of MenC-CRM197/Aluminium Hydroxide/LHD153R or aluminium 
hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
2. To explore the frequency of B cells specific for MenC polysaccharide and CRM197 
protein at baseline (Day 1) and at Day 8, Day 29 and Day 181 after vaccination with  
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
MenC-CRM197/Aluminium Hydroxide/LHD153R or the aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. Subsequently, the B cell 
repertoire of the antigen specific B cells will be analyzed in a selected subset of 
subjects. 
3. To explore the baseline T cell mediated immunity to CRM197 and to evaluate the 
frequency and quality of CRM197 specific T cells induced by MenC- 
CRM197/Aluminium Hydroxide/ LHD153R compared to aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at Day 8 and Day 29. 
4. To evaluate biomarkers that may be predictive for safety and/or innate immune 
activation. 
5. To explore the biophysical and functional characteristics of antibodies induced by 
MenC-CRM197/Aluminium Hydroxide/LHD153R or aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. (Amended: 19 June 
2017) 

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Study Design: 
This Phase 1, randomized, observer-blind, dosage-escalation study will be performed at 
a single center. In total, approximately 80 healthy male and healthy non-pregnant female 
adults (18-45 years of age) will be enrolled in the study. Subjects will be randomized to 
receive a single IM vaccination of either the licensed aluminium hydroxide adjuvanted 
Meningococcal C-CRM197 Conjugate Vaccine (i.e. 10 µg MenC conjugated to CRM197, 
adjuvanted with 1 mg aluminium hydroxide) or one of four dosages of the 
investigational vaccine, MenC-CRM197/Aluminium Hydroxide/LHD153R (i.e. 10 µg 
MenC conjugated to CRM197, adjuvanted with 1 mg aluminium hydroxide and one of 
four dosages [12.5, 25, 50 or 100 µg] of LHD153R). 
For the dosage-escalation of LHD153R, the subjects will be enrolled into 1 of 4 cohorts, 
in a stepwise manner with 20 subjects per cohort. Subjects in all cohorts will be 
randomized in a 1:4 ratio, to receive either aluminium hydroxide adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine (control) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R with increasing doses of LHD153R.Cohort 1 will receive 12.5 μg 
of LHD153R; Cohort 2 will receive 25 μg of LHD153R; Cohort 3 will receive 50 μg of  
 
Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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LHD 153; and Cohort 4 will receive 100 μg of LHD153R (Table 1). 
 Table 1: 
Subjects Randomized per Cohort and Treatment Dosage Group 
Cohort 
Group 
Subjects/ 
Group 
MenC  
Dosage*  
(µg) 
Adjuvant Dosages  
Total 
Volume/Dose 
Total 
Subjects/Cohort 
Aluminium  
Hydroxide  
(mg) 
LHD153R  
(µg) 
1 
A 
4 
10 
1 
0 
0.5 mL 
20 
 
 
 
 
 
 
 
B 
16 
10 
1 
12.5 
0.5 mL 
 
2 
A 
4 
10 
1 
0 
0.5 mL 
20 
C 
16 
10 
1 
25 
0.5 mL 
3 
A 
4 
10 
1 
0 
0.5 mL 
20 
D 
16 
10 
1 
50 
0.5 mL 
4 
A 
4 
10 
1 
0 
0.5 mL 
20 
E 
16 
10 
1 
100 
0.5 mL 
*Conjugated to 12.5-25 µg CRM197 
After vaccination, all subjects will be confined to the clinical site for 24 hours for 
clinical observation, including but not limited to observations for solicited and 
unsolicited adverse events, body temperature measurements and blood sampling for 
exploratory endpoint measurements. 
Importantly, all cohorts will have a staggered entry based on Data Monitoring 
Committee (DMC) reviews. 
▫ For each cohort, the first 5 subjects (i.e. the first 1:4 randomization block) to receive 
either aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate 
Vaccine (n=1) or MenC-CRM197/Aluminium Hydroxide/LHD153R (n=4) will be 
treated at a vaccination rate of 1 subject each day. 
▫ After entry of the first 5 subjects in each cohort, the enrollment will be paused. The 
remaining 15 subjects for each cohort will be enrolled only after DMC review of the 
safety results obtained through Day 14 has been finalized (Table 2). 
▫ In addition, enrollment of the first 5 subjects in the next cohort will only proceed after 
the Day 14 safety results of the first 5 subjects of the previous cohort have been 
reviewed by the DMC (Table 2). 
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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▫ Furthermore, all available Day 14 and Day 29 safety results will be included in DMC 
reviews between the different enrollment stages. 
 Table 2: 
Overview of staggered entry of subjects based on DMC reviews 
Stage 
Dosage Cohort 
MenC-CRM197/ 
Aluminium Hydroxide (n) 
MenC-CRM197/ 
Aluminium Hydroxide 
/LHD153R (n) 
1   
1  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 14 Safety Results 
2 
1  
3 
12 
2  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 29 and Stage 2 Day 14 Safety Results 
3 
2  
3 
12 
3  
1 
4 
Enrollment pause until DMC review of Stage 2 Day 29 and Stage 3 Day 14 Safety Results 
4 
3  
3 
12 
4  
1 
4 
Enrollment pause until DMC review of Stage 3 Day 29 and Stage 4 Day 14 Safety Results 
5 
4  
3 
12 
The DMC review will be performed according to predefined stopping/pausing guidelines 
used to ensure the safety of study subjects. These stopping/pausing guidelines are based 
on FDA guidance and with grading scales from the CBER Guidance for Industry 
“Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials”. See protocol section 3.6 for further details. 
Safety Measurements 
Schedule of safety data collection: 
▫ Solicited local and systemic adverse events (AEs), body temperature and all 
unsolicited AEs will be collected until Day 14. 
▫ All serious adverse events (SAEs), medically attended AEs, AEs leading to study 
withdrawal, new onset of chronic disease (NOCDs), and adverse events of special 
interest (AESIs) will be collected from the date of signed informed consent to study  
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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completion at Day 366. 
▫ All concomitant medications administered in relation to the reported AEs will be 
collected from vaccination to study completion at Day 366. 
Solicited local AEs include injection site erythema, injection site induration, injection 
site pain and injection site swelling. Solicited systemic AEs include body temperature ≥ 
38.0°C (as measured orally), loss of appetite, nausea, fatigue, generalized myalgia, 
generalized arthralgia, headache, chills, vomiting, diarrhea, generalized rash and 
urticaria. 
All AESIs will be reported in the same manner as SAEs. All AEs will be monitored until 
resolution or, if the AE becomes chronic, a cause is identified. If an AE is unresolved at 
the conclusion of the study, a clinical assessment will be made by the investigator and 
the medical monitor to determine whether or not continued follow-up of the AE is 
warranted. 
The relationship of the study treatment to any AE will be determined by the investigator 
as probably related, possibly related, or not related; the relationship of the study 
treatment to any SAE will be determined by the investigator as probably 
related/suspected, or not related. 
Safety Laboratory Parameters 
To assess laboratory AEs, blood and urine samples will be collected from each subject 
as outlined in Table 3 to perform blood chemistry, hematology, and urine analyses. 
Safety laboratory samples will be drawn from all subjects at pre-vaccination screening 
(between Day -28 and Day -3) at Day 1 (pre-vaccination and 24h after vaccination), at 
Day 8 and at Day 29. Safety laboratory assessments will include sodium, potassium, 
chloride, bicarbonate, blood urea nitrogen, creatinine, liver function tests (ALT, AST), a 
complete blood count and C-reactive protein. A urine sample will be collected at the 
same time-points and will be assessed for the presence of protein, glucose and red blood 
cells. 
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Primary and Secondary Immunogenicity Measurements 
Four blood samples per subject (i.e. at Day 1, Day 8, Day 29 and Day 181) will be 
collected for serum preparation and determination of antibody-mediated immune 
responses to MenC-CRM197 as outlined in Table 3 and Table 4. See section 7.3 for 
further details. 
Exploratory Measurements 
In all subjects who agree by signing a separate Informed Consent, additional blood 
samples will be collected at Day 1, Day 4, Day 8, Day 29 and Day 181 for exploratory 
assays as outlined in Table 3 and Table 4. The purpose of these assays is to assess the 
systemic exposure of LHD153, to determine the frequency and quality of B- and T-cells 
specific for MenC polysaccharide and/or CRM197 and to evaluate biomarkers that may 
be predictive of safety and/or innate immune activation. Subsequently, MenC-CRM197 
specific B-cell repertoires will be analyzed in a selected subset of subjects, dependent on 
the results from primary and secondary immunogenicity measurements and the volume 
of  blood  remaining for additional testing. See section 7.4 for further details. All 
exploratory analyses may be performed after the Clinical Study Report (CSR) has been 
completed, in which case these data will be submitted as an addendum to the CSR. 
Number of Subjects planned: 
Approximately 80 adult subjects will be randomized, with anticipated dropout rates of 
5% by Day 181 (last serology time point), and 10%, by Day 366 (last safety time point). 
Sample size is not driven by statistical assumptions for formal hypothesis testing, but the 
proposed number of subjects will be sufficient to provide a descriptive summary of the 
safety and immunogenicity of the study vaccine. 
Study Population and Subject Characteristics: 
Healthy adult male and female volunteers between 18-45 years of age, inclusive. 
The list of inclusion and exclusion criteria is included in protocol section 4.0. 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
Study Vaccines: 
The MenC-CRM197 conjugate is a lyophilized powder consisting of 10 µg of MenC 
polysaccharide conjugated to 12.5-25 µg CRM197 carrier protein. The MenC-CRM197 
lyophilized powder will be reconstituted with adjuvant by the unblinded designated site 
staff member who is to follow the procedure as described in the vaccine preparation 
instructions in the Investigator Site File (i.e. the vaccine will be prepared in the clinic 
prior to administration). 
The lyophilized MenC-CRM197 powder will be reconstituted with either: 
(a) 
aluminium hydroxide adjuvant 
(b) Aluminium Hydroxide/LHD153R adjuvant with specified dosages of LHD153R 
(12.5, 25, 50 or 100 µg) 
The components for each formulation of MenC-CRM197 will be provided in a separate 
kit. 
Aluminium Hydroxide/LHD153R with specified dosages of LHD153R will be prepared  
by dilution of the highest Aluminium Hydroxide/LHD153R dosage (100 µg of 
LHD153R) with aluminium hydroxide. 
In each cohort, subjects will be randomized to receive one injection of MenC- 
CRM197/Aluminium Hydroxide/LHD153R adjuvant or aluminium hydroxide adjuvanted  
Meningococcal C-CRM197 Conjugate Vaccine. The 0.5 mL of vaccine will be injected 
IM in the deltoid muscle, with preference that the injection is administered in the 
nondominant arm. 

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Primary Safety Endpoint: 
Safety will be assessed by measuring the frequency of local and systemic solicited AEs, 
unsolicited AEs, SAEs, AESIs, NOCDs, and safety laboratory data for all subjects.  
Specifically, 
▫ The frequency and percentage of subjects with solicited local and systemic AEs 
through Day 14. Time intervals after vaccination that will be summarized are: 30  
 
Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 

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min post-vaccination, Days 1-4 (without 30 min), Days 5-8, Days 8-14, Days 1-8 
(without 30 min) and Days 1-14 (without 30 min). 
▫ The frequency and percentage of subjects with any unsolicited AEs from the day of 
vaccination (Day 1) to Day 14. 
▫ The frequency and percentage of subjects with SAEs, medically attended AEs,  AEs 
leading to study withdrawal, NOCDs, AESIs for the following time periods: day of 
signed informed consent until study completion (Day 366), day of vaccination (Day 
1) to Day 29 and Day 29 to study completion (Day 366). 
▫ The absolute values and changes in hematology, chemistry, and urinalysis parameters. 
▫ The frequency and percentage of subjects with abnormal laboratory parameter values 
as classified by investigator normal ranges (low, normal, high) and as classified by 
CBER toxicity grading scales, when available. 
Primary Immunogenicity Endpoint: 
Geometric mean titers (GMTs) measured by hSBA directed against MenC from samples 
collected on Day 1 (baseline, before vaccination) and Day 29 as well as the GMR of the 
titers (Day 29 / Day 1). 
Secondary Immunogenicity Endpoints: 
▫ GMTs and corresponding GMRs measured by hSBA directed against MenC for 
samples collected at Day 8 and Day181. 
▫ Percentage of subjects with hSBA seroresponse at Day 8, Day 29, and Day 181. 
seroresponse is defined as a post vaccination hSBA ≥8 for subjects with a baseline 
hSBA <4 or have an increase of at least 4 times the baseline hSBA level for subjects 
with pre-vaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against MenC measured by ELISA 
for samples collected on Day 1 (baseline, prior to vaccination), Day 8, Day 29, and 
Day 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations  
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
to MenC measured by ELISA on Day 8, Day 29, and Day 181 relative to baseline (Day 
1). 
Exploratory Immunogenicity Endpoints: 
Testing and analyses of exploratory immunogenicity endpoints may be performed after 
the Clinical Study Report (CSR) has been completed, in which case these data will be 
submitted as an addendum to the CSR. 
1. Serum concentration of LHD153 at Day 1 baseline (prior to vaccination), Day 1 (1h , 
2h, 4h, 8h, and 24h after vaccination) and Day 4 by LC-MS/MS. 
2. Frequency of MenC polysaccharide-specific and CRM197-specific B cells at Day 1 
(baseline), Day 8, Day 29, and Day 181 by ELISPOT. 
3. Diversity of the MenC polysaccharide-specific B-cell repertoire at Day 1 (baseline), 
Day 8, Day 29, and Day 181 by immunoglobulin cDNA sequencing. 
4. Frequency and quality of T cells specific for CRM197 at Day 1 (baseline), Day 8, and 
Day 29 by flow cytometry using intracellular staining with a panel of cytokines and 
staining of surface markers to identify cell populations. 
5. Serum concentrations of a panel of 30 chemokines and cytokines at Day 1 baseline 
(prior to vaccination), Day 1 (6h and 24h after vaccination), Day 4, and Day 8 by 
electrochemo-luminescence based assay. 
6. Gene expression profile in whole blood at Day 1 baseline (prior to vaccination), Day 
1 (6h and 24h after vaccination), Day 4, and Day 8 by RNA micro array analysis. 
7. Number and activation status of myeloid and lymphoid cell populations at Day 1 
baseline (prior to vaccination), Day 1 (24h after vaccination), Day 4 and Day 8 by 
flow cytometry. 
 

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
8. Antigen specific antibody isotype, Fc receptor binding capability and antibody 
glycosylation state will be assessed at Day 1 (baseline), Day 29, and Day 181.  
9. Functionality of MenC-specific antibodies to fix complement, promote 
antibodydependent cell mediated cytoxicity (ADCC), induce phagocytosis (ADCP) 
and activate FcR+ cells in vitro will be also assessed at Day 1 (baseline), Day 29, 
and Day 181.(Amended: 19 June 2017) 
Statistical Analyses: 
The study is exploratory in nature, thus analyses will be descriptive and no formal 
hypothesis testing will be performed. 
Primary Safety Analyses 
The primary safety analyses will be based on the safety set for solicited and unsolicited 
adverse events. There is no statistical null hypothesis associated with the safety 
objective, which will be analyzed descriptively. 
Immunogenicity Analyses 
The primary immunogenicity analyses will be based on the per-protocol set (PPS) on 
Day 29. The primary analyses will also be performed using the Full Analysis Set (FAS) 
as a measure of the sensitivity/robustness of the results. All other immunogenicity 
assessments will be performed using the PPS or the appropriate subset of subjects. The 
antibody concentrations/titers will be summarized using GMC/GMTs and two-sided 
95% confidence intervals (CIs) constructed by exponentiation (base 10) of the least 
square means of the logarithmically transformed (base 10) antibody titer. The 95% CIs 
will be obtained from an analysis of covariance (ANCOVA) with baseline 
concentration/titer as a covariate. Additional details will be further described in the 
Statistical Analysis Plan. 
The immunogenicity endpoints based on subjects meeting criteria for seroconversion or 
achieving a certain threshold value will be summarized using frequencies and 
percentages and associated two-sided 95% Clopper-Pearson CIs. For analyses of 
seroconversion, separate summaries may be provided based on seropositivity status at  

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Name of Sponsor: 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V132_01EXP 
Generic name of study vaccine(s): 
MenC-CRM197/Aluminium  
Hydroxide/LHD153R and 
Meningococcal C-CRM197 Conjugate 
Vaccine 
baseline. 
Interim Analysis: 
An Interim Analysis will be performed on the immunogenicity and safety data collected 
from all subjects until Day 29, after all cohorts have been enrolled. Further details 
regarding the interim analysis are contained in section 8.6. 
Data Monitoring Committee: 
An independent DMC will be implemented to review safety data during scheduled 
periodic reviews. The DMC will review safety data collected until Day 14, as described 
in the DMC charter and in the Statistical Analysis Plan, after enrollment of the first 5 
subjects in each cohort, before proceeding with enrollment of the remaining 15 subjects 
in each cohort. In addition, enrollment of the first 5 subjects of the next cohort will only 
proceed after the Day 14 safety results of the first 5 subjects of the previous cohort have 
been reviewed. Furthermore, all available Day 14 and Day 29 safety results will be 
included in DMC reviews between the different enrollment stages. Further information 
regarding the DMC is discussed in more detail in the protocol, section 3.7. 

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Table 3: 
Time and Events Table – Treatment Period (until Day 29) 
 
Visit Type 
Study Day 
Visit Window (Days) 
Visit Number 
Clinic Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
-28 to -3 
1 
4 
8 
15 
22 
29 
n/a 
n/a 
n/a 
-1/+1 
+1 
n/a 
-2/+2 
Screening  
1 
2 
3 
4 
5 
6 
Study Event 
References 
 
 
 
 
 
 
 
Study Treatment 
 
 
 
 
 
 
 
Vaccination 
Section 5.2 
 
X 
 
 
 
 
 
Screening and Safety 
 
 
 
 
 
 
 
Informed Consent  
Section 5.1.1 
X 
 
 
 
 
 
 
Demographic Data & Medical History 
Sections 5.1.2 
X 
 
 
 
 
 
 
Physical Exam 
Sections 5.1.2 and 5.2.1 
X 
Xa 
 
 
 
 
 
Safety Laboratory blood draw (10 ml) 
Section 7.1.7 
X 
Xb 
 
X 
 
 
X 
Urinalysis 
Sections 7.1.7 
X 
Xb 
 
X 
 
 
X 
Pregnancy Test 
Sections 5.1.2 and 5.2.1 
X 
Xa 
 
 
 
 
 
Exclusion/Inclusion Criteria 
Section 4.0 
X 
Xa 
 
 
 
 
 
Randomization 
Section 5.2.3 
 
Xa 
 
 
 
 
 

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30 min and 24 hr Post Injection Assessment 
Section 5.2.5 
 
Xc 
 
 
 
 
 
Subject Diary Dispensed with Training 
Section 5.2.5 
 
X 
 
 
 
 
 
Subject Diary Reminder 
Section 5.2.5 
 
 
X 
X 
 
 
 
Subject Diary Reviewed and Collected 
Section 5.3.1 
 
 
 
 
X 
 
 
Assess all solicited AEs 
Section 7.1.1 and 7.1.3 
 
 
 
 
X 
 
 
Assess all unsolicited AEs 
Sections 7.1.2 and 7.1.3 
X 
X 
X 
X 
X 
 
 
 
Visit Type 
Study Day 
Visit Window (Days) 
Visit Number 
Clinic Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
-28 to -3 
1 
4 
8 
15 
22 
29 
n/a 
n/a 
n/a 
-1/+1 
+1 
n/a 
-2/+2 
Screening  
1 
2 
3 
4 
5 
6 
Study Event 
References 
 
Assess SAEs 
Section 7.1.4 
X 
X 
X 
X 
X 
X 
X 
Assess AESIs 
Section 7.1.4.1 
X 
X 
X 
X 
X 
X 
X 
Assess NOCDs, medically attended AEs, AEs 
leading to withdrawal  
Sections 7.1.3 
X 
X 
X 
X 
X 
X 
X 
Assess relevant medications 
Sections 5.1.2 and 6.5 
X 
X 
X 
X 
X 
X 
X 
Blood draws for Immunogenicity and Exploratory Objectives 
Serum Blood Draws (Primary/Secondary Objectives; 10 mL)  
Section 3.5 
 
Xa 
 
X 
 
 
X 

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Serum Blood Draws (Exploratory Objectives; 5 mL)  
Section 3.5 
 
Xd 
X 
X 
 
 
 
Whole Blood Draws (Exploratory Objectives; 3 mL) 
Section 3.5 
 
Xe 
X 
 
 
 
 
Whole Blood Draws (Exploratory Objectives; 5 mL) 
Section 3.5 
 
Xf 
X 
X 
 
 
 
Whole Blood Draws (Exploratory Objectives; 20 mL) 
Section 3.5 
 
Xg 
X 
 
 
 
 
Whole Blood Draws (Exploratory Objectives; 50 mL) 
Section 3.5 
 
 
 
 
 
 
X 
Whole Blood Draws (Exploratory Objectives; 70 mL) 
Section 3.5 
 
Xa 
 
X 
 
 
 
Notes: 
a. 
Procedure must be performed prior to vaccination. 
b. 
Two blood draws (2 x 10 ml) and two urine samples must be taken at Study Day 1, i.e. at baseline (prior to vaccination) and at 24h after vaccination. 
c. 
Vital signs will be measured at 30 min and 24h. Additional body temperature measurement must be performed at 2, 4, 6, 8, 10, 12 and 18h after 
vaccination. 
d. 
Three Serum Blood Draws (3 x 5ml) must be taken at Study Day 1, i.e. at baseline (prior to vaccination), at 6h and at 24h after vaccination. 
e. 
Six Whole Blood Draws (6 x 3 mL) must be taken at Study Day 1, i.e. at baseline (prior to vaccination) and at 1, 2, 4, 8 and 24h after vaccination. 
f. 
Three Whole Blood Draws (3 x 5 mL) must be taken at Study Day 1, i.e. at baseline (prior to vaccination), at 6h and at 24h after vaccination. g. Whole 
Blood Draw (20 mL) at Study Day 1 must be taken at 24h after vaccination. 
Table 4: 
Time and Events Table – Follow-up Period (until Day 366) 
Visit Type 
Study Day 
Visit Window (Days) 
Visit Number 
Clinic Visit 
Clinic Visit 
Clinic Visit 
Phone Call 
Phone Call 
Clinic Visit 
85 
113 
181 
209 
271 
366 
-7 to +7 
-7 to +7 
-7 to +7 
-14 to +14 
-14 to +14 
-14 to +14 
7 
8 
9 
10 
11 
12 
Study Event 
References 
 
 
Safety 
 
Assess SAEs 
Section 7.1.4 
X 
X 
X 
X 
X 
X 

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Assess AESI 
Section 7.1.4.1 
X 
X 
X 
X 
X 
X 
Assess NOCDs, medically attended 
AEs, AEs leading to withdrawal 
Sections 7.1.3 
X 
X 
X 
X 
X 
X 
Assess relevant medications 
Sections 5.1.2 and 6.5 
X 
X 
X 
X 
X 
X 
Blood draws for Immunogenicity and Exploratory Objectives 
 
Serum Blood Draw (Secondary 
Objective; 10 mL) 
Section 3.5 
 
 
X 
 
 
 
Whole Blood Draw  
(Exploratory Objectives; 50 mL) 
Section 3.5 
 
 
X 
 
 
 
Study Completion Procedures 
 
Study Terminationa 
Section 5.5 
 
 
 
 
 
X 
Notes: 
a. Subjects who terminate the study early are recommended to complete certain study-related procedures. See section 5.5 for further details. 
 

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LIST OF ABBREVIATIONS 
ADCC 
Antibody-dependent cell mediated cytotoxicity 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BZN 
Benzonaphthyridines 
CBER 
Center for Biologics Evaluation and Research 
cDNA 
Complementary deoxyribonucleic acid   
CI 
Confidence interval 
CRF 
Case report form 
CRM197 
Cross Reacting Material 197 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
EC 
Ethics committee 
EDC 
Electronic data capture 
ELISA 
Enzyme-linked immunosorbent assay 
ELISPOT 
Enzyme-Linked ImmunoSpot 
EMA 
European Medicines Agency 
FACS 
Fluorescence-activated cell sorting 
FAS 
Full analysis set 
FDA 
Federal Drug Agency 
GCP 
Good clinical practice 
GMC 
Geometric mean concentration 
GMP 
Good manufacturing practice 

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GMT 
Geometric mean titer 
GMR 
Geometric mean ratio 
HEENT  
Head, ears, eyes, nose and throat 
HIV 
Human immunodeficiency virus 
 
HPV 
Human papillomavirus 
hSBA 
Human complement serum bactericidal assay 
ICF 
Informed consent form 
ICH 
International Committee for Harmonization 
IM 
Intramuscular 
IRB 
Institutional review board 
IV 
Intravenous 
LLQ 
Lower limit of quantification 
MenC 
Meningococcal type C 
MPL 
Monophosphoryl lipid A 
NCR 
No carbon required 
NOCD 
New Onset of Chronic Disease 
PEG 
Polyethylene glycol 
PO 
Per oral 
PP 
Per protocol 
RNA 
Ribonucleic acid (RNA 
SAE 
Serious Adverse Event 
SMIP 
Small molecule immune potentiator 
TLR 
Toll-like receptor 
VSAE 
Vaccine serious adverse event 
1.0  
BACKGROUND AND RATIONALE 
1.1  
Background 

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MenC-CRM197 Conjugate Vaccine 
Meningococcal disease worldwide is predominantly a disease of infants and young 
children. N. meningitidis serogroup B and C remain the most prevalent strains in North 
America and Europe, (Rosenstein, N. et al., 2001) and together cause more than 95% of 
reported cases of meningococcal disease in Europe (Connolly, M, et al., 1999). In Europe, 
N. meningitidis serogroup C (MenC) is one of the major serogroups causing invasive 
disease. Case fatality in Germany has ranged between 6% and 8% between 1999 and 
2006, and has remained generally consistent across the different European countries, 
varying between 6-11%, with the case fatality rate being notably higher for serogroup C 
disease than for serogroup B (European Centre for Disease Prevention and Control, 
2011). Since MenC vaccination was added to Germany’s routine schedule for children in 
2006, there has been a reported decline in MenC incidence. However, the decline was not 
as rapid when compared to other European countries (Hellenbrand, W. et al., 2013). 
The GSK Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) comprises MenC 
oligosaccharides conjugated to the protein carrier, CRM197, a nontoxic mutant of 
diphtheria toxin. The vaccine has been shown to be safe and immunogenic and able to 
prime infants, toddlers and young children for immunological memory (see 
Meningococcal C-CRM197 Conjugate Vaccine Summary of Product Characteristics).  
In Germany, the Standing Committee on Vaccination (STIKO) of the Robert Koch  
Institute recommends a single dose of MenC conjugate vaccine in children over the age of  
12 months as part of the routine vaccination campaign (Robert Koch Institute 
Epidemiologisches Bulletin, August 2013). For specific indications, e.g. in case of 
postexposure prophylaxis, the recommended schedule for primary immunization of 
infants between 2 to 12 months of age with a MenC conjugate vaccine is two dosages 
given with an interval of at least 2 months. 
Although the Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) represents an 
example of how vaccination with a well characterized, purified polysaccharide antigen 
can yield pivotal public health triumphs, there remains a need for further improvement of 
the MenC vaccine. A more potent MenC vaccine formulation might yield an increase in 
the magnitude of the antigen-specific immune response enabling a reduction of the 
antigen dosage. Furthermore, induction of a more rapid antigen-specific immune response 
may enable a reduction in the number of doses needed for post-exposure prophylaxis in 
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Vaccine Adjuvants 
Immunization with purified protein or polysaccharide antigens typically results in the 
induction of a modest antibody response with little or no T cell response when compared 
to vaccines comprised of whole or killed bacteria or viruses that have inherent 
immunepotentiating activity. The need to increase the immunogenic response of 
wellcharacterized and purified antigens that display suboptimal immunogenicity when 
used alone affirms the essential role for the use of adjuvants. Vaccine adjuvants may 
significantly reduce the amount of antigen needed (Del Giudice, G, et al., 2013) and may 
induce a more rapid immune response enabling a reduction in the number of doses in a 
regimen. 
Besides reducing the antigen dosage or number of doses in the vaccine regimen, there is 
now an increased appreciation of the capacity of adjuvants to increase not just overall 
antibody titer but also to increase the number of functional antibodies and/or antibodies 
with higher affinity for vaccine antigens. Many pathogens, such as influenza viruses, 
HIV, human papilloma virus (HPV) and the malaria parasite, display substantial antigenic 
drift, subtype and/or strain variations. Therefore, the ability of adjuvants to broaden an 
immune response profile could be crucial to the success of vaccines against such targets. 
Previous studies have shown that the broadening effect of adjuvants may be mediated via 
expansion of B cell diversity, not merely through increased titers (Khurana, et al., 2010, 
2011). Clinically, antibody response broadening by adjuvants such as AS04 or oil-inwater 
emulsions has been demonstrated in HPV vaccines and influenza, respectively (Bissett, 
SL et al., 2014; Del Giudice, G et al., 2013). 
One unmet need is the development of vaccines for effective T cell responses. Several 
vaccines in development are aimed at eliciting T cell responses, which historically have 
not been induced by the most commonly used adjuvants in vaccines for human use, such 
as aluminium hydroxide. Therefore, an objective of many adjuvant discovery and 
development programs is to elicit more effective engagement of T-helper cells for 
optimizing the quality, breadth and durability of antibody responses, or, to induce effector 
CD4+ or CD8+ T cells to kill intracellular pathogens. One approach for new generation 
vaccines is the use of agonists for Toll-like receptors (TLRs) that activate innate immune 
receptors, mainly on antigen presenting cells, and facilitate the generation of T helper cell 
responses. 
Adjuvants that are currently employed in human vaccines licensed for use in the USA 
and/or Europe include aluminium salts, oil-in-water emulsions (MF59, AS03 and AF03), 
virosomes, and AS04 (Alving, CR, et al., 2012). Among the most advanced adjuvants 
systems is AS04 which is used in the Cervarix® HPV vaccine and consist of the TLR4 

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ligand monophosphoryl lipid A (MPL) combined with aluminium salt. MPL, along with 
QS21, is also part of the adjuvant system (AS01) in the RTS, S malaria vaccine which has 
been evaluated in a Phase 3 clinical trial (Regules, JA, et al., 2011). Another clinically 
advanced adjuvant is CpG oligodeoxynucleotide (ODN), a TLR9 ligand contained in the 
Heplisav® vaccine candidate for hepatitis B from Dynavax, that has completed a Phase 3 
clinical trial (Reed, SG, et al., 2013). 
Small molecule immune potentiators as a new class of vaccine adjuvants 
A new class of adjuvants, small molecule immune potentiators (SMIPs), has been 
identified that activate immune cells by targeting TLR7 and TLR8. Imiquimod and 
Resiquimod (R848) are clinically advanced TLR7 and/or TLR8 SMIPs that are used as 
immunotherapeutics. Although Imiquimod and Resiquimod have been studied extensively 
as vaccine adjuvants in preclinical models (Vasilakos et al. 2013), they were never 
optimized for this use and, in general, compare poorly to other pre-clinical and clinical 
adjuvant candidates. Furthermore, when Imiquimod is applied topically (it is a licensed 
topical treatment for viral and malignant skin lesions) it induces strong local and systemic 
inflammatory reactions, and is poorly tolerated (Bauza, et al. 2009; Campanelli, et al. 
2005; Meyer, et al. 2008). 
Unlike traditional drugs, TLR7 SMIPs activate innate immunity and initiate a cascade of 
immune responses that can have systemic impact and endure after the compound has been 
cleared from the organism. For SMIPs as vaccine adjuvants this difference is highlighted 
further by the fact that 2-3 local IM injections drive antigen-specific B and T cell 
responses at distal sites and these can provide protection in the form of immunologic 
memory (Tacken,  et al. 2011; Ilyinskii, et al., 2014). Therefore, limiting the systemic 
exposure of the SMIP adjuvants has been postulated as an approach to both increase 
vaccine efficacy and minimize side effects associated with systemic and generalized 
inflammation. GSK is currently developing a novel adjuvant, containing a SMIP from the 
benzonaphthryridines (BZN) series, LHD153, which targets TLR7. The objective driving 
the discovery of this new TLR7 ligand was to develop a vaccine adjuvant with high 
efficacy in increasing the vaccine specific immune response and with minimal side 
effects. To obtain this objective it was postulated that the ideal compound would remain 
localized at the site of injection to help trigger the immune reaction to vaccine antigens, 
yet maintain a low systemic distribution. At the same time this compound had to be 
soluble to make industrial scale-up and manufacturing feasible. Soluble BZN were 
engineered so that they could be formulated with aluminium salts with the aim of limiting 
their systemic exposure and keeping them localized in the muscle for short time after 
immunization. The strongest adsorption to aluminium hydroxide particles is obtained 
through ligand exchange of hydroxyl and/or phosphate groups on the surface of 
aluminium hydroxide or phosphate with soft anionic moieties such as phosphates, 

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phosphonates, phosphites, sulfates and carboxylates. To drive the adsorption to 
aluminium hydroxide through ligand exchange, LHD153 was functionalized with a 
polyethylene glycol (PEG) linker and a terminal phosphonate. Furthermore, LHD153 was 
stabilized with arginine salt to allow scale up for GMP manufacturing, yielding 
LHD153R. As predicted, unformulated LHD153R exhibited high levels of systemic 
exposure when injected IM in mice, rats and dogs, whereas the serum concentrations of 
LHD153R adsorbed to aluminium hydroxide (Aluminium Hydroxide/LHD153R) was 
dramatically reduced. Moreover, Aluminium Hydroxide/LHD153R remained localized to 
the injection site. 
Preclinical studies using Aluminium Hydroxide/LHD153R to date confirm the activation 
of the TLR7 pathway and subsequent boost of both the humoral and cellular immune 
response. Moreover, Aluminium Hydroxide/LHD153R displays a unique 
pharmacokinetic profile as demonstrated by its minimal systemic exposure, potentially 
minimizing any systemic inflammatory response associated with tolerability issues. 
Aluminium hydroxide/LHD153R has achieved proof of concept in animal models using 
several vaccine antigens including MenC, MenB, rabies, HIV and respiratory syncytial 
virus (RSV). In vitro toxicity of LDH153R has been assessed, and in vivo nonclinical 
tolerability and safety of LHD153R and Aluminium Hydroxide/LHD153R have been 
evaluated in rats, dogs and non-human primates. LHD153R was not phototoxic, genotoxic 
or mutagenic (Ames and chromosomal aberration tests), and did not cause local or 
systemic toxicity in dogs or rats. Furthermore, Aluminium Hydroxide/LHD153R was well 
tolerated in rhesus monkeys. 
1.2  
Rationale 
The aim of this study is to assess the safety of Aluminium Hydroxide/LHD153R 
adjuvanted MenC-CRM197 conjugate vaccine (MenC-CRM197/Aluminium  
Hydroxide/LHD153R) and to compare the antibody-mediated immune response elicited 
by MenC-CRM197/Aluminium Hydroxide/LHD153R with the licensed aluminium 
hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®). 
Furthermore, a comprehensive set of exploratory objectives has been selected to assess 
the systemic exposure of LHD153 after intramuscular injection and to evaluate the quality 
of the specific immune response against MenC-CRM197 in detail and to evaluate 
biomarkers that may be predictive of safety and/or innate immune activation. 
The licensed Meningococcal C-CRM197 Conjugate Vaccine (Menjugate®) has been 
chosen as the primary vaccine candidate to assess the safety and immunopotentiating 
properties of Aluminium Hydroxide/LHD153R for several reasons. Firstly, the safety and 

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immunogenicity profiles of the Meningococcal C-CRM197 Conjugate Vaccine have been 
well established through years of commercial use. Secondly, a more potent 
Meningococcal C-CRM197 Conjugate Vaccine might enable a reduction of the antigen 
dosage or the number of doses needed in infants between 2 and 12 months of age. Finally, 
Meningococcal C-CRM197 is a well-characterized, single conjugate antigen preparation 
which provides an ideal setting to explore the potential of this new Aluminium 
Hydroxide/LHD153R adjuvant. 
2.0  
OBJECTIVES 
2.1  
Primary Objectives 
Primary Safety Objective 
To assess the safety of MenC-CRM197/Aluminium Hydroxide/LHD153R as compared to 
that of aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. 
Primary Immunogenicity Objective 
To compare the antibody responses of MenC-CRM197/Aluminium Hydroxide/LHD153R 
and aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at 
Day 29, as measured by human complement serum bactericidal assay (hSBA) directed 
against MenC. 
2.2  
Secondary Objectives 
Secondary Immunogenicity Objective(s) 
1. To compare the antibody responses of MenC-CRM197/Aluminium  
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal CCRM197 
Conjugate Vaccine at Day 8 and Day 181 after vaccination, as measured by hSBA 
directed against MenC. Baseline antibody titers will also be measured by hSBA. 
2. To compare the antibody responses of MenC-CRM197/Aluminium 
Hydroxide/LHD153R and aluminium hydroxide adjuvanted Meningococcal CCRM197 
Conjugate Vaccine, at Day 8, Day 29 and Day 181 after vaccination, as measured by 
an enzyme-linked immunosorbent assay (ELISA) to MenC. Baseline antibody 
concentrations will also be measured by ELISA. 
2.3  
Exploratory Objectives 

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1. To evaluate the systemic exposure of LHD153 at several early time-points after IM 
injection of MenC-CRM197/Aluminium Hydroxide/LHD153R or Meningococcal 
CCRM197 Conjugate Vaccine. 
2. To explore the frequency of B cells specific for MenC polysaccharide and CRM197 
protein at baseline (Day 1) and at Day 8, Day 29 and Day 181 after vaccination with 
MenC-CRM197/Aluminium Hydroxide/LHD153R or the aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. Subsequently, the B cell 
repertoire of the antigen specific B cells will be analyzed in a selected subset of 
subjects. 
3. To explore the baseline T cell mediated immunity to CRM197 and to evaluate the 
frequency and quality of CRM197 specific T cells induced by 
MenCCRM197/Aluminium Hydroxide/ LHD153R compared to aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine at Day 8 and Day 29. 
4. To evaluate biomarkers that may be predictive for safety and/or innate immune 
activation. 
5. To explore the biophysical and functional characteristics of antibodies induced by 
MenC-CRM197/Aluminium Hydroxide/LHD153R or aluminium hydroxide 
adjuvanted Meningococcal C-CRM197 Conjugate Vaccine. (Amended: 19 June 
2017) 
 

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3.0 
STUDY DESIGN 
3.1 
Overview of Study Design 
This is a Phase 1, randomized, observer blind, adjuvant dosage-escalation study. It will be 
performed at a single center. In total, approximately 80 healthy male and healthy 
nonpregnant female adults (18-45 years of age) will be enrolled in the study. 
Subjects will be randomized to receive a single IM vaccination of either the licensed 
aluminium hydroxide adjuvanted Meningococcal C-CRM197 Conjugate Vaccine 
(Menjugate®) or the investigational vaccine, MenC-CRM197/Aluminium 
Hydroxide/LHD153R. 
The dosage of LHD153R will be escalated from 12.5 µg to 100 µg.  For the 
dosageescalation of LHD153R, the subjects will be enrolled into 1 of 4 cohorts, in a 
stepwise manner with 20 subjects per cohort. Subjects in all cohorts will be randomized in 
a 1:4 ratio, to receive either aluminium hydroxide adjuvanted Meningococcal C-CRM197 
Conjugate Vaccine (control) or MenC-CRM197/Aluminium Hydroxide/LHD153R with 
increasing doses of LHD153R. Subjects assigned to MenC-CRM197/Aluminium 
Hydroxide/LHD153R in Cohort 1 will receive 12.5 μg of LHD153R; Subjects in Cohort 2 
will receive 25 μg of LHD153R; Subjects in Cohort 3 will receive 50 μg of LHD153R; 
Subjects in Cohort 4 will receive 100 μg of LHD153R (Table 3.1-1). 
Table 3.1-1: Subjects Randomized per Cohort and Treatment Dosage Group 
Cohort 
Group 
Subjects/ 
Group 
MenC 
Dosage* 
(µg) 
Adjuvant Dosages 
Total 
Volume/Dose 
Total 
Subjects/Cohort 
Aluminium  
Hydroxide  
(mg) 
LHD153R  
(µg) 
1 
A 
4 
10 
1 
0 
0.5 mL 
20 
 
 
 
 
 
 
 
B 
16 
10 
1 
12.5 
0.5 mL 
 
2 
A 
4 
10 
1 
0 
0.5 mL 
20 
C 
16 
10 
1 
25 
0.5 mL 
3 
A 
4 
10 
1 
0 
0.5 mL 
20 
D 
16 
10 
1 
50 
0.5 mL 
4 
A 
4 
10 
1 
0 
0.5 mL 
20 
E 
16 
10 
1 
100 
0.5 mL 
*Conjugated to 12.5-25 µg CRM197 
All cohorts will have a staggered entry. For each cohort, the first 5 subjects (i.e. the first  
1:4 randomization block) to receive either aluminium hydroxide adjuvanted  

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Meningococcal C-CRM197 Conjugate Vaccine (n=1) or MenC-CRM197/Aluminium 
Hydroxide/LHD153R (n=4) will be vaccinated at rate of 1 subject each day. 
After entry of the first 5 subjects in each cohort, the enrollment will be paused. The 
remaining 15 subjects for each cohort will be enrolled only after DMC review of the 
safety results obtained through Day 14 has been finalized (Table 3.1-2). In addition, 
enrollment of the first 5 subjects of the next cohort will only proceed after the Day 14 
safety results of the first 5 subjects of the previous cohort have been reviewed by the 
DMC. Furthermore, all available Day 14 and Day 29 safety results will be included in 
DMC review between the different enrollment stages. 
Table 3.1-2: Overview of staggered entry of subjects based on DMC reviews 
Stage 
Dosage Cohort 
MenC-CRM197/ 
Aluminium Hydroxide (n) 
MenC-CRM197/ 
Aluminium Hydroxide 
/LHD153R (n) 
1   
1  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 14 Safety Results 
2 
1  
3 
12 
2  
1 
4 
Enrollment pause until DMC review of Stage 1 Day 29 and Stage 2 Day 14 Safety Results 
3 
2  
3 
12 
3  
1 
4 
Enrollment pause until DMC review of Stage 2 Day 29 and Stage 3 Day 14 Safety Results 
4 
3  
3 
12 
4  
1 
4 
Enrollment pause until DMC review of Stage 3 Day 29 and Stage 4 Day 14 Safety Results 
5 
4  
3 
12 
Post-vaccination procedures include collection of urine specimens at Day 1, Day 8 and 
Day 29 for safety assessment and blood specimens at Day 1, Day 8, Day 29 and Day 181 
for safety assessment and evaluation of the primary and secondary immunogenicity 
endpoints. Furthermore, additional blood specimens will be collected for assessment of 
exploratory endpoints at Day 1, Day 4, Day 8, Day 29 and Day 181 from those subjects 
that signed an additional informed consent concerning blood collection for exploratory 
assessment. 
3.2  
Study Period 

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Each subject should expect to participate in the study for approximately 12 months, from 
the time of enrolment through the last study visit. 
3.3  
Blinding Procedures 
This study is designed as an observer-blind study. For each dosage cohort, subjects, 
investigators, laboratories and the sponsor will be blinded to vaccine assignments. 
To maintain the blindness within each cohort, designated nurse(s) or physician(s) will be 
responsible for administering the study vaccines to the subjects, and will be instructed not 
to reveal the identity of the study vaccines neither to the subject nor to the investigative 
site personnel (investigator, study nurse, monitor) involved in the conduct or monitoring 
of the trial. This (these) designated individual(s) will have no contact with the subjects 
after the administration of the study vaccine. Furthermore, unblinded monitors are 
assigned to reconcile actual vaccine treatment. 
Study unblinding, at the group level, is planned for an Interim Analysis of the safety and 
immunogenicity data obtained up to Day 29 after all cohorts are enrolled and for full 
unblinding at the End of Study. 
Except in the case of medical necessity, a subject’s treatment should not be unblinded 
without the approval of the Sponsor. In such instance of medical emergency, every effort 
should be made to contact the Sponsor prior to unblinding. If unblinding should occur (by 
either accidental unblinding or emergency unblinding for a serious adverse event) prior to 
completion of the study, the investigator must promptly contact the Sponsor and 
document the circumstances on the appropriate forms. 
Emergency unblinding 
Emergency unblinding should only be undertaken when it is essential for effective 
treatment of the subject. The investigator will receive a blinded code break envelope for 
each subject, with the details of drug treatment included. Emergency code break 
envelopes must be stored in a secure place but be accessible in case of emergency. In an 
emergency, the envelope can be opened to determine the treatment. The envelope is not to 
be opened for any reason other than an emergency. When the investigator opens the 
envelope he/she must note the date, time, and reason for opening it and retain this 
information with the case report form documentation. The unblinded treatment code 
should not be recorded in the case report form. 
It is the investigator’s responsibility to ensure that there is a procedure in place to allow 
access to the code break envelope in case of emergency. The investigator must provide 

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the subject with an emergency card to contact the clinical unit in cases of emergency and 
will inform the subject how to contact his/her backup in cases of emergency when he/she 
is unavailable. Subjects may continue the study after unblinding for safety follow-up. 
For emergency unblinding, the corresponding Parexel standard operating procedure 
should be followed: 
 Annotate, sign and date the code break envelope. 
 Immediately inform Sponsor. 
 Complete the Randomization Code Break Form. 
 File the Randomization Code Break Form and the annotated envelope with the 
participant’s source documents. 
 Provide the Sponsor as soon as feasible, with a copy of the completed Randomization 
Code Break Form. 
3.4  
Data Collection 
3.4.1 
Data Collected from Subjects 
The following data will be collected from each subject over the duration of their study 
participation: 
▫ Demographic Information 
▫ Adverse Events 
▫ Medical History 
▫ Concomitant Medications 
▫ Vital signs 
All data collected must only be identified using the Subject ID, as described in section 
5.2.3. 
3.4.2 
Tools Used for Data Collection 
Data will be recorded in the Subject Diary and collected on Case Report Forms (CRFs). 
Subject Diary 
Subject Diaries will be the only source document allowed for solicited local and systemic 
adverse events (including body temperature measurements), starting after the initial 24 

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hours post-vaccination observation period at the clinic. The following additional rules 
apply to documentation of safety information collected in the Subject Diary: 
1. No corrections or additions to the Subject Diary will be allowed after it is delivered to 
the site. 
2. Any blank or illegible fields on the Subject Diary must be described as missing in the  
CRF. 
3. Any corrections to the Subject Diary must be performed by the person completing the 
Subject Diary and should include a single strike through line through the incorrect 
value or text with a brief explanation for each change, the initials of that person, and 
date of correction. 
Case Report Forms 
This study utilizes CRFs to collect study-related data from each subject. A qualified site 
staff member(s) is required to enter subject data in the CRFs based on the medical 
information available in each subject’s record. The following additional rules apply to 
documentation of Subject Diary information collected in the CRFs: 
1. The site must enter all readable entries in the Subject Diary into the CRF, including 
those values that may be biologically implausible (e.g. body temperature: 400°C). 
2. Any illegible or implausible data should be reviewed with the subject. If an 
underlying solicited or unsolicited adverse event is described on review with the 
subject, this should be described in the source document and reported as an 
unsolicited adverse event in the appropriate CRF (e.g., if the subject above confirms 
body temperature of 40°C on the day in which body temperature: 400°C was written 
into his/her Subject Diary, this fever of 40°C should be recorded in the appropriate 
CRF). 
3. Any newly described safety information (including a solicited adverse event) must not 
be written into the Subject Diary and must be described in the study file as a verbally 
reported adverse event. Any adverse event reported in this fashion must be described 
as an unsolicited adverse event and therefore, entered in the appropriate CRF. 
Data should be entered into the CRF in a timely fashion following each subject’s clinic 
visit, study procedure, or phone call. Each subject’s CRF casebook will be compared with 
the subject’s source records by a GSK-approved study monitor (or designee) over the 
duration of the study in order to ensure data collection accuracy. 

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3.5  
Collection of Clinical Specimens 
The following clinical specimens are required to be collected from each subject in this 
study: 
▫ Blood 
▫ Urine 
Processing of each specimen should be completed by a qualified site member. Testing of 
clinical specimens will be performed by a GSK or designated laboratory. 
Blood Specimens 
Before Vaccination 
▫ At the Pre-vaccination Screening Visit (between Day -28 to -3) one sample of 
approximately 10 ml blood will be drawn from all subjects. 
▫ At Visit 1 (Day 1) - prior to vaccination – two samples of approximately 10 ml blood 
will be drawn from all subjects. 
▫ At Visit 1 (Day 1) - prior to vaccination - the following blood samples will be drawn 
from subjects that gave additional informed consent for blood collection for 
exploratory assays: 
- 
One sample of approximately 3 ml 
- 
Two samples of approximately 5 ml 
- 
One sample of approximately 70 ml 
After Vaccination 
▫ At Visit 1 (Day 1) - 1 hour after vaccination - one sample of approximately 3 ml blood 
will be drawn from subjects that gave additional informed consent for blood collection 
for exploratory assays. 
▫ At Visit 1 (Day 1) - 2 hours after vaccination - one sample of approximately 3 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 4 hours after vaccination - one sample of approximately 3 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 

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▫ At Visit 1 (Day 1) - 6 hours after vaccination – two samples of approximately 5 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 8 hours after vaccination - one sample of approximately 3 ml 
blood will be drawn from subjects that gave additional informed consent for blood 
collection for exploratory assays. 
▫ At Visit 1 (Day 1) - 24 hours after vaccination - one sample of approximately 10 ml 
blood will be drawn from all subjects. 
▫ At Visit 1 (Day 1) - 24 hours after vaccination - the following blood samples will be 
drawn from subjects that gave additional informed consent for blood collection for 
exploratory assays: 
- 
One sample of approximately 3 ml 
- 
Two samples of  approximately 5 ml 
- 
One sample of approximately 20 ml 
▫ At Visit 2 (Day 4) the following blood samples will be drawn from subjects that gave 
additional informed consent for blood collection for exploratory assays: 
- 
One sample of  approximately 3 ml 
- 
Two samples of  approximately 5 ml 
- 
One sample of approximately 20 ml 
▫ At Visit 3 (Day 8) two samples of approximately 10 ml blood will be drawn from all 
subjects. 
▫ At Visit 3 (Day 8) the following blood samples will be drawn from subjects that gave 
additional informed consent for blood collection for exploratory assays 
- 
Two samples of approximately 5 ml 
- 
One sample of approximately 70 ml 
▫ At Visit 6 (Day 29) two samples of approximately 10 ml blood will be drawn from all 
subjects. 
▫ At Visit 6 (Day 29) one sample of approximately 50 ml blood will be drawn from 
subjects that gave additional informed consent for blood collection for exploratory 
assays. 

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▫ At Visit 9 (Day 181) one sample of approximately 10 ml blood will be drawn from all 
subjects. 
▫ At Visit 9 (Day 181) one sample of approximately 50 ml blood will be drawn from 
subjects that gave additional informed consent for blood collection for exploratory 
assays. 
The blood will be used for screening and safety laboratory assessments, immunological 
serology assays, pharmacokinetic analysis, cell mediated immunity assays and gene 
expression and protein production assays. See section 5.1.2, section 5.2.1 and section 7.0 
for additional details. 
Processing of each blood specimen should be completed in accordance with the study 
specific Clinical Specimen Laboratory Manual. 
The total amount of blood collected over the study period for all subjects will be 
approximately 90 ml. 
For subjects that signed an additional informed consent for blood collection for 
exploratory assays the total amount of blood collected over the study period will be 
approximately 441 ml. 
Urine Specimens 
Urine will be collected at the Pre-vaccination Screening Visit (between Day -28- to -3), at 
Visit 1 (Day 1; before vaccination and 24 hours after vaccination), at Visit 3 (Day 8) and 
at Visit 6 (Day 29). Results will be recorded in the source document and CRF. 
Urine will be collected from all subjects for safety laboratory assessments and drugs-
ofabuse testing. Furthermore, urine will be collected for pregnancy testing in all females. 
3.6  
Stopping/Pausing Guidelines 
Stopping/pausing guidelines are predefined criteria that halt the conduct of a study (either 
a vaccine group or the entire study). These guidelines are used to ensure the safety of study 
subjects.  
The following criteria, based on FDA guidance and with grading scales adapted from the 
CBER Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive vaccine Clinical Trials”, will be used for this study: 

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1. The study will be halted (no new enrollments and no further investigational product 
administered) and a full safety review by the DMC and the IRB/EC will be performed 
if one of the following occurs. 
a. One subject experiences a serious adverse event (SAE) assessed as possibly or 
probably related to investigational product or, 
b. There is a subject death assessed as possibly or probably related to the 
investigational product. 
2. The safety data will also be provided to the health authorities and potential restart of 
the study will require authorization from IRB/EC and health authorities.If one or more 
subjects experience a Grade 4 AE (see Appendix C, D, E and F for grading scales), 
vital sign or clinically significant laboratory abnormality that cannot be clearly 
attributed to another cause, vaccination will be suspended and a full safety review by 
the DMC and the IRB/EC will be performed. Potential continuation of the study will 
require authorization from IRB/EC. 
3. If six or more subjects experience a Grade 3 AE (see Appendix A, B, C, D, E and F 
for grading scales), vital sign or clinically significant laboratory abnormality, dosage 
escalation will be suspended for that vaccine and  a full safety review by the DMC 
and the IRB/EC will be performed. Potential continuation of the study will require 
authorization from IRB/EC. 
The sponsor or the investigator (following consultation with the sponsor) has the right to 
discontinue the study at any time. If the clinical study is prematurely terminated, the 
investigator must promptly inform the study subjects and must assure appropriate therapy 
and follow-up for the subjects. All procedures and requirements pertaining to the 
archiving of the documents must be followed.  All other study materials (such as study 
vaccines) must be returned to the sponsor or destroyed after sponsor approval. 
3.7  
Data Monitoring Committee 
An independent DMC will be formed to review safety data during scheduled periodic 
reviews. The DMC may also perform reviews on an ad hoc basis as needed. DMC 
membership will consist of at least 3 individuals who are external to the site and sponsor, 
and will include 1 statistician who is independent from the study team. The names of the 
independent DMC members are mentioned in the DMC charter. 
Subjects will be enrolled in a stepwise manner in each of the four vaccine dosage cohorts  
(Cohort 1: 12.5 μg LHD153R, Cohort 2: 25 μg of LHD153R, Cohort 3: 50 μg of  
LHD153R and Cohort 4: 100 μg of LHD153R). The DMC will review all safety data, as 
described in the DMC charter and in the Statistical Analysis Plan, after the first 5 subjects 

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in each cohort have completed Visit 4 and their data are available for analysis, and before 
enrollment of the remaining subjects in the respective cohort and before enrollment of the 
first 5 subjects in the subsequent cohort. In addition, in between the different enrollment 
stages, the DMC will review all available safety data of subjects that have completed 
Visit 4 and all available safety data of subjects that have completed Visit 6. 
The specific roles and responsibilities of the DMC members and other personnel involved 
will be documented in the DMC charter. The DMC charter will be finalized before the 
start of the study and will outline in detail all pausing and stopping rules according to the 
Clinical Study Protocol. 
3.8  
Premature Withdrawal from Study 
Subjects may withdraw at any time, or be dropped from the study at the discretion of the 
investigator should any untoward effects occur and/or for safety reasons. In addition, a 
subject may be withdrawn by the investigator or the Sponsor if he/she violates the study 
plan or for administrative reasons. The investigator or study coordinator must notify the 
Sponsor immediately when a subject has been withdrawn due to an adverse event. 
The circumstances above are referred to as premature withdrawal from the study, and the 
reason for premature withdrawal should be clearly documented and detailed in the source 
documentation. The investigator should make every attempt to evaluate the subject’s 
safety, including resolution of ongoing AEs, at the time of premature withdrawal. If a 
subject wants to withdraw from the study prior to the last planned study visit, the subject 
will be asked to be followed for safety for the duration of the study. When a subject 
withdraws, or is withdrawn, from the study, the procedures described in section 5.5.1 
should be completed if possible. 
The reasons for premature withdrawal from the study include: Adverse event, death, 
withdrawal of consent, lost to follow-up, administrative reason, and protocol deviation. 
These reasons are described in greater detail below. 
Adverse Event 
For any subject withdrawn from study participation prior to the planned Study  
Termination Visit, it is important to determine if an AE was associated with the reason for 
discontinuing the study. This AE must be identified on the appropriate CRF page by 
indicating “Withdrawn from study due to AE”. Any ongoing AEs at the time of study 
withdrawal must be followed until resolution or stabilization. 
Death 

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For any subject withdrawn from study participation due to death, this should be noted on 
the appropriate CRF page and the associated SAE that led to the death must be reported. 
Withdrawal of consent 
The subject can withdraw consent for participation in the study at any time without 
penalty or loss of benefit to which the subject is otherwise entitled. Reason for early 
termination should be deemed as “withdrawal of consent” if the subject withdraws from 
participation due to a non-medical reason (i.e., reason other than AE). If the subject 
intends to withdraw consent from the study, the investigator should clarify if the subject 
will withdraw completely from the study or if the subject will continue study participation 
for safety, or a subset of other study procedures. If the subject requests complete 
withdrawal from the study, no further study interventions will be performed with the 
subject. 
Lost to Follow-Up 
For subjects who fail to show up for study visits (clinic or telephone contacts), study staff 
is encouraged to make at least three documented attempts to contact the subject by 
telephone and at least one documented written attempt to contact the subject to encourage 
the completion of study termination procedures. These efforts to contact the subject must 
be recorded in the source document. The termination date for the subject to be captured 
on the appropriate CRF page is the date of the last contact (clinic visit or telephone) with 
the subject. 
Administrative Reason 
Examples for subjects withdrawn from the study due to administrative reason can include: 
Sponsor decision to terminate the study, subject meeting a pre-specified withdrawal 
criterion, subject discontinuation for insurance issues, moving, no time, etc. This reason 
should be noted in the appropriate CRF page and any ongoing AEs at the time of study 
withdrawal must be followed until resolution/stabilization. 
If the clinical study is prematurely terminated by the Sponsor, the investigator is to 
promptly inform the study subjects and local EC/IRB and should assure appropriate 
therapy and follow up for the subjects. All procedures and requirements pertaining to the 
archiving of study documents should be followed. All other study materials (study 
medication/vaccines, etc.) must be returned to the Sponsor. 

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For subjects who are withdrawn from the study due to receipt of an excluded 
medication/vaccination or due to significant protocol non-compliance, this reason should 
be noted in the appropriate CRF page. 
Protocol Deviation 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. In general, subjects associated with protocol deviations 
may remain in the study unless continuation in the study jeopardizes the subject’s health, 
safety, or rights. 
Investigators will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact GSK or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are 
permitted. If the investigator feels a change to the protocol would improve the conduct of 
the study this must be considered a protocol amendment, and unless such an amendment 
is agreed upon by GSK and approved by the IRB/EC and health authorities it cannot be 
implemented. 
Any subject who becomes pregnant during the study should be encouraged to continue 
participating in the study for safety follow-up. The site must complete a Pregnancy Report 
CRF (initial report) as soon as possible after learning of pregnancy occurrence (see 
section 7.1.6 for further details). If the subject withdraws from the study for any of the 
above categories except death, the site will obtain permission from the subject to continue 
to remain in contact with her until the outcome of the pregnancy is known, even if the 
outcome is not known until after the subject reaches the end of the routine study period. 
3.9  
End of Study 
Most clinical trials intended to support the efficacy/immunogenicity and safety of an 
Investigational Product proceed to full completion of planned sample size accrual. 
A subject is considered to have completed this study when he/she has: (1) received the 
intended dose of study vaccine and (2) completed 365 days (Visit 12) of safety follow-up 
after receiving the study vaccine. 
Evaluation of the primary and secondary immunogenicity objectives requires the testing 
of biological samples from all study subjects, which can only be completed after all 
samples are collected. The last samples for the analysis of the primary and/or secondary 
objectives will be taken at Visit 9 (Day 181). For the purpose of this protocol, End of 

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Study is defined as the completion of the testing of such biological samples, to be 
achieved no later than 8 months after collection of the last biological sample at Visit 9. 

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4.0  
SELECTION OF STUDY POPULATION 
4.1  
Inclusion Criteria 
In order to participate in this study, all subjects must meet all of the inclusion criteria 
described. 
1. Male or female individuals of 18 through 45 years of age on the day of informed 
consent. 
2. Healthy volunteers with good physical and mental health status, determined on the 
basis of the medical history, a physical examination and the results of the screening 
tests as judged by the investigator. 
3. Individuals who have voluntarily given written informed consent after the nature of 
the study has been explained according to local regulatory requirements, prior to study 
entry. 
4. Individuals who can comply with study procedures including follow-up1. 
5. Individuals that are able to understand, read and write German language. 
6. Females of childbearing potential who are using an effective birth control method2 
which they intend to use for at least 30 days after the study vaccination. 
4.2  
Exclusion Criteria 
Each subject must not have or must not be: 
1. Progressive, unstable or uncontrolled clinical conditions. 
2. Hypersensitivity, including allergy, to any component of vaccines, medicinal products 
or medical equipment whose use is foreseen in this study. 
                                                 
1 A subject is considered to be compliant if the Investigator judges that the subject will complete the Subject 
Diary, return for all the follow-up visits and be available for telephone calls as scheduled in the study. 
2 The following birth control methods are considered effective: 
- 
Hormonal contraceptive (such as oral, injection, transdermal patch, implant) if used for at least 30 
days prior to informed consent 
- 
Diaphragm with spermicide, tubal occlusion device 
- 
Intrauterine device (IUD) 

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- 
Tubal ligation 
- 
Male partner using condom with spermicide 
- 
Male partner having been vasectomized at least six months prior to informed consent 
3. Clinical conditions representing a contraindication to intramuscular vaccination and 
blood draws. 
4. Abnormal function of the immune system resulting from: 
a. Clinical conditions. 
b. Systemic administration of corticosteroids (PO/IV/IM) for more than 14 
consecutive days within 90 days prior to informed consent. 
c. Administration of antineoplastic and prescription immunomodulating agents or 
radiotherapy within 90 days prior to informed consent. 
5. Received immunoglobulins or any blood products within 180 days prior to informed 
consent. 
6. Received an investigational or non-registered medicinal product within 30 days prior 
to informed consent or intend to participate in another clinical study at any time 
during the conduct of this study. 
7. Vulnerable subjects (e.g. persons kept in detention), study personnel or an immediate 
family or household member of study personnel, subjects with legal incapacity or 
limited legal capacity 
8. Any relevant deviation from the laboratory parameters at screening as judged by the 
investigator. 
9. Previously received any vaccine that included a MenC antigen. 
10. Previously suspected or confirmed disease caused by N. meningitides. 
11. Had household contact with and/or intimate exposure to an individual with culture 
proven MenC. 
12. A positive serum or urine pregnancy test prior to the study vaccine administration or 
are currently lactating. 
13. A positive drugs-of-abuse test prior to the study vaccine administration 
14. Received any other vaccines within 30 days prior to enrolment in this study or who 
are planning to receive any vaccine within 30 days from the administration of study 
vaccines. 

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15. Any other condition that, in the opinion of the investigator, might interfere with the 
results of the study or pose additional risk to the subject due to participation in the 
study. 
4.3  
Criteria for Delay of Vaccination or Blood Draw 
There may be instances when individuals meet all eligibility criteria for vaccination or 
blood draw yet have a transient clinical circumstance which may warrant delay of 
vaccination or blood draw. Under such circumstances, a subject may be considered 
eligible for study enrolment after the appropriate window for delay has passed and 
inclusion/exclusion criteria have been rechecked, and if the subject is confirmed to be 
eligible. 
Reasons for delay of vaccination include: 
▫ Body temperature elevation ≥38.0°C (measured orally) within 3 days prior to intended 
study vaccination. 
▫ Use of antipyretics and/or analgesic medications within 24 hours prior to vaccination. 
Reasons for delay of blood draw include: 
▫ Subject has received a dose of systemic antibiotics less than 6 days before blood 
collection for the hSBA directed against MenC. 
 

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5.0  
STUDY PROCEDURES 
The sections that follow provide an overview of the procedures that are to be followed in 
enrolling, evaluating, and following subjects who participate in this clinical study. Visits 
can be either clinic visits or safety follow-up telephone calls, as specified in the Table 
below and in the Time and Events Tables 3 and 4 of the Study Synopsis. 
Table 5.0-1: Study procedures 
Visit Category 
Procedures 
Pre-vaccination Clinic Visit 
Section 5.1 describes procedures to be followed 
prior to subject enrollment, including: informed 
consent and screening procedures. 
Vaccination Clinic Visit 
Section 5.2 describes procedures to be followed 
during the vaccination clinic visit, including: 
prevaccination procedures, enrolment, 
randomization, vaccination and post-vaccination 
procedures. 
Post-vaccination Visits 
Section 5.3 describes follow-up clinic visits and 
safety follow-up calls. 
Unscheduled Visits 
Section 5.4 describes possible procedures to be 
followed at unscheduled clinic visit. 
Study Termination Visit 
Section 5.5 describes procedures to be followed at 
the last study visit for a subject (may include early 
termination visit). 
5.1 
Pre-vaccination Clinic Visit(s) 
The Pre-vaccination Clinic Visit must be performed in the period between Day -28 and 
Day -3. 
This section describes the procedures that must be performed for each potential subject 
prior to enrollment, including obtaining informed consent and screening. 
5.1.1  
Informed Consent 
"Informed consent" is the voluntary agreement of an individual or his/her legal 
guardian(s) to participate in research. Consent must be given with free will of choice, and 
without undue inducement. The individual must have sufficient knowledge and 
understanding of the nature of the proposed research, the anticipated risks and potential 
benefits, and the requirements of the research to be able to make an informed decision. 

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Informed consent following local IRB/EC guidance must be obtained before conducting 
any study-specific procedure (i.e., all of the procedures described in the protocol). Prior to 
any additional blood sample collection for exploratory objectives, a secondary informed 
consent must be signed by subjects. The process of obtaining informed consent should be 
documented in the subject source document in addition to maintaining a copy of the 
signed and dated informed consent. 
5.1.2  
Screening 
After an individual has consented to participate in the study and informed consent is 
signed, that individual will be given a unique Screening Number. The subject’s unique 
Screening Number will be documented in the Screening and Enrolment log. The 
eligibility of the subject will be determined based on the inclusion and exclusion criteria 
listed in section 4.0 and evaluated during this screening procedure. 
Screening procedures at the Pre-vaccination Clinical Visit (between Day -28 and Day -3) 
will include the following: 
▫ Review of demographic data, including age, gender, race, body weight and height. 
▫ Review of medical history, including but not limited to any medical history, ongoing 
illnesses or injuries that may be relevant to subject eligibility for study participation. 
Relevant medical history can also include any medical history that contributes to the 
understanding of an adverse event that occurs during study participation, if it 
represents an exacerbation of an underlying disease/pre-existing problem. 
▫ Perform physical examination, including but not limited to: 
- 
Assessment of general appearance 
- 
Collection of vital signs, including body temperature, blood pressure, heart rate 
and respiratory rate 
- 
Examination of head, ears, eyes, nose and throat (HEENT) 
- 
Examination of skin 
- 
Auscultation of heart and lungs 
▫ Collection and review of prior and concomitant medications or vaccinations taken 
prior to start of study (refer to section 6.5 for further details). 
▫ Collection of any unsolicited AEs occurring prior to administration of the study 
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▫ Blood draw (approximately 10 ml) for Safety Laboratory assessments, measurement of 
Hepatitis B surface antigen, anti-Hepatitis C virus antibodies, anti-HIV 1 and 2 
antibodies and serum pregnancy test (all women). 
▫ Urine sample for Safety Laboratory assessments and drugs-of-abuse testing. 
NOTE: A general physical examination is to be performed by a qualified health care 
practitioner. “Qualified health care practitioner” refers to any licensed health care 
professional who is permitted by institutional policy to perform physical examinations 
and who is identified within the Study Staff Signature Log. 
Data collected during the Pre-vaccination Screening Clinic Visit must be written in the 
source document (see section 9.1) and will be captured in the screening CRF Forms. In 
the event that the individual is determined ineligible for study participation, he/she is 
considered a screen failure. The reason for screen failure must be documented in the 
Screening and Enrolment log. 
5.2  
Vaccination Clinic Visit(s) 
This section describes the procedures to be performed at the Vaccination Clinic Visit 
(Visit 1, Day 1), including: pre-vaccination procedures, enrolment, randomization, 
prevaccination blood draw, vaccination and post-vaccination procedures. 
5.2.1  
Pre-vaccination Procedures 
During pre-vaccination procedures at Visit 1 (Day 1), the eligibility of the subject will be 
confirmed based on the inclusion and exclusion criteria listed in section 4.0. 
Pre-vaccination procedures at Visit 1 (Day 1) will include the following: 
▫ Review of systems by means of a structured interview that queries the subject as to any 
complaints the subject has experienced across each organ system. 
▫ Perform physical examination, including but not limited to: 
- 
Assessment of general appearance 
- 
Assessment of body weight and collection of vital signs, including body 
temperature, blood pressure, heart rate, and respiratory rate 
- 
Examination of head, ears, eyes, nose and throat (HEENT) 
- 
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- 
Auscultation of heart and lungs 
▫ Collection and review of prior and concomitant medications or vaccinations taken, or 
recalled, since the last visit (refer to section 6.5 for further details). 
▫ Collection of any unsolicited AEs occurring prior to administration of the study 
vaccine. 
▫ One blood sample (approximately 10 ml) will be drawn from all subjects for serology 
testing. 
▫ One blood sample (approximately 10 ml) will be drawn from all subjects for baseline 
Safety Laboratory assessments. 
▫ One urine sample for baseline Safety Laboratory assessments, pregnancy testing (all 
women) and drugs-of-abuse testing. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of blood draws are provided in section 3.5. 
NOTE: A general physical examination is to be performed by a qualified health care 
practitioner. “Qualified health care practitioner” refers to any licensed health care 
professional who is permitted by institutional policy to perform physical examinations 
and who is identified within the Study Staff Signature Log. 
Data collected during pre-vaccination procedures at Visit 1 must be written in the source 
document (see section 9.1). In the event that the individual is determined ineligible for 
study participation, he/she is considered a screen failure. The reason for screen failure 
must be documented in the Screening and Enrolment log. If the individual is determined 
to be eligible for the study, he/she can be enrolled into the study. 
5.2.2 
Enrolment 
After an individual is determined to be eligible for study participation, the investigator 
will enroll the subject into an Electronic Data Capture (EDC) system where the 
randomization to the treatment group will occur. The Screening Number ceases to be used 
and remains in the Screening and Enrolment Log only. 
If for any reason, after signing the informed consent form (ICF), the subject who is 
eligible and enrolled fails to be randomized, this is called a randomization failure. In this 
case the early termination study procedures must be applied. The reason for all 
randomization failures should be recorded in the Screening and Enrolment Log and in the 

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source document as specified in the Source Data Agreement. The information on subjects 
who are randomization failures should be kept distinct from subjects who are screen 
failures, as described in section 5.1.2 and section 5.2.1. 
5.2.3 
Randomization 
Enrolled subjects will be randomized and automatically assigned a unique Subject ID. 
The Subject ID will be the subject’s unique identification number for all CRFs and 
associated study documentation that will be used for the duration of the study. 
If for any reason, after signing the informed consent form (ICF), the eligible subject is 
enrolled and randomized but fails to undergo treatment, this is an Early Termination and 
the reason should be recorded in source document as specified in the Source Data 
Agreement/Source Data Verification Form. The information on these Early Termination 
subjects should be kept distinct in the source documentation from randomization failures, 
which are described in section 5.2.2. 
5.2.4 
Vaccination 
After completing the pre-vaccination procedures at Visit 1 (Day 1), administer the vaccine 
to the subject according to the procedures described in section 6.3. Observe the blinding 
procedures described in section 3.3. 
5.2.5 
Post-vaccination Procedures 
The following post-vaccination procedures will be performed at Visit 1 (Day 1): 
▫ After vaccination, the subject will be observed for at least 30 minutes for any 
immediate solicited and unsolicited AEs, body temperature measurement and vital 
signs at 30 min after vaccination. All safety and body temperature data collected 
during this time are to be recorded in the subject’s source document. 
▫ After vaccination, the subject will be observed for at least 24 hours at the clinic 
including observation for solicited and unsolicited AEs, body temperature 
measurements. Body temperature measurements must be performed at 2, 4, 6, 8, 10, 
12, 18 and 24 hours after vaccination and additional vital signs at 24h after 
vaccination. All safety and body temperature data collected during this time are to be 
recorded in the subject’s source. 
▫ One blood sample (approximately 10 ml) will be drawn from all subjects at 24 hours 
after vaccination for Safety Laboratory assessments. 

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▫ One urine sample will be collected from all subjects at 24 hours after vaccination for 
Safety Laboratory assessments. 
▫ From those subjects that signed an additional Informed Consent for exploratory assays, 
additional blood samples will be drawn in the first 24 hours after vaccination. Details 
regarding the number and volume of post-vaccination blood draws are provided in 
section 3.5. 
After the initial 24 hours inpatient observation period, a Subject Diary will be used in this 
study to document solicited and unsolicited AEs until Day 14. The Subject Diary is the 
only source for collection of solicited AEs after the initial 24 hours inpatient observation 
period. Therefore, it is critical that the subject completes the Subject Diary correctly. 
The following training regarding completion of the Subject Diary must be provided: 
▫ The subject should be trained on how and when to complete each field of the Subject 
Diary. 
▫ The subject should be trained on how to self-measure local solicited adverse events 
and body temperature. The measurement of solicited local adverse events is to be 
performed using the ruler provided by the site. 
▫ The subject should be instructed how to perform body temperature measurement using 
the thermometer provided by the site. If the subject feels unusually hot or cold during 
the day, the subject should check their body temperature. If the subject has fever, the 
highest body temperature observed that day should be recorded in the Subject Diary. 
Subject Diary training should be directed at the individual(s) who will perform the 
measurements of adverse events and who will enter the information into the Subject 
Diary. This individual may not be the subject, but if a person other than the subject enters 
information into the Subject Diary, this person’s identity must be documented in the 
Subject Diary. Any individual that writes in the Subject Diary must receive training on 
completion of the Diary Card at the time of the visit. This training must be documented in 
the subject’s source record. 
The site should schedule the next study activity (clinic visit) with the subject. 
The subject will receive a written reminder of the next planned study activity. The subject 
will be reminded to complete the Subject Diary and to contact the site if there are any 
questions, and to contact the site immediately (or as soon as the subject is medically 
stable) if the subject has a medical condition that leads to a hospitalization or an 
emergency room visit. 

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5.3  
Post-vaccination Visit(s) 
5.3.1  
Subject Diary Reminder, Safety Follow-up and/or Post-vaccination 
Blood Draw Clinic Visits 
Subject Diary reminder, Safety follow-up and/or post-vaccination blood draw clinic visits 
will be performed on Day 4 (Visit 2), Day 8 (Visit 3), Day 15 (Visit 4), Day 29 (Visit 6), 
Day 85 (Visit 7), Day 113 (Visit 8) and Day 181 (Visit 9) 
At Day 4 (Visit 2) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. All unsolicited AEs, SAEs, AESIs, 
medically attended AEs, AEs leading to study withdrawal and NOCD must be 
recorded on source documents. Any concomitant medications or vaccinations 
associated with those events must also be recorded on the source documents. 
▫ All subjects will be reminded to complete the Subject Diary and to contact the site if 
there are any questions, and to contact the site immediately (or as soon as the subject 
is medically stable) if the subject has a medical condition that leads to a 
hospitalization or an emergency room visit. No changes to the Subject Diary should 
be done at the clinic visit. 
▫ From those subjects who signed an additional Informed Consent for exploratory 
assays, additional blood samples will be drawn. Details regarding the number and 
volume of blood draws are provided in section 3.5. 
▫ The site should schedule the next study activity (clinic visit) with the subject and the 
subject will receive a written reminder of the next planned study activity. 
At Day 8 (Visit 3) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. The healthcare professional reviewing these data will discuss the 
symptoms (if any) reported by the subject and will determine if any additional 
diagnoses and/or adverse events are present. All unsolicited AEs, SAEs, AESIs, 
medically attended AEs, AEs leading to study withdrawal and NOCD must be 

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recorded on source documents. Any concomitant medications or vaccinations 
associated with those events must also be recorded on the source documents. 
▫ The subject will be reminded to complete the Subject Diary and to contact the site if 
there are any questions, and to contact the site immediately (or as soon as the subject 
is medically stable) if the subject has a medical condition that leads to hospitalization 
or an emergency room visit. No changes to the Subject Diary should be done at the 
clinic visit. 
▫ Blood draw (approximately 10 ml) from all subjects for Safety Laboratory 
assessments. 
▫ Urine sample from all subjects for Safety Laboratory assessments. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 

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▫ From those subjects who signed an additional Informed Consent for exploratory 
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volume of blood draws are provided in section 3.5. 
The site should schedule the next study activity (clinic visit) with the subject and the 
subject will receive a written reminder of the next planned study activity. 
At Day 15 (Visit 4) the following procedures will be performed: 
▫ The Subject Diary will be collected and reviewed. No changes to the Subject Diary 
should be done at the clinic visit. For details on the Subject Diary see sections 3.4.2, 
and 5.2.5. The healthcare professional reviewing these data will discuss the symptoms 
(if any) reported by the subject and will determine if any additional diagnoses and/or 
adverse events are present. All unsolicited AEs until Day 14, solicited local and 
systemic AEs persisting at Day 14, SAEs, AESIs, medically attended AEs, AEs 
leading to study withdrawal and NOCD must be recorded on source documents. All 
concomitant medications or vaccinations associated with those events must also be 
recorded on the source documents. 
▫ The site should schedule the next study activity (safety phone call) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 29 (Visit 6) the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events 
occurred and if any concomitant medications or vaccines were taken / received in the 
time since the last clinic visit. The healthcare professional reviewing these data will 
discuss the symptoms (if any) reported by the subject and will determine if any 
additional diagnoses and/or adverse events are present. Any solicited local and 
systemic AEs continuing beyond Day 14, SAEs, AESIs, medically attended AEs, AEs 
leading to study withdrawal and NOCD must be recorded on source documents. All 
concomitant medications or vaccinations associated with those events must also be 
recorded on the source documents. 

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▫ Blood draw (approximately 10 ml) from all subjects for Safety Laboratory 
assessments. 
▫ Urine sample from all subjects for Safety Laboratory assessments. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 
volume of post-vaccination blood draws are provided in section 3.5. 
The site should schedule the next study activity (clinic visit) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 85 and Day 113 (Visit 7 and Visit 8), the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events 
occurred and if any concomitant medications or vaccines were taken / received in the 
time since the last clinic visit. The healthcare professional reviewing these data will 
discuss the symptoms (if any) reported by the subject and will determine if any 
additional diagnoses and/or adverse events are present. Any solicited local and 
systemic AEs continuing beyond Day 14, SAEs, AESIs, medically attended AEs, AEs 
leading to study withdrawal and NOCD must be recorded on source documents. All 
concomitant medications or vaccinations associated with those events must also be 
recorded on the source documents. 
▫ The site should schedule the next study activity (clinic visit) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
At Day 181 (Visit 9), the following procedures will be performed: 

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▫ The subject will be interviewed to determine if any unsolicited adverse events 
occurred and if any concomitant medications or vaccines were taken / received in the 
time since the last clinic visit. The healthcare professional reviewing these data will 
discuss the symptoms (if any) reported by the subject and will determine if any 
additional diagnoses and/or adverse events are present. Any solicited local and 
systemic AEs continuing beyond Day 14, SAEs, AESIs, medically attended AEs, AEs 
leading to study withdrawal and NOCD must be recorded on source documents. All 
concomitant medications or vaccinations associated with those events must also be 
recorded on the source documents. 
▫ Blood draw (approximately 10 ml) from all subjects for serology testing. 
volume of post-vaccination blood draws are provided in section 3.5. 
The site should schedule the next study activity (safety phone call) with the subject. 
▫ The subject will receive a written reminder of the next planned study activity. The 
subject will be reminded to contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. 
5.3.2  
Safety Follow-up Calls 
Safety follow-up calls will be performed on Day 22 (Visit 5), Day 209 (Visit 10) and Day 
271 (Visit 11) and include the following procedures: 
▫ Safety follow-up calls are calls made to the subject by a healthcare professional 
designated on the site log. These calls will follow a script which will facilitate the 
collection of relevant safety information. The subject will be interviewed according to 
the script, and information relating to solicited local and systemic AEs persisting 
beyond Day 14 and unsolicited adverse events including SAEs, AESIs, medically 
attended AEs, AEs leading to study withdrawal, and/or NOCD and concomitant 
medications or vaccinations associated with those events. All safety information 
described by the subject must be written down in a designated location within the 
source document and not written on the script used for the telephone call. 

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▫ The site should schedule the next study activity (clinic visit or study termination visit) 
with the subject. 
▫ The subject will be reminded to contact the site if there are any questions and to 
contact the site immediately (or as soon as the subject is medically stable) if the 
subject has a medical condition that leads to a hospitalization or an emergency room 
visit. 
5.4  
Unscheduled Visits  
An unscheduled visit describes a non-routine study visit triggered by a specific event. 
These could include anticipated or unanticipated adverse events or interventions. 
The following procedures should be carried out for all unscheduled visits: 
1. Evaluate the subject’s vital signs body temperature, heart rate, and blood pressure and 
perform a symptom-directed physical examination. 
2. Record any observed AEs in the source documents. 

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3. Record any concomitant medications or vaccinations associated with AEs in the 
source documents. 
5.5  
Study Termination Visit 
The study termination visit is scheduled on Day 366 (Visit 12). The termination visit is a 
clinic visit. For visit procedures to be performed for a subject whose planned study 
participation ends prematurely, please see section 5.5.1. 
At the Study Termination clinic visit the following procedures will be performed: 
▫ The subject will be interviewed to determine if any unsolicited adverse events occurred 
and if any concomitant medications or vaccines were taken / received in the time since 
the last clinic visit. 
▫ The healthcare professional reviewing these data will discuss the symptoms (if any) 
reported by the subject and will determine if any additional diagnoses and/or adverse 
events are present. 
▫ Medically attended AEs, SAEs, NOCDs, or AESIs will be recorded on source 
documents. 
▫ All medications taken or vaccines received will also be recorded on the source 
documents. 
▫ The site will review with the subject the plan of when information relating to the 
subject’s participation in the study may be available (e.g., study results, treatment 
assignments). It will also be discussed how information relating to the subject’s 
participation in the study will be shared with the subject’s healthcare provider, if the 
subject chooses to share this information. 
▫ The site will complete the termination CRF page and this will mark the completion of 
the subject’s participation in the study. 
5.5.1  
Early Termination Visit 
The date of termination is the date of the last contact in which the subject’s health status 
was assessed or, in cases where the subject does not agree to any further safety follow-up, 
it is the date consent is withdrawn. This date should be recorded on the appropriate CRF 
page. 
When a subject is withdrawn from treatment or withdraws from the study, the investigator 
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The reason(s) for the early termination must be included in the subject’s source 
documentation. If the Early Termination Visit is a telephone call, collect as much 
information as possible. Early Termination Visits include subjects who were randomized 
but not treated. 
At the clinic visit or during the telephone call, the following procedures should be 
performed, when possible: 
▫ Collection and review of Subject Diary (if not already collected). 
▫ Interview of subject to collect unsolicited adverse events, medically attended AEs, AEs 
leading to withdrawal, SAEs, AESIs, and NOCD. 
▫ Interview of subject to collect concomitant medications and/or vaccinations. 
▫ Symptom-directed physical assessment, at least including measurement of vital signs 
(body temperature, respiratory rate, blood pressure, heart rate) and a check of general 
appearance (in case of clinic early termination visit). 
▫ Draw a blood sample (approximately 10 ml) and a urine sample for Safety Laboratory 
assessment (in case of clinic early termination visit). 
▫ The site will review with the subject the plan of when information relating to the 
subject’s participation in the study may be available (e.g., study results, treatment 
assignments). It will also be discussed how information relating to the subject’s 
participation in the study will be shared with the subject’s healthcare provider, if the 
subject chooses to share this information. 
▫ The site will complete the appropriate CRF page and this will mark the completion of 
the subject’s participation in the study. 
6.0  
TREATMENT OF SUBJECTS 
All vaccines associated with this study are to be stored separately from other vaccines and 
medications in a secure location under appropriate storage conditions with temperature 
monitoring. All vaccines associated with this study must be checked for expiration 
date prior to use. Expired vaccines must not be administered to subjects. 
6.1  
Study Vaccine(s) 
The term ‘study vaccine’ refers to those vaccines provided by the Sponsor, which will be 
evaluated as part of the study objectives. The study vaccines specific to this study are 
described in Table 6.1-1. 

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Table 6.1-1: Study Vaccine Composition 
Group A (Control) Meningococcal C-CRM197 Conjugate Vaccine 
 
Vaccine Component 
Quantity per 0.5 ml dose 
 
 
Vial Containing Vaccine Conjugate 
 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
 
Aluminum Hydroxide Solvent Components (for 0.5 mL dose) 
 
Aluminum hydroxide 
1.0 mg 
Sodium Chloride 
3.5 mg 
Sterile water for injection, up to 
0.5 ml 
 
 
Group B (12.5µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
12.5 µg 
Sodium Chloride 
3.4 mg 

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Histidine  
0.1 mg 
Tris 
30 µg 
Sterile water for injection, up to 
0.5 ml 
 
 
Group C (25 µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
25 µg 
Sodium Chloride 
3.4 mg  
Histidine 
0.2 mg 
Tris 
61 µg 
Sterile water for injection, up to 
0.5 ml 
 
 
Group D (50µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 

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Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
50 µg 
Sodium Chloride 
3.2 mg 
Histidine 
0.4 mg 
Tris 
121 µg 
Sterile water for injection, up to 
0.5 ml 
 
Group E (100µg LHD153R) - MenC-CRM197/Aluminium Hydroxide/LHD153R 
Vaccine Component 
Quantity per 0.5 ml dose 
 
Vial Containing Vaccine Conjugate 
Meningococcal C oligosaccharide conjugated to 
10 µg  
CRM197 protein isolated and purified from C diphtheria CRM c7β197M8 
12.5-25 µg 
Mannitol 
7.3 mg 
Sodium dihydrogen phosphate monohydrate 
0.092 mg 
 
Aluminum Hydroxide/LHD153R Solvent Components (for 0.5 mL dose) 
Aluminum hydroxide 
1.0 mg 
LHD153R 
100 µg 
Sodium Chloride 
2.9 mg 
Histidine 
0.8 mg 
Tris 
243 µg 
Sterile water for injection, up to 
0.5 ml 
6.2  
Non-Study Vaccines 

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The term ‘non-study vaccine’ refers to those vaccines which will be intentionally given to 
study subjects but not formally included in the analysis of study objectives. 
No non-study vaccines are planned for this study. Any non-study vaccines administered 
during the study conduct will be captured in the CRF as concomitant medications and/or 
vaccinations. 
6.3  
Vaccine Preparation and Administration 
The investigator or designee will be responsible for oversight of the administration of 
vaccine to subjects enrolled in the study according to the procedures stipulated in this 
study protocol. All vaccines will be administered only by unblinded personnel who are 
qualified to perform that function under applicable local laws and regulations for the 
specific study site. 
The vaccine components will be provided in 5 separate kits (i.e. one for the control and 
one for each of the 4 dosage groups). The vaccine components must be mixed prior to 
vaccination taking into account the appropriate aseptic procedures. Detailed vaccine 
preparation and administration instructions, including the maximal administration period, 
will be provided to investigators prior to study start and must be filed in the Investigator 
Site File. 
PRECAUTIONS TO BE OBSERVED IN ADMINISTERING STUDY VACCINE: 
- 
Prior to vaccination, subjects must be determined to be eligible for study vaccination 
and it must be clinically appropriate in the judgment of the investigator to vaccinate. 
Eligibility for vaccination prior to first study vaccine administration is determined by 
evaluating the entry criteria outlined in protocol sections 4.0. 
- 
Study vaccines must not be administered to individuals with known hypersensitivity 
to any component of the vaccines. 
- 
Standard immunization practices are to be observed and care should be taken to 
administer the injection intramuscularly. Before administering vaccine, the 
vaccination site is to be disinfected with a skin disinfectant (e.g., 70% alcohol). Allow 
the skin to dry. DO NOT inject intravascularly. 
- 
As with all injectable vaccines, trained medical personnel and appropriate medical 
treatment must be readily available in case of anaphylactic reactions following 
vaccine administration. For example, epinephrine 1:1000, diphenhydramine, and/or 
other medications for treating anaphylaxis should be available. 

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6.4 
Vaccine Administration Error or Overdose of Vaccine 
Vaccine administration error is defined as receiving a dose of study vaccine that was not 
reconstituted as instructed or administered by a different route from the intended route of 
administration. An overdose of study vaccine (whether accidental or intentional) is 
defined when a dosage higher than the recommended dosage is administered in one dose 
of study vaccine. 
Any vaccine administration error or overdose of study vaccine detailed in this protocol 
must be reported as an adverse event, and if the vaccine administration error or overdose 
is associated with a serious adverse event, it must be reported as such within 24 hours to 
the Sponsor. 
6.5 
Prior and Concomitant Medications and Vaccines 
All medications, vaccines and blood products taken or received by the subject within 180 
days prior to the start of the study are to be recorded in the appropriate CRF. 
Medications taken for prophylaxis are those intended to prevent the onset of symptoms. 
Medications taken for treatment are intended to reduce or eliminate the presence of 
symptoms that are present. 
NOTE: Use of antipyretics/analgesics within 24 hours prior to vaccine administration is a 
reason to delay study vaccination (see section 4.3). 
Concomitant medications include all medications (including vaccines) taken 
by/administered to the subject at and after enrolment and must be documented in the 
appropriate CRF. 
When recording concomitant medications/vaccines, they should be checked against the 
study entry criteria in section 4.0, to ensure that the subject should be enrolled in the 
study. 
6.6  
Vaccine Supply, Labeling, Storage and Tracking 
The Sponsor will ensure the following: 
▫ Supply the study vaccines. 
▫ Appropriate labeling of all study vaccines provided that complies with the legal 
requirements of each country where the study is to be performed. 

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The investigator must ensure the following: 
▫ Acknowledge receipt of the study vaccines by a designated staff member at the site, 
including: 
- 
Confirmation that the vaccines were received in good condition 
- 
Confirmation to the Sponsor of the temperature range during shipment from the  
Sponsor to the investigator’s designated storage location 
- 
Confirmation by the Sponsor that the vaccines are authorized for use. 
▫ Proper storage of the study vaccines, including: 
- 
Storage in a secure, locked, temperature-controlled location. 
- 
Proper storage according to the instructions specified on the labels. 
- 
Appropriate record keeping and inventory of the study vaccines, including regular 
documentation of adequate storage temperature. 
▫ Appropriate use of the study vaccines, including: 
- 
No use of vaccines prior to receipt of authorization for use from the Sponsor. 
- 
Use only in accordance with the approved protocol. 
- 
Proper handling, including confirmation that the vaccine has not expired prior to 
administration. 
- 
Appropriate documentation of administration of vaccines to study subjects 
including: 
▪ 
Date, dosage, batch/lot numbers, expiration dates, unique identifying 
numbers assigned to subjects and study vaccines, and time of vaccine 
administration. This information will be maintained in an accountability log 
that will be reviewed by the site monitor. 
▪ 
Reconciliation of all vaccines received from the Sponsor. Reconciliation is 
defined as maintaining records of which and how many vaccines were 
received, which vaccines were administered to subjects, which vaccines 
were destroyed at the site, and which vaccines were returned to the Sponsor, 
as applicable. 
▫ Proper adherence to the local institutional policy with respect to destruction of study 
vaccines. 

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▫ Complete record keeping of vaccine use, wastage, return or destruction, including 
documentation of: 
- 
Copy of the site’s procedure for destruction of hazardous material. 
- 
Number of doses destroyed, date of destruction, destruction code (if available), 
method of destruction, and name of individual performing destruction. 
Vaccines that have been stored differently from the manufacturer’s indications must not 
be used unless the Sponsor provides written authorization for use. In the event that the use 
cannot be authorized, the Sponsor will make every effort to replace the vaccine supply. 
All vaccines used in conjunction with this protocol must be stored separately from normal 
hospital/practice stocks to prevent unintentional use of study vaccines outside of the 
clinical study setting. 
Monitoring of vaccine accountability will be performed by the study monitor during site 
visits and at the completion of the study. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator must ensure that all unused study vaccines, packaging and supplementary 
labels are destroyed locally (upon approval from Sponsor) or returned to the Sponsor. 

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7.0 
ASSESSMENTS 
7.1 
Safety Assessment 
The measures of safety used in this study are based on previous study data and based on 
comparable routine clinical/laboratory procedures. They include a close vigilance for, and 
stringent reporting of selected local and systemic adverse events routinely monitored in 
vaccine studies as indicators of reactogenicity. 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product at any dose that does 
not necessarily have to have a causal relationship with this treatment. Therefore, an AE 
can be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the investigational product. 
This definition includes intercurrent illnesses or injuries and exacerbation of pre-existing 
conditions. 
The period of observation for AEs extends from the time the subject signs informed 
consent until he or she completes the specified safety follow-up period (Day 366) or 
terminates the study early (whichever comes first). AEs occurring after the informed 
consent form is signed but prior to receiving study vaccine/product will be documented as 
an adverse event and recorded within the source documents. However, any AEs occurring 
prior to receipt of any study vaccine will be analyzed separately from “treatment 
emergent” AEs (AEs occurring after administration of the first study vaccine). 
Adverse events are collected as either solicited or unsolicited adverse events. Solicited 
events are derived from organized data collection systems, such as Subject Diaries or 
interview. 
7.1.1 
Solicited Adverse Events 
The term “reactogenicity” refers to solicited signs and symptoms (“solicited adverse 
events”) occurring in the hours and days following a vaccination, to be collected by the 
subject after the first 24 hours inpatient observation period at Day 1until Day 14, using a 
pre-defined Subject Diary. 
The following solicited adverse events are included in the Subject Diary. Each adverse 
event is to be assessed using the scoring system shown in Appendix A (Solicited Local 
AEs) and Appendix B (Solicited Systemic AE): 

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Solicited Local Adverse Events 
Solicited local AEs include: 
- 
injection site erythema 
- 
injection site induration 
- 
injection site pain 
- 
injection site swelling Solicited Systemic Adverse Events 
Solicited systemic AEs include: 
- 
body temperature ≥38.0°C (as measured orally) 
- 
loss of appetite 
- 
nausea 
- 
fatigue 
- 
generalized myalgia 
- 
generalized arthralgia 
- 
headache - 
chills 
- 
vomiting 
- 
diarrhea 
- 
generalized rash 
- 
urticaria 
Other Solicited Data 
Other solicited data collected per Subject Diary include: 
▫ Use of analgesics/antipyretics recorded as “absent” or “present” and summarized by 
“for treatment” or “for prophylaxis” 
▫ Body temperature as recorded daily, ideally at same time, by the oral route 
The study staff must review the data entered into the Subject Diary as described in 
sections 3.4.2 and 5.3.1. 

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NOTE: Any solicited adverse event that meets any of the following criteria must be 
entered into the subjects’ source documents (see section 9.1) and also as an adverse event 
in the appropriate CRF: 
▫ Solicited local or systemic adverse event that continues beyond Day 14 after 
vaccination. 
▫ Solicited local or systemic adverse event that leads to a visit to a healthcare provider 
(medically attended adverse event, see section 7.1.3). 
▫ Solicited local or systemic adverse event leading to the subject withdrawing from the 
study or the subject being withdrawn from the study by the investigator (adverse event 
leading to withdrawal, see section 7.1.3). 
▫ Solicited local or systemic adverse event that otherwise meets the definition of a 
serious adverse event (see section 7.1.4). 
7.1.2  
Unsolicited Adverse Events 
An unsolicited adverse event is an adverse event that was not solicited using a Subject 
Diary and that was spontaneously communicated by a subject who has signed the 
informed consent. 
7.1.3  
Evaluation of Adverse Events 
Every effort should be made by the investigator to evaluate safety information reported by 
a subject for an underlying diagnosis and to capture this diagnosis as the event in the AE 
page. In other words, the practice of reporting only symptoms (e.g., “cough” or “ear 
pain”) are better reported according to the underlying cause (e.g., “asthma exacerbation” 
or “otitis media”). 
The severity of events reported on the appropriate CRF page will be determined by the 
investigator as: 
Mild: 
transient with no limitation in normal daily activity. 
Moderate: 
some limitation in normal daily activity. 
Severe: unable to perform normal daily activity. 
The relationship of the study treatment to an AE will be determined by the investigator 
based on the following definitions: 

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1. Not Related 
The AE is not related to an investigational vaccine if there is evidence that clearly 
indicates an alternative explanation. If the subject has not received the vaccine, the timing 
of the exposure to the vaccine and the onset of the AE are not reasonably related in time, 
or other facts, evidence or arguments exist that reasonably suggest an alternative 
explanation, then the AE is not related. 
2. Possibly Related 
The administration of the investigational vaccine and AE are considered reasonably 
related in time and the AE could be explained by exposure to the investigational vaccine 
or by other causes. 
3. Probably Related 
Exposure to the investigational vaccine and AE are reasonably related in time and no 
alternative explanation has been identified. 
The relationship of the study treatment to an unsolicited AE will be determined by the 
investigator.  
Note: solicited AEs will not be evaluated for relationship to study treatment. Grading for 
severity of solicited local and systemic AEs is described in Appendix A and Appendix B. 
Adverse events will also be evaluated by the investigator for the co-existence of any of 
the other following conditions: 
▫ “Medically attended adverse event”: an adverse event that leads to a visit to a 
healthcare provider. 
▫ “New onset of chronic disease” (NOCD): an adverse event that represents a new 
diagnosis of a chronic medical condition that was not present or suspected in a subject 
prior to study enrolment. 
▫ AEs leading to withdrawal: adverse events leading to study or vaccine withdrawal. 
All AEs, regardless of severity, will be monitored until resolution or until the investigator 
assesses them as chronic or stable. All subjects experiencing AEs - whether considered 
associated with the use of the study vaccine or not - must be monitored until symptoms 
subside and any abnormal laboratory values have returned to baseline, or until there is a 

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satisfactory explanation for the changes observed, or until death, in which case a full 
pathologist’s report should be supplied, if possible. 
7.1.4  
Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose results in one or more of the following: 
▫ Death. 
▫ Is life-threatening (i.e., the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred); it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
▫ Required or prolonged hospitalization. 
▫ Persistent or significant disability/incapacity (i.e., the event causes a substantial 
disruption of a person’s ability to conduct normal life functions). 
▫ Congenital anomaly/or birth defect. 
▫ An important and significant medical event that may not be immediately life 
threatening or resulting in death or hospitalization but, based upon appropriate 
medical judgment, may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed above. 
Adverse events which do not fall into these categories are defined as non-serious. 
It should be noted that a severe adverse event need not be serious in nature and that a 
serious adverse event need not, by definition, be severe. 
Serious adverse events will be captured both on the Vaccines Serious Adverse Event 
(VSAE) form as well as on the appropriate CRF page. All SAEs will be evaluated by the 
investigator for relationship of the event to study vaccine. SAEs that are judged to be 
possibly or probably related to the study vaccine should be reported to the Sponsor as 
related/suspected events. 
The relationship of the study treatment to an SAE will be determined by the investigator 
based on the following definitions: 
1. Related/suspected 
The SAE is judged by the investigator to be possibly or probably related to the study 
vaccine on the appropriate CRF page (see section 7.1.3). 

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2. Not Related 
The SAE is not related if exposure to the study vaccine has not occurred, or the 
occurrence of the SAE is not reasonably related in time, or the SAE is considered 
unlikely to be related to use of the study vaccine, i.e., there are no facts (evidence) or 
arguments to suggest a causal relationship. 
The relationship of the study vaccine to an SAE will be determined by the investigator. 
In addition, SAEs will be evaluated by the Sponsor or designee for “expectedness.” An 
unexpected AE is one that is not listed in the current Summary of Product Characteristics 
or the Investigator’s Brochure or an event that is by nature more specific or more severe 
than a listed event. 
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded on the appropriate CRF. If the onset of an event occurred before the subject 
entered the study (e.g., any pre-planned hospitalization for conditions like cosmetic 
treatments or for non-emergency routine visits for a pre-existing condition), the 
hospitalization would not lead to an AE being classified as serious unless, in the view of 
the investigator, hospitalization was prolonged as a result of participation in the clinical 
study or was necessary due to a worsening of the pre-existing condition. 
7.1.4.1  
Adverse Events of Special Interest 
Certain adverse events of special interest (AESIs) are monitored after the administration 
of immunostimulatory agents. All subjects enrolled in this study will be monitored for 
AESIs for the entire follow-up period. The AESIs will be defined according to MedDRA 
preferred terms. The investigator will be provided with a list of AESIs prior to study start. 
Receipt of this list will be notified and stored, along with the list of AESIs, in the 
Investigator Site File. During the course of the trial the list of AESIs may change. If this 
occurs, the investigators will be advised of the change and confirmation of receipt will be 
documented. The updated list of AESIs and documentation of receipt are also stored in 
the Investigator Site File. The occurrence of any of these adverse events will be treated as 
a serious adverse event (SAE), meeting the criterion of a “medically important event.” 
Subjects will be assessed for diagnosis of an AESI at the following visits: 
- 
Pre-vaccination clinic visit (Day -28 to Day -3)  
- 
Visit 1 (Day 1, pre-vaccination) 
- 
Visit 2 (Day 4) 

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- 
Visit 3 (Day 8) 
- 
Visit 4 (Day 15) 
- 
Visit 5 (Day 22; Safety Follow-Up Call) 
- 
Visit 6 (Day 29) 
- 
Visit 7 (Day 85) 
- 
Visit 8 (Day 113) 
- 
Visit 9 (Day 181) 
- 
Visit 10 (Day 209; Safety Follow-Up Call) 
- 
Visit 11 (Day 271; Safety Follow-Up Call) 
- 
Visit 12 (Day 366; Study Termination Visit) 
At these visits a qualified health care practitioner listed on the site’s responsibilities and 
delegation logs will conduct a review of organ systems and a targeted physical exam and 
will evaluate subjects for any new signs or symptoms that could indicate one of the AESIs 
as specified in the list of AESIs stored in the Investigator Site File. They will also 
interview the subject about recent medical history and any new diagnosis that could 
indicate an AESI. Medical records related to any new medical event or diagnosis will be 
requested, reviewed by the site staff, and recorded in the subject’s source documents. 
A diagnosis of an AESI will be reported in the same manner and time frame as an SAE 
using the VSAE form. The investigator must notify GSK within 24 hours. The AESI 
diagnosis, as well as any medications taken to treat the condition, will be recorded in the 
subject’s source documents and on the appropriate CRF. 
7.1.5  
Methods for Recording Adverse Events and Serious Adverse Events 
All findings regarding Adverse Events must be reported on the appropriate CRF page and 
on the VSAE form, if applicable, which is part of the Investigator Site File. All findings 
in subjects experiencing AEs must be reported also in the subject's source document. 
All SAEs which occur during the course of the study, whether considered to be associated 
with the study vaccination or not, must be reported within 24 hours of the site becoming 
aware of the event to GSK or its designee. Specific instructions and contact details for 
collecting and reporting SAEs to GSK will be provided to the investigator. 

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All SAEs are also to be documented on the appropriate CRF page. Any medication or 
other therapeutic measures used to treat the AE will be recorded on the appropriate 
CRF(s) in addition to the outcome of the AE. 
After receipt of the initial report, representatives of GSK or its designee will contact the 
investigator if it is necessary to obtain further information for assessment of the event. 
All SAEs must be reported by the investigator to his/her corresponding EC and applicable 
regulatory authorities in accordance with institutional policy/regulatory requirements and 
adequate documentation of this notification must be provided to the Sponsor. 
GSK or its designee must also comply with the applicable regulatory requirement(s) 
related to the reporting of suspected unexpected serious adverse vaccine reactions (also 
known as SUSARs) to the regulatory authority(ies) and the IRB/EC. If a SUSAR or other 
safety signal relating to use of one of the study vaccines is reported to GSK or its 
designee, the Sponsor will communicate the information to the investigator and the 
investigator will be responsible for submitting this information to the EC and other 
relevant authorities. 
7.1.5.1 
Post-Study Events 
Any suspected SAE that occurs outside of the protocol-specified follow-up period or after 
the end of the study but considered to be caused by the study vaccine must be reported to 
GSK or its designee. These SAEs will be processed by GSK or its designee as during the 
course of the study, until 3 months after the last scheduled study visit. Instructions and 
contact details for collecting and reporting these suspected SAEs will be provided to the 
investigator. 
7.1.6  
Pregnancies 
To ensure subjects’ safety, each pregnancy in a subject after study vaccination must be 
reported to GSK within 72 hours of the site learning of its occurrence. If the subject 
agrees to submit this information, the pregnancy must be followed to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. This follow-up should occur even if intended duration of safety follow-up 
for the study has ended. 
Pregnancy data must be recorded on a Pregnancy Report CRF (initial report) and 
Pregnancy Follow-Up CRF (outcome report). 

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Any pregnancy outcome meeting the definition of a SAE (see section 7.1.4) must also be 
reported on the VSAE Report Form. 
7.1.7  
Safety Laboratory Measurements 
Blood and urine samples will be collected from all subjects at the Pre-vaccination  
Screening, at Visit 1 (pre-vaccination and 24 hours after vaccination), at Visit 3 and at 
Visit 6 as outlined in Time and Events Table 3. The blood safety laboratory assessments 
will include sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, 
liver function tests (ALT, AST), a complete blood count and C-reactive protein. The urine 
safety laboratory assessments will include protein, glucose and red blood cells. An 
additional blood and urine sample will be collected in case of a clinic Early Termination 
Visit as outlined in section 5.5.1. 
All testing will be conducted by qualified and certified laboratories. The Investigator 
must assess all safety laboratory results. Abnormal laboratory values must be classified 
by the Investigator as clinically significant or not. Abnormal laboratory values that are 
considered clinical significant will be defined following the FDA CBER Guidance for 
Industry “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials” dated September 2007, or the institution’s normal 
ranges if they differ from CBER guidance. Please see Appendix C, D and E for further 
details on the Toxicity Grading Scales according to CBER. 
Retesting may be performed in case of abnormal values per guidance of the investigator.  
7.2  
Efficacy Assessment 
Efficacy measurement will not be performed as part of this study. 
7.3  
Immunogenicity Assessment 
The measures to assess the primary and secondary immunogenicity endpoints for this 
study are standard, i.e., widely used and generally recognized as reliable, accurate, and 
relevant (able to describe the quality and extent of the immune response). 
The assay’s used in this study to assess the primary and immunogenicity endpoints are 
human serum bactericidal assay (hSBA) and ELISA specific for MenC 
The hSBA is a functional measure of the ability of specific antibodies, in conjunction with 
human complement, to kill MenC indicator strains, and is widely used and generally 
recognized as the serological correlate of protection. The specific ELISA will be used to 

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measure the induction of antibodies directed against MenC following vaccination with the 
study vaccines. 
Blood samples (approximately 10 ml) to obtain serum for hSBA and ELISA assays will 
be collected at Day 1, Day 8, Day 29 and Day 181 (refer to section 3.5 for detailed 
specimen collection procedures). 
Testing will be conducted by a GSK or designated laboratory in a blinded manner 
towards the treatment group. Laboratory contact details are listed in the Protocol 
Ancillary Document. 
All data will be captured at the laboratory and transferred via Electronic Data Transfer  
(EDT) 
Details on all blood sample handling steps are described in the Clinical Specimen Lab 
Manual provided to the study site. 
7.4 
Exploratory Measurements 
In those subjects who agree to a separate Informed Consent, additional blood samples will 
be collected at Day 1, Day 4, Day 8, Day 29 and Day 181 for exploratory measurements. 
The purpose of these exploratory measurements is to assess the systemic exposure of 
LHD153, to further delineate vaccine induced antigen specific immune responses and to 
evaluate biomarkers that may be predictive for safety and/or innate immune activation. 
All exploratory measurements will be conducted by a GSK or a designated laboratory. 
Laboratory contact details are listed in the Protocol Ancillary Document. 
Exploratory measurements may be performed after the Clinical Study Report (CSR) has 
been completed, in which case these data will be submitted as an addendum to the CSR. 
Systemic exposure of LHD153 
Systemic exposure of LHD153 will be assessed by analyzing LHD153 blood plasma 
levels at Day 1 (baseline, 1, 2, 4, 8 and 24h after vaccination) and Day 4 using 
LC/MS/MS. Time-points for assessment of clinical exposure of LHD153 have been 
selected based on non-clinical data in dogs and rats. 
Vaccine-induced antigen-specific immune responses 
The frequency of B cells specific for MenC polysaccharide and CRM197 will be 
determined by enzyme-linked immunosorbent spot (ELISPOT) at Day 1, Day 8, Day 29 
and Day 181 in order to evaluate the baseline specific B-cell frequency (Day 1), the peak 

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of plasmablast responses (Day 8), the peak of B cell memory responses (Day 29), and the 
persistence of memory B cell responses (Day 181). 
Subsequently, the diversity of the antigen specific B-cell repertoire will be analyzed in a 
selected subset of subjects. The selection of the subset will be based on the most 
pronounced response to the study vaccines when compared to baseline as determined by 
the primary and secondary immunogenicity assessment. 
The diversity of the elicited B-cell receptors will be assessed through sequence analysis of 
complementary DNA (cDNA) generated from immunoglobulin (Ig) messenger RNA 
(mRNA). The Ig cDNAs will be analyzed from antigen-specific B cells obtained at Day 1, 
Day 29 and/or Day 181 and plasmablasts isolated at Day 8. The analysis of the B-cell 
receptor diversity does not have the intent nor the capability to identify or rule out any 
genetic modifications in the RNA or DNA that are presumably linked to disease or 
predisposition to disease. 
The frequency of T cells specific for the CRM197 protein at baseline (Day 1), at Day 8 and 
at Day 29 after vaccination with the study vaccines will be determined by FACS analysis 
using intracellular staining with a panel of cytokines and surface markers to identify cell 
populations. 
To evaluate the biophysical and functional properties of MenC-specific antibodies 
induced by the study vaccines, biophysical and cell-based assays will be performed on 
serology samples collected at Day 1 (baseline), Day 29, and Day 181. Antigen specific 
antibody isotypes, Fc Receptor binding and the antibody glycosylation state will be 
assessed. Functional ability of the MenC-specific antibodies to fix complement, to 
promote antibody-dependent cell mediated cytoxicity (ADCC), to induce phagocytosis 
(ADCP) and to activate FcR+ cells in vitro will be assessed at Day 1 (baseline), Day 29, 
and Day 181. (Amended: 19 June 2017) 
Early Markers for Safety and Innate immune activation 
The evaluation of potential biomarkers of safety and innate immune activation will be 
performed on blood specimens collected at Day 1 (baseline, 6h and 24h after vaccination) 
and Day 4. 
The vaccine-induced production of inflammatory cytokines and chemokines will be 
monitored on serum samples using a commercially available electrochemoluminescence 
assay for a panel of pro-inflammatory cytokines and chemokines, including Eotaxin, 
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IL15, IL-16, IL-17A, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IP-10, MCP-1, MCP-
4, MDC, MIP-1a, MIP-1b, TARC, TNF-a, TNF-b, VEGF. 
The vaccine-induced expression of genes and gene families will be monitored on whole 
blood samples using of RNA microarrays by existing technologies. The RNA micro array 
analysis does not have the intent nor the capability to identify or rule out any genetic 
modifications in the RNA or DNA that are presumably linked to disease or predisposition 
to disease. 
The vaccine-induced changes in myeloid (e.g. monocytes and dendritic cells) and 
lymphoid (e.g. NK cells, NKT cells) cell numbers and their activation status will be 
assessed using flow cytometry. 
8.0  
STATISTICAL CONSIDERATIONS 
8.1  
Endpoints 
8.1.1 
Primary Endpoint(s) 
8.1.1.1  
Primary Safety Endpoint(s) 
The measures for assessing safety and tolerability (by vaccine group within each cohort 
and by LHD153R adjuvant dosage group overall) are as follows: 
▫ The frequency and percentage of subjects with solicited local and systemic  AEs 
through Day 14. Time intervals after vaccination that will be summarized are:30 
minutes post-vaccination, Days 1-4 (without 30 minutes), Days 5-8, Days 8-14, Days 
1-8 (without 30 minutes) and Days 1-14 (without 30 minutes). 
▫ The frequency and percentage of subjects with any unsolicited AEs from the day of 
vaccination (Day 1) to Day 14. 
▫ The frequency and percentage of subjects with SAEs, medically attended AEs,  AEs 
leading to study withdrawal, NOCDs, AESIs for the following time periods: day of 
signed informed consent until study completion (Day 366), day of vaccination (Day 1) 
to Day 29, and Day 29 to study completion (Day 366). 
▫ The absolute values and changes in hematology, chemistry, and urinalysis parameters 
(see section 7.1.7). 
▫ The frequency and percentage of subjects with abnormal laboratory parameter values 
as classified by investigator normal ranges (low, normal, high) and as classified by 
CBER toxicity grading scales, when available. 

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8.1.1.2  
Primary Efficacy Endpoint(s) 
Not applicable. 
8.1.1.3  
Primary Immunogenicity Endpoint(s) 
The primary immunogenicity endpoints are the GMTs measured by hSBA directed 
against MenC from samples collected on Day 1 (baseline, before vaccination) and Day 29 
as well as the GMR of the titers (Day 29 / Day 1). 
8.1.2 
Secondary Endpoint(s) 8.1.2.1 
 Secondary Safety Endpoint(s) 
Not applicable. 
8.1.2.2  
Secondary Efficacy Endpoint(s) 
Not applicable. 
8.1.2.3  
Secondary Immunogenicity Endpoint(s) 
The secondary immunogenicity endpoints are: 
▫ GMTs and corresponding GMRs measured by hSBA directed against MenC for 
samples collected at Day 8 and Day181. 
▫ Percentage of subjects with hSBA seroresponse at Days 8, 29, and 181. Seroresponse 
is defined as a post vaccination hSBA ≥8 for subjects with a baseline hSBA <4 or 
have an increase of at least 4 times the baseline hSBA level for subjects with 
prevaccination hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against MenC measured by ELISA 
for samples collected on Days 1 (baseline, prior to vaccination), 8, 29, and 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations to 
MenC as measured by ELISA on Day 8, 29, and 181 relative to baseline (Day 1). 
8.1.3  
Exploratory Immunogenicity Endpoint(s) 
The exploratory immunogenicity endpoints are based on results of testing which may not 
be performed until after the study report has been finalized and will be further refined 
prior to testing. They include the following: 

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▫ Serum concentration of LHD153 at Day 1 baseline (prior to vaccination), Day 1 (1h , 
2h, 4h, 8h, and 24h after vaccination), Day 4 by LC-MS/MS. 
▫ Frequency of MenC polysaccharide-specific and CRM197-specific B cells at Day 1 
(baseline), Day 8, Day 29, and Day 181 by ELISPOT. 
▫ Diversity of MenC polysaccharide-specific B-cell repertoire at Day 1 (baseline), Day 
8, Day 29, and Day 181 by immunoglobulin cDNA sequencing. 
▫ Frequency and quality of T cells specific for CRM197 at Day 1 (baseline), Day 8, and 
Day 29 by flow cytometry analysis using intracellular staining with a wide panel of 
cytokines and surface markers to identify cell populations. 
▫ Serum concentrations of a panel of 30 chemokines and cytokines at Day 1 baseline 
(prior to vaccination), Day 1 (6h and 24h after vaccination), Day 4, and Day 8 by 
multiplex Electro-chemo-luminescence based assay. 
▫ Gene expression profile in whole blood at Day 1 baseline (prior to vaccination), Day 1 
(6h and 24h after vaccination), Day 4, and Day 8 by RNA micro array analysis. 
▫ Number and activation status of myeloid and lymphoid cell populations at Day 1 
baseline (prior to vaccination), Day 1 (24h after vaccination), Day 4 and Day 8 by 
flow cytometry. 
▫ Antigen-specific antibody isotype, Fc receptor and antibody glycosylation state will 
be assessed at Day 1 (baseline), Day 8, Day 29, and Day 181 by biochemical and 
cell-based assays.  
▫ Functionality of MenC-specific antibodies to fix complement, promote 
antibodydependent cell mediated cytoxicity (ADCC), induce phagocytosis and 
activate FcR+ cells in vitro will be also assessed at Day 1 (baseline), Day 8, Day 29, 
and Day 181. (Amended: 19 June 2017) 
8.2  
Success Criteria 
The study has no formal statistical hypotheses and will not be declared positive or 
negative according to given rules. The selection of an appropriate LHD153R adjuvant 
dosage for future studies will be determined by the joint evaluation of the 
immunogenicity and safety profiles of each dosage group. 8.2.1  
Success Criteria 
for Primary Objective(s) Not applicable. 

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8.2.2  
Success Criteria for Secondary Objective(s) 
Not applicable. 
8.3  
Analysis Sets 
8.3.1  
All Enrolled Set 
All screened subjects who provide informed consent and provide demographic and/or 
baseline screening assessments, regardless of the subject’s randomization and treatment 
status in the study and received a Subject ID. 
8.3.2  
All Exposed Set 
All subjects in the enrolled set who receive a study vaccination. 
8.3.3  
Safety Set 
Safety Set (solicited adverse events and other solicited reactions) 
All subjects in the Exposed Set who: 
▫ Provide post vaccination reactogenicity data. 
Safety Set (unsolicited adverse events) 
All subjects in the Exposed Set who: 
▫ Have post-vaccination unsolicited adverse event records. 
Safety Set (overall) 
All subjects in the Exposed Set who: 
▫ Have either post-vaccination adverse event or reactogenicity records. 
Subjects will be analyzed as “treated” (i.e., according to the vaccine a subject received, 
rather than the vaccine to which the subject may have been randomized). 
8.3.4  
Full Analysis Set (FAS) Efficacy/Immunogenicity Set 
All subjects in the Enrolled Set who: 

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▫ Receive a study vaccination AND provide efficacy/immunogenicity data at relevant 
time points. 
FAS sets will be analyzed “as randomized” (i.e., according to the vaccine a subject was 
designated to receive, which may be different from the vaccine the subject actually 
received). 
8.3.5  
Per Protocol (PP) Set Efficacy/Immunogenicity Set 
All subjects in the FAS efficacy/immunogenicity set who: 
▫ Are not excluded due to reasons (see section 8.3.8) defined prior to unblinding or 
analysis. 
PPS are subsets of FAS and should always be defined even if the objectives do not require 
it. 
Examples for subjects excluded due to other reasons than protocol deviations are: 
- 
Subjects who withdrew informed consent. 
- 
Premature withdrawal due to an adverse event. 
Exclusions need to be considered by objective/time point, i.e., sometimes not all data of a 
subject but only part of the subject's data will be removed from the PPS analysis. 
8.3.6  
Other Analysis Sets  
All subjects in the Enrolled Set who consent to additional blood draws, receive a study 
vaccination AND provide exploratory assay data at relevant time points will be included 
in an exploratory assay subset. 
8.3.7  
Subgroups 
Selected immunogenicity analyses may be provided based on seropositivity status at 
baseline. 
8.3.8  
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. A protocol deviation may be a reason to remove data from 
an analysis set at the time of analysis. Reportable protocol deviations will be defined as 
exclusionary from the analysis according to protocol objectives and endpoints, which will 

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be specified in the Statistical Analysis Plan. In some cases exclusion of data may be due 
to a reason other than a protocol deviation, e.g. early termination. 
8.4  
Statistical Analysis Plan 
This section provides a summary of the statistical methodology to be used. A more 
detailed description of analysis methods will be provided in a separate Statistical Analysis 
Plan which may also include additional exploratory analyses not explicitly mentioned in 
the following sections. 
8.4.1  
Analysis of Demographic and Baseline Characteristics 
Descriptive statistics (number of non-missing observations, mean, standard deviation, 
median, minimum and maximum) for age, height and weight at enrolment will be 
calculated overall and by vaccine group and LHD153R adjuvant dosage. 
Distributions of subjects by sex and ethnic origin will be summarized overall and by 
vaccine group and LHD153R adjuvant dosage. 
8.4.2  
Analysis of Primary Objective(s) 
8.4.2.1  
Analysis of Primary Safety Objective(s) 
Safety of the study vaccines will be assessed in all subjects in terms of the frequency and 
percentage of reported AEs as well as by changes in clinical laboratory values.  
8.4.2.1.1  
Analysis of Extent of Exposure 
The frequency and percentage of subjects with vaccinations will be summarized by 
vaccine group and LHD153R adjuvant dosage, by cohort and overall, for the Enrolled Set. 
8.4.2.1.2  
Analysis of Solicited Local, Systemic and Other Adverse Events 
All solicited adverse events will be summarized according to defined severity grading 
scales. Use of medication to prevent/treat fever will be summarized according to 
frequencies and percentages reporting “Yes” and “No”. 
Frequencies and percentages of subjects experiencing each adverse event will be 
presented for each symptom severity. Summary tables showing the occurrence of any 
local or systemic adverse event overall and at each time point will also be presented. 

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Post-vaccination solicited adverse events reported from Day 1 to Day 14 will be 
summarized for the intervals Day 1-4 (without 30 minutes), Day 5-8, Day 1-8 (without 30 
minutes), Day 8-14 and Day 1-14 (without 30 minutes) by maximal severity and by 
vaccine group and LHD153R adjuvant. The severity of solicited local adverse events, 
including injection-site erythema, swelling and induration will be summarized according 
to categories based on linear measurement: 25-50 mm, 51-100 mm, > 100 mm. 
Injection site pain and systemic reactions (except fever) occurring up to Day 14 will be 
summarized according to “mild”, “moderate” or “severe”. 
Each solicited local and systemic adverse event will also be further summarized as “none” 
versus “any”. 
Implausible measurements (for further definition see Statistical Analysis Plan) will be left 
out of the analysis. 
Use of antipyretics and analgesics will be summarized by frequency by type of use 
(prophylactic versus treatment) and percentage of subjects reporting use. The influence of 
antipyretics and analgesics use on the occurrence of specific adverse events (e.g., fever, 
pain) will be assessed. 
Body temperature will be summarized by 0.5 °C and 1.0 °C increments from 36.0 °C up 
to ≥40 °C. 
8.4.2.1.3  
Analysis of Unsolicited Adverse Events 
This analysis applies to all adverse events occurring during the study, judged either as 
probably related, possibly related, or not related to vaccination by the investigator, 
recorded in the CRF, with a start date on or after the date of first vaccination. AE starting 
prior to the first vaccination will only be listed. The original verbatim terms used by 
investigators to identify adverse events in the CRFs will be mapped to preferred terms 
using the MedDRA dictionary. The adverse events will then be grouped by MedDRA 
preferred terms into frequency tables according to system organ class. 
All reported adverse events, as well as adverse events judged by the investigator as at 
least possibly related to study vaccine, will be summarized according to system organ 
class and preferred term within system organ class. These summaries will be presented by 
vaccination group and LHD153R adjuvant dosage for each cohort and by interval of study 
observation. When an adverse event occurs more than once for a subject, the maximal 
severity and strongest relationship to the vaccine group will be counted. 

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Separate summaries will be produced for the following categories: 
▫ Serious adverse events. 
▫ Adverse events that are possibly or probably related to vaccine. 
▫ Adverse events of special interest. 
▫ New onset of chronic disease. 
▫ Adverse event leading to withdrawal. 
▫ Adverse events leading to a medically attended visit. 
▫ Adverse event by data source. 
Data listings of all adverse events will be provided by subject. In addition, adverse events 
in the categories above will be provided as listed data. 
8.4.2.1.4  
Analysis of Safety Laboratory Values 
The investigator must review all safety laboratory results (see Section 7.1.7). Abnormal 
laboratory values and clinically significant changes in values from pre-vaccination 
(Screening Visit) will be assessed, using medical judgment, based on the FDA CBER  
Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent  
Volunteers Enrolled in Preventive Vaccine Clinical Trials” dated September 2007, or the 
institution’s normal ranges if they differ from CBER guidance. Please see Appendix C, D 
and E for further details. 
The following information will be provided: 
▫ Change in absolute laboratory value from pre-vaccination (Screening Visit) and Day 1  
(Visit 1) baseline to Day 1 (24 hours after vaccination), Day 8 (Visit 3) and Day 29 
(Visit 6) after vaccination. 
▫ The classification of laboratory values and/or their changes from pre-vaccination 
according to the CBER toxicity grading scale. 
▫ 3 x 3 shift tables by visit using the categorization of laboratory values according to 
institutional normal reference ranges (below, within, above). 8.4.2.2  
Analysis 
of Primary Efficacy Objective(s) 
Not applicable. 

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8.4.2.3  
Analysis of Primary Immunogenicity Objective(s) 
8.4.2.3.1  
Statistical Hypotheses 
There are no statistical hypotheses associated with the primary immunogenicity 
objectives. All analyses are descriptive. 
8.4.2.3.2  
Analysis Sets 
The primary immunogenicity analyses will be based on the per-protocol set (PPS) at Day 
29. The primary analyses will be repeated using the Full Analysis Set (FAS) as a measure 
of the sensitivity/robustness of the results (further details are given in section 8.3). 
8.4.2.3.3 
Statistical Methods 
Before any statistical analysis that assumes normally distributed observations, antibody 
titers will be log10-transformed. Individual titers below the limit of quantitation (LLQ) 
will be set to half that limit. 
Geometric Mean Titers 
The logarithmically (base 10) transformed antibody titers will be modeled using an 
analysis of covariance (ANCOVA) model with a qualitative factor for LHD153R 
adjuvant dosage (0 [for unadjuvanted MenC], 12.5, 25, 50 or 100 µg) and log (base 10) 
pre-vaccination titer as a covariate. The adjusted GMT and the two-sided, 95%, 
confidence intervals (CIs) of the GMT will be calculated based on this model as will the 
ratio of GMTs and corresponding CIs. The adjusted GMT and two-sided 95% CIs will be 
constructed by exponentiation (base 10) of the least square means of the logarithmically 
transformed (base 10) antibody titer. The ratio of GMTs (LHD153R adjuvant dosage 
minus MenC), and corresponding two-sided 95% CIs, will be constructed by 
exponentiation (base 10) of the least square differences obtained from this model. The 
model can be written as:  
log10 (yik) = µ + αi + βxik + εik 
where µ represents a common overall mean, αi represents the adjuvant dose group i effect, 
β represents the common slope for the log10 pre-vaccination titer, xik for subject k in 
adjuvant dose group I, and εik represents random error for subject k in adjuvant dose 
group i. 
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The logarithmically (base 10) transformed within subject ratio of antibody titers (Day 29 / 
pre-vaccination) will be modeled using an analysis of variance model with a qualitative 
factor for LHD153R adjuvant dosage (0 [for non-LHD153R adjuvanted MenC], 12.5, 25, 
50 or 100 µg). The adjusted GMR and the two-sided, 95% CIs of the GMR will be 
calculated based on this model. The model can be written as: 
log10 (yik) = µ + αi + εik 
where µ represents a common overall mean, αi represents the adjuvant dose group i effect 
and εik represents random error for subject k in adjuvant dose group i. 
Handling of missing values 
For immunogenicity data, it may be reasonable to consider missing immunogenicity 
values as missing completely at random (MCAR), i.e., not informative. Therefore, the 
primary analysis will comprise a complete case analysis only, without introducing any 
bias. Imputation methods will not be used. 
8.4.3  Analysis of Secondary Objective(s) 8.4.3.1 
 Analysis of Secondary Safety Objective(s) Not 
applicable. 
8.4.3.2  
Analysis of Secondary Efficacy Objective(s) 
Not applicable. 
8.4.3.3  
Analysis of Secondary Immunogenicity Objective(s) 
8.4.3.3.1  
Statistical Hypotheses 
There are no statistical hypotheses associated with the secondary immunogenicity 
objectives. All analyses are descriptive. 
8.4.3.3.2  
Analysis Sets 
The secondary immunogenicity analyses will be based on the PPS (further details are 
given in section 8.3) or the appropriate subset of subjects. 
8.4.3.3.3  
Statistical Methods 
The secondary immunogenicity endpoints are: 

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▫ GMTs and corresponding GMRs measured by hSBA directed against MenC for 
samples collected at Day 8 and Day181. 
▫ Percentage of subjects with hSBA seroresponse at Days 8, 29, and 181. seroresponse is 
defined as a post vaccination hSBA ≥8 for subjects with a baseline hSBA <4 or have 
an increase of at least 4 times the baseline hSBA level for subjects with prevaccination 
hSBA ≥4. 
▫ Antibody geometric mean concentrations (GMCs) against MenC measured by ELISA 
for samples collected on Days 1 (baseline, prior to vaccination), 8, 29, and 181. 
▫ The percentage of subjects with at least a 4-fold increase in antibody concentrations to 
MenC as measured by ELISA on Day 8, 29, and 181 relative to baseline (Day 1). 
The GMTs for samples collected at Day 8 and Day 181 as well as the GMCs for samples 
collected at Day 1, Day 8, Day 29, and Day 181 will be analyzed using the same approach 
as for the primary immunogenicity endpoint. 
The remaining immunogenicity endpoints are based on subjects meeting criteria for 
seroconversion or achieving a certain threshold value. These endpoints will be 
summarized using frequencies and percentages by LHD153R adjuvant dosage (0 [for 
non-LHD153R adjuvanted MenC], 12.5, 25, 50 or 100 µg). Two-sided 95% 
ClopperPearson CIs will also be provided for percentages. For analyses of 
seroconversion, separate summaries may be provided based on seropositivity status at 
baseline. 
8.4.4  
Analysis of Exploratory Objectives 
Testing and analyses of exploratory endpoints may be performed after the Clinical Study 
Report (CSR) has been completed, in which case these data will be submitted as an 
addendum to the CSR. 
In general, concentration and titer results will be summarized for each LHD153R adjuvant 
dosage group using geometric means and associated 2-sided 95% confidence intervals; 
and, categorical data will be summarized using frequencies and percentages, with 
corresponding two-sided, 95% confidence intervals. 
8.5  
Sample Size and Power Considerations of Primary Objectives 
Sample size is not driven by statistical assumptions for formal hypothesis testing, but was 
based on the safety objective for the study. The table below provides the probability for 

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various combinations of sample size (N) and presumed true frequency of a given event 
within an individual vaccine group  
Frequency 
of Event 
Probability to Observe at Least 1 Subject with a Given Event For  
Various Choices of N 
4 
8 
12 
16 
0.05 
0.1855 
0.3366 
0.4596 
0.5599 
0.10 
0.3439 
0.5695 
0.7176 
0.8147 
0.15 
0.4780 
0.7275 
0.8577 
0.9257 
0.20 
0.5904 
0.8322 
0.9313 
0.9718 
0.30 
0.8250 
0.9423 
0.9862 
0.9967 
0.40 
0.8704 
0.9832 
0.9978 
0.9997 
The proposed combinations of sample sizes within each cohort are 4 aluminium 
hydroxide adjuvanted MenC-CRM197 and 16 MenC-CRM197 plus an assigned-level of 
LHD153R adsorbed to aluminium hydroxide. If all four cohorts are fully enrolled, there 
will be 16 subjects receiving aluminium hydroxide adjuvanted MenC-CRM197. 
With 16 subjects, events which occur at a frequency of 15% or more will be detected with 
at least 90% probability; and, events which occur at a frequency of 10% or more will be 
detected with 81% probability. With 4 subjects, events which occur at a frequency of 30% 
or more will be detected with at least 80% probability. Intermediate values of 8 and 12 are 
provided to correspond to sample sizes in the MenC-CRM197 after cohort 2 and cohort 3 
are fully enrolled. 
8.6  
Interim Analysis 
The DMC will be reviewing the accumulating safety data from the study in order to 
continue enrollment of subjects within a cohort and whether to enroll subjects into the 
next cohort. 
In addition to these periodic reviews, there will be a safety and immunogenicity interim 
analysis for the selection of an LHD153R adjuvant dosage based on the data collected 
through Day 29 from subjects enrolled in all cohorts. This analysis will be performed by 
personnel not involved in study decisions. The results will be unblinded at the group level 
thereby preserving the blind for individual subjects. No adjustment to the overall alpha 

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will be performed as the data collected subsequent to this analysis involve secondary and 
exploratory endpoints. 
 

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9.0  
SOURCE DOCUMENTATION, STUDY MONITORING AND 
AUDITING 
Study monitoring and auditing will be standardized and performed in accordance with the 
Sponsor’s or delegated contract research organization’s (CRO) standard operating 
procedures and applicable regulatory requirements (e.g., FDA, EMA, and ICH 
guidelines). 
Prior to enrolment of the first study subject, GSK or delegate will train investigators 
and/or their study staff on the study protocol, all applicable study procedures, 
documentation practices and all electronic systems. CRFs must be completed for each 
enrolled subject (see section 8.3.1 for definition of enrolled subject). Documentation of 
screened but not enrolled subjects must be maintained at the site and made available for 
review by the site monitor. 
9.1  
Source Documentation 
Prior to the start of the study, the site staff participating in the study conduct will be 
instructed on what documents will be required for review as source documents. The kinds 
of documents that will serve as source documents will be agreed between Sponsor or 
delegate and investigator and designees and specified in the SDA/Source Data 
Verification Form prior to subject enrolment. 
In addition, source documentation must include all of the following: subject identification 
(on each page), eligibility and participation, proper informed consent procedures, dates of 
visits, adherence to protocol procedures, adequate reporting and follow-up of adverse 
events, documentation of prior/concomitant medication/vaccines, study vaccine 
receipt/dispensing/return records, study vaccine administration information, any data 
collected by a telephone conversation with the subject and date of completion and reason. 
The subject must also allow access to the subject’s medical records. Each subject must be 
informed of this prior to the start of the study and consent for access to medical records 
may be required in accordance with local regulations. 
All safety data reported by subjects must be written down in source documents. If there 
are multiple sources of information (e.g., Subject Diary, verbal report of the subject, 
telephone contact details, medical chart) supporting the diagnosis of an adverse event, 
these sources must be identified in the source documents, discrepancies between sources 
clarified, the ultimate diagnosis must be justified and written in the source documents, 
and this diagnosis must be captured in the appropriate CRF page. The CRF must also 

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capture which source(s) of information were used to determine the adverse event (e.g., 
subject recall, medical chart, Subject Diary). 
9.2  
Study Monitoring, Auditing and Source Data Verification 
Prior to enrolment of the first study subject, GSK or its designee (e.g., a CRO) will 
develop a Monitoring Plan to specify how centralized and/or on-site monitoring, 
including clinical specimens reconciliation, will be performed for the study. Study 
progress will be monitored as frequently as necessary to ensure: 
▫ that the rights and well-being of human subjects are protected, 
▫ the reported study data are accurate, complete, and verifiable from the source 
documents and 
▫ the conduct of the study is in compliance with the current approved 
protocol/amendment(s), GCP and applicable regulatory requirements. 
Contact details for the team involved in study monitoring will be provided to the 
investigator. Study data recorded on CRFs will be verified by checking the CRF entries 
against source documents in order to ensure data completeness and accuracy as required 
by study protocol. 
Additional documents such as the investigator site file, pharmacy records, and informed 
consent documentation must also be available for review if requested. Arrangements for 
monitoring visits will be made in advance in accordance with the monitoring plan, except 
in case of emergency. 
The investigator and/or site staff must make source documents of subjects enrolled in this 
study available for inspection at the time of each monitoring visit and Sponsor audits, 
when applicable. These documents must also be available for inspection, verification and 
copying, as required by regulations, by officials of the regulatory health authorities (e.g., 
FDA, EMA and others) and/or ECs/IRBs. The investigator and study site staff must 
comply with applicable privacy, data protection and medical confidentiality laws for use 
and disclosure of information related to the study and enrolled subjects. 
10.0  
DATA MANAGEMENT 
10.1 
Data Entry and Management 
In this study, all clinical data (including, but not limited to, AE/SAEs, concomitant 
medications, medical history, and physical assessments), safety data, and immunogenicity 
data will be entered into an EDC system, which is compliant with Title 21 Part 11 policies 

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of the Code of Federal Regulations (FDA, 1997). The data system includes password 
protection and internal quality checks. The EDC system will be designed and validated by 
the Sponsor prior to activation for data entry by sites. The investigator or designated 
delegate must review data entered and electronically sign the CRFs to verify their 
accuracy. 
Access to the EDC system for data entry or review will require training and distinct 
individual access code assignments to those site staff members who will be entering study 
data and those involved in study oversight who may review study data. Data are collected 
within the EDC system, to which the Sponsor and site monitors have exclusively “read 
only” access. 
Paper CRFs will be provided for each pregnant subject by the Sponsor. All appropriate 
pregnant subject data collected will be recorded on this form. One copy must be retained 
by the investigator, and all other copies (including the original copy) will be returned as 
directed by the Sponsor. Instructions on how to complete this form will be provided to the 
investigator. 
10.2  
Data Clarification 
As part of the conduct of the trial, the Sponsor may have questions about the data entered 
by the site, referred to as queries. The monitors and the Sponsor are the only parties that 
can generate a query. All corrections and clarifications will be entered into the EDC 
system and will be identified by the person entering the information, the reason for the 
change, as well as the time of the changes made. If changes are made to a previously and 
electronically signed CRF, the investigator must confirm and endorse the changes 
10.3  
Data Protection 
GSK respects the subjects’ rights to privacy and will ensure the confidentiality of their 
medical information in accordance with all applicable laws and regulations. 
The Sponsor as Data Controller according to the European Directive on the protection of 
individuals with regard to the processing of personal data and on the free movement of 
such data (95/46/EC) confirms herewith compliance to Directive 95/46/EC in all stages of 
Data Management. 
 

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11.0  
RECORD RETENTION 
Investigators must retain all study records required by GSK and by the applicable 
regulations in a secure and safe facility. The investigator must consult a GSK 
representative before disposal of any study records, and must notify the Sponsor of any 
change in the location, disposition, or custody of the study files. Essential documents 
must be retained for 15 years. “Essential documents” are defined as documents that 
individually and collectively permit evaluation of the conduct of a study and the quality of 
the data produced. These documents should be retained for a longer period, however, if 
required by the applicable national regulatory or institutional requirements.  
These principles of record retention will also be applied to the storage of laboratory 
samples, provided that the integrity of the stored sample permits testing. 
 

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12.0  
USE OF INFORMATION AND PUBLICATION 
GSK assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov, and in compliance with current regulations. 
GSK also assures that key results of this clinical study will be posted in a publicly 
accessible database within the required time-frame from the End of Study as defined in 
section 3.9. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
GSK must be notified of any intent to publish data collected from the study and prior 
approval from GSK must be obtained prior to submission for publication. 
 

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13.0  
ETHICS 
13.1  
Regulatory and Ethical Compliance 
The study will be conducted in compliance with the protocol, GCP and applicable 
regulatory requirement(s). 
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, European 
Directive 2001/20/EC, GSK codes on protection of human rights, and with the ethical 
principles laid down in the Declaration of Helsinki (European Council 2001, US Code of 
Federal Regulations, ICH 1997). 
13.2  
Informed Consent Procedures 
Eligible subjects may only be included in the study after providing written informed 
consent or assent, as described in section 5.1.1. Before the start of the study, the 
investigator will have the informed consent and any other materials that will be provided 
to the subjects reviewed and approved by the IRB/EC. This review and approval will be 
documented and stored with other study documents. The investigator or designee must 
fully inform the subject or legal guardian of all pertinent aspects of the study. A copy of 
the written informed consent will be given to the subject or the designee. The 
subject/designee must be allowed ample time to ask about the details of the study and to 
make a decision as to whether or not to participate in the study. The subject and/or legal 
guardian(s) must sign the consent form indicating their agreement to participate in the 
study before any study-related procedures are conducted. The informed consent process 
may be conducted up to 28 days prior to vaccination on Day 1. If the subject is unable to 
read and write, a witness must be present during the informed consent discussion and at 
the time of informed consent signature. 
Prior to the start of the study, GSK will provide to investigators a proposed informed 
consent form that complies with the ICH GCP guideline and regulatory requirements and 
is considered appropriate for this study. Any changes to the proposed consent form 
suggested by the investigator must be agreed to by GSK before submission to the IRB/EC 
and a copy of the approved version must be provided to GSK after IRB/EC approval. 
Women of childbearing potential should be informed that taking the study medication 
may involve unknown risks to the fetus if pregnancy were to occur during the study and 
agree that in order to participate in the study they must adhere to the contraception 
requirements indicated in the protocol for the duration of the study. In case of doubt on 

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the ability of a subject to adhere to these requirements, that subject should not be allowed 
in the study 
13.3  
Responsibilities of the Investigator and IRB/EC 
The protocol and the proposed informed consent form must be reviewed and approved by 
a properly constituted IRB/EC before study start. Properly constituted IRB/EC is defined 
in ICH Guideline for Good Clinical Practice E6 (R1), Section 3 (ICH, 1997). A signed 
and dated statement that the protocol and informed consent have been approved by the 
IRB/EC must be given to GSK before study initiation. Prior to study start and at any time 
the protocol is amended during study conduct, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance 
with these documents and all of the instructions and procedures found in this protocol and 
to give access to all relevant data and records to GSK monitors, auditors, GSK Clinical 
Quality Assurance representatives, designated agents of GSK, IRBs/ECs, and regulatory 
authorities as required. If an inspection of the clinical site is requested by a regulatory 
authority, the investigator must inform GSK immediately that this request has been made. 
The investigator also responsible for the following: 
▫ Maintaining a list of appropriately qualified persons to whom the investigator has 
delegated significant study-related duties. 
▫ Demonstrating the capability of recruiting the required number of suitable subjects 
within the recruitment period. 
▫ Demonstrating sufficient time and staffing to properly conduct and complete the study 
within the agreed study period. 
▫ Ensuring that all persons assisting with the study are adequately informed about the 
protocol, the investigational product(s), and their study-related duties and functions 
▫ Ensuring that appropriately trained health care professionals are responsible for all 
study-related medical decisions and for ensuring appropriate medical care of subjects 
experiencing any adverse event related to the study. 
▫ If permission to do so is given by the subject, ensuring that the subject’s primary 
healthcare provider is informed of the subject’s participation in the study. 
The investigator should not implement any deviation from, or changes of the protocol 
without agreement by the Sponsor and prior review and documented approval/favourable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an 
immediate hazard(s) to study subjects, or when the change(s) involves only logistical or 

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administrative aspects of the study (e.g., change in monitor(s), change of telephone 
number(s)). In addition, the investigator, or person designated by the investigator, should 
document and explain any deviation from the approved protocol. 
The investigator may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior IRB/IEC 
approval/favourable opinion. As soon as possible, the implemented deviation or change, 
the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be 
submitted: 
(a) to the IRB/IEC for review and approval/favourable opinion, 
(b) to the Sponsor for agreement and, if required, 
(c) to the regulatory authority(ies). 
13.4  
Protocol Amendments 
An amendment is a written description of change(s) to or formal clarification of a study 
protocol which may impact on the conduct of the clinical study, potential benefit of the 
clinical study, or may affect subject safety, including changes of study objectives, study 
design, subject population, sample sizes, study procedures, or significant administrative 
aspects. An administrative change of a study protocol is a minor correction or clarification 
that has no significant impact on the way the clinical study is to be conducted and no 
effect on subject safety (e.g., change of telephone number(s), logistical changes). Protocol 
amendments must be approved by GSK, health authorities where required, and the 
IRB/EC. In cases when the amendment is required in order to protect the subject safety, 
the amendment can be implemented prior to IRB/EC approval. Notwithstanding, the need 
for formal approval of a protocol amendment, the investigator is expected to take any 
immediate action required for the safety of any subject included in this study, even if this 
action represents a deviation from the protocol. In such cases, GSK should be notified of 
this action, the IRB/EC at the study site, and, if required by local regulations, the relevant 
health authority should be informed within 10 working days. 
14.0  
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U.S. Department of Health and Human Services, Food and Drug Administration, CBER  
(2009): Guidance for Industry Patient-Reported Outcome Measures: Use in Medical  
Product Development to Support Labeling Claims 
Vasilakos JP, and Tomai MA. The use of Toll-like receptor 7/8 agonists as vaccine 
adjuvants." Expert Rev Vaccines 2013; 12: 809-819. 
World Medical Association General Assembly Declaration of Helsinki - Ethical  
Principles for Medical Research Involving Human Subjects (1996) 
 

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APPENDIX A: GRADING SCALES FOR SOLICITED LOCAL ADVERSE  
EVENTS* 
(Adapted from CBER 2007b) 
Adverse event Following  
Administration of  
Injectable Product  
Mild (Grade 
1)  
Moderate 
(Grade 2)  
Severe 
(Grade 3)  
Pain 
present but does not 
interfere with activity 
interferes with activity 
prevents daily activity 
Induration / Swelling /  
Erythema 
25 – 50 mm 
51 – 100 mm 
> 100 mm  
*This toxicity grading scale is adapted from CBER 2007 to enable ease of reporting by Subjects in the 
source documents for ‘patient reported’ solicited adverse events.. ‘Grade 4’ is not listed here but will be 
defined in the Statistical Analysis Plan as necessary. 
 

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APPENDIX B: GRADING SCALES FOR SOLICITED SYSTEMIC ADVERSE  
EVENTS* 
(Adapted from CBER 2007b) 
Systemic  
Adverse event 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Fever 
°C 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 - 102 
39.0 – 40 
102.1 - 104 
°F 
Chills 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Loss of Appetite 
Loss of appetite without 
decreased oral intake  
decreased oral intake  
without weight loss 
decreased oral intake with 
weight loss 
Nausea 
Nausea present but not 
interfering with oral intake 
Nausea leading to decreased 
oral intake 
Nausea leading to minimal to 
no oral intake 
Vomiting 
1-2 episodes/24 hours 
>2 episodes/24 hours 
requires outpatient 
hydratation 
Diarrhea 
2-3 loose stools /24 hours 
4-5 loose stools /24 hours 
6 or more watery stools /24 
hours or requires outpatient 
IV hydration 
Generalized  
Myalgia 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Generalized  
Arthralgia 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Headache 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Fatigue 
present but does not interfere 
with activity 
interferes with activity 
prevents daily activity 
Generalized  
Rash 
localized area of the skin (1 
extremity only) 
moderate area of the skin 
(2 or more body regions 
without whole body 
involvement) 
most of the skin 
Urticaria 
localized area of the skin (1 
extremity only) 
moderate area of the skin 
(2 or more body regions 
without whole body 
involvement) 
most of the skin 

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*This toxicity grading scale is adapted from CBER 2007b to enable ease of reporting by Subjects in the 
source documents for ‘patient reported’ solicited adverse events. ‘Grade 4’ is not listed here but will be 
defined in the statistical analysis plan as necessary 

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TOXICITY SCALES FOR LABORATORY ABNORMALITIES  
PRO-01 TEMP 06 / Atlas No. 293620 
Version No. 2 / Version Date: December 2, 2013 
APPENDIX C:  
(SERUM CLINICAL CHEMISTRY)  
Serum*,** 
Mild (Grade 1)  
Moderate 
(Grade 2)  
Severe 
(Grade 3)  
Potentially Life  
Threatening  
(Grade 4)*** 
Sodium – Hyponatremia 
mEq/L  
132 – 134  
130 – 131  
125 – 129  
< 125  
Sodium – Hypernatremia 
mEq/L  
144 – 145  
146 – 147  
148 – 150  
> 150  
Potassium – Hypokalemia 
mEq/L  
3.5 – 3.6  
3.3 – 3.4  
3.1 – 3.2  
< 3.1  
Potassium – Hyperkalemia 
mEq/L  
5.1 – 5.2  
5.3 – 5.4  
5.5 – 5.6  
> 5.6  
Blood Urea Nitrogen  
BUN mg/dL  
23 – 26  
27 – 31  
> 31  
Requires dialysis  
Creatinine – mg/dL  
1.5 – 1.7  
1.8 – 2.0  
2.1 – 2.5  
> 2.5 or requires 
dialysis  
Liver Function Tests –ALT,  
AST  
increase by factor  
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN  
5.1 – 10 x ULN  
> 10 x ULN  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 

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**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 
***The clinical signs or symptoms associated with laboratory abnormalities might result in characterization 
of the laboratory abnormalities as Potentially Life Threatening (Grade 4). For example. a low sodium value 
that falls within a grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia event if 
the subject had a new seizure associated with the low sodium value. “ULN” = the upper limit of the normal 
range. 
APPENDIX D:  
(HEMATOLOGY) 
Hematology*,** 
Mild 
(Grade 1)  
Moderate  
(Grade 2)  
Severe 
(Grade 3)  
Potentially Life  
Threatening  
(Grade 4)  
Hemoglobin (Female) 
gm/dL  
11.0 – 12.0  
9.5 – 10.9  
8.0 – 9.4  
< 8.0  
Hemoglobin (Female) 
change from baseline 
value - gm/dL  
Any decrease – 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
Hemoglobin (Male) 
gm/dL  
12.5 – 13.5  
10.5 – 12.4 
8.5 – 10.4  
< 8.5  
Hemoglobin (Male) 
change from baseline 
value – gm/dL  
Any decrease – 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
WBC Increase - cell/mm3 
10,800 – 15,000  
15,001 – 20,000  
20,001 – 25, 000  
> 25,000  

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WBC Decrease cell/mm3 
2,500 – 3,500  
1,500 – 2,499  
1,000 – 1,499  
< 1,000  
Platelets Decreased 
cell/mm3 
125,000 – 140,000 
100,000 – 124,000 
25,000 – 99,000  
< 25,000  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate.  
**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 
APPENDIX E:  
(URINE) 
Urine*,** 
Mild 
(Grade 1)  
Moderate  
(Grade 2)  
Severe 
(Grade 3)  
Potentially Life  
Threatening  
(Grade 4)  
Protein  
Trace  
1+  
2+  
Hospitalization or 
dialysis  
Glucose  
Trace  
1+  
2+  
Hospitalization for 
hyperglycemia  
Blood (microscopic) – 
red blood cells per high 
power field (rbc/hpf)  
1 - 10  
11 – 50  
> 50 and/or gross 
blood  
Hospitalization or 
packed red blood 
cells (PRBC) 
transfusion  
*The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate. 

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**Laboratory values that fall in the normal range may be assigned a category of “Grade 0.” 

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APPENDIX F: TOXICITY SCALES FOR VITAL SIGNS 
Vital Signs* 
Mild 
(Grade 1)  
Moderate  
(Grade 2)  
Severe 
(Grade 3)  
Potentially Life  
Threatening  
(Grade 4)  
Tachycardia - beats per 
minute 
101-115 
116-130 
>130 
ER visit or 
hospitalization for 
arrhythmia 
Bradycardia - beats per 
minute** 
40-44 
35-39 
<35 
ER visit or 
hospitalization for 
arrhythmia 
Hypertension (systolic) - 
mm Hg 
141-150 
151-155 
>155 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypertension (diastolic) - 
mm Hg 
91-95 
96-100 
>100 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypotension (systolic) 
mm Hg  
85-89 
80-84 
<80 
ER visit or 
hospitalization for 
hypotensive shock 
Respiratory Rate – 
breaths per minute*** 
21-23 
24-27 
>27 
Intubation 
*Subject should be at rest for all vital signs measurements 
**Resting heart rate for young healthy subject population is between 45-90 per minute 
***Respiratory rate for young healthy subject population is between 12-20 breaths per minute 
APPENDIX G: PROTOCOL AMENDMENTS SUMMARY OF CHANGES 
GlaxoSmithKline Biologicals SA 
Vaccines R &D 
Protocol Amendment 6 
eTrack study number  
205496 (MENCLHD153R-AL (V132)-001 and 
Abbreviated Title (V132_01EXP)) 
EudraCT number 
2014-002430-31 

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Amendment number: 
Amendment 6 
Amendment date: 
19 June 2017 
Co-ordinating author: 
Rationale/background for 
changes:  
biophysical the 
study vaccines. 
PPD 
 Scientific Writer 
onality of specific antibodies induced by  
o include an add
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Synopsis  
In the Exploratory Objectives section, the following objective has been added: 
To explore the biophysical and functional characteristics of antibodies induced by 
MenC-CRM197/Aluminium Hydroxide/LHD153R or aluminium hydroxide adjuvanted 
Meningococcal C-CRM197 Conjugate Vaccine. 
In the Exploratory endpoints section, the following text has been added: 
Exploratory immunogenicity endpoints: 
Testing and analyses of exploratory immunogenicity endpoints may be performed after 
the Clinical Study Report (CSR) has been completed, in which case these data will be 
submitted as an addendum to the CSR. 
• 
Antigen specific antibody isotype, Fc receptor binding capability and antibody 
glycosylation state will be assessed at Day 1 (baseline), Day 29, and Day 181.  
• 
Functionality of MenC-specific antibodies to fix complement, promote 
antibodydependent cell mediated cytoxicity (ADCC), induce phagocytosis 
(ADCP) and activate FcR+ cells in vitro will be also assessed at Day 1 
(baseline), Day 29, and Day 181 
Section 2.3: Exploratory objectives: The following objective has been added: 

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To explore the biophysical and functional characteristics of antibodies induced by 
MenC-CRM197/Aluminium Hydroxide/LHD153R or aluminium hydroxide adjuvanted 
Meningococcal C-CRM197 Conjugate Vaccine. 
Section 7.4 Exploratory measurements: The following text has been added. 
To evaluate the biophysical and functional properties of MenC-specific antibodies 
induced by the study vaccines, biophysical and cell-based assays will be performed on 
serology samples collected at Day 1 (baseline), Day 29, and Day 181. Antigen specific 
antibody isotypes, Fc Receptor binding and the antibody glycosylation state will be 
assessed. Functional ability of the MenC-specific antibodies to fix complement, to 
promote antibody-dependent cell mediated cytoxicity (ADCC), to induce phagocytosis 
(ADCP) and to activate FcR+ cells in vitro will be assessed at Day 1 (baseline), Day 29, 
and Day 181. 
Section 8.1.3 Exploratory Immunogenicity endpoint(s): The following text has been 
added: 
The exploratory immunogenicity endpoints are based on results of testing which may not 
be performed until after the study report has been finalized and will be further refined 
prior to testing 
▫ Antigen-specific antibody isotype, Fc receptor and antibody glycosylation state will 
be assessed at Day 1 (baseline), Day 8, Day 29, and Day 181 by biochemical and 
cell-based assays. 
▫ Functionality of MenC-specific antibodies to fix complement, promote 
antibodydependent cell mediated cytoxicity (ADCC), induce phagocytosis and 
activate FcR+ cells in vitro will be also assessed at Day 1 (baseline), Day 29, and 
Day 181. 

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Protocol Sponsor Signatory Approval 
Page 1 of 2 
eTrack study number and 
Abbreviated Title 
205496 (MENCLHD153R-AL (V132)-001 
(V132_01EXP)) 
Date of protocol Amendment 
19 June 2017 
Detailed Title  
A Phase 1, Randomized, Observer-Blind, 
DosageEscalation Study to Evaluate the Safety and  
Immunogenicity of an Aluminium  
Hydroxide/LHD153R Adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine Compared to 
Aluminium  
Hydroxide Adjuvanted Meningococcal C-CRM197 
Conjugate Vaccine in Healthy Adults (18-45 years of 
age) 
Sponsor signatory 
Antonio Gonzalez Lopez 
Clinical Research and Development 
Lead 
Signature 
 
Date 
 
For internal use only 

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Protocol Investigator Approval 
eTrack study number and 
Abbreviated Title 
205496 (MENCLHD153R-AL (V132)-001 
(V132_01EXP)) 
Date of protocol Amendment 
19 June 2017 
Detailed Title  
A Phase 1, Randomized, Observer-Blind, 
DosageEscalation Study to Evaluate the Safety and  
Immunogenicity of an Aluminium  
Hydroxide/LHD153R Adjuvanted Meningococcal 
CCRM197 Conjugate Vaccine Compared to 
Aluminium  
Hydroxide Adjuvanted Meningococcal C-CRM197 
Conjugate Vaccine in Healthy Adults (18-45 years of 
age) 
Investigator name 
Signature 
 
Date 
 
For internal use only 

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PPD