A Phase 3, Randomized, Double-Blind Study of the Safety, Tolerability, Lot-to-Lot Consistency, Immunogenicity & Non-Interference With Concomitant Vaccinations of Serum Institute of PNEUMOSIL in Healthy Infants in The Gambia
Phase: PHASE3
Conditions: Pneumonia, Pneumococcal
Sponsor: PATH

1 
 
VAC-056 
A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety, 
Tolerability, Lot-to-Lot Consistency, Immunogenicity, and Non-
Interference with Concomitant Vaccinations of Serum Institute of 
India’s 10-Valent Pneumococcal Conjugate Vaccine 
(PNEUMOSIL®) in Healthy Infants in The Gambia 
 
 
 
CONFIDENTIAL 
 
 June 1, 2018 
 
 
 
Sponsored by: 
PATH Vaccine Solutions (PATH) 
 
 
 
Study Director: 
Steve Lamola, MD 
 
 
 
Principal Investigator: 
Ed Clarke, MB ChB, PhD 
 
 
 
 
 Version 5.0 of June 1, 2018   
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone or used 
except as authorized by PATH 

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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ........................................................................................................................ 2 
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................................... 6 
STATEMENT OF COMPLIANCE ........................................................................................................ 9 
PROTOCOL SIGNATURE PAGE ...................................................................................................... 10 
KEY ROLES AND CONTACT INFORMATION .............................................................................. 11 
PROTOCOL SUMMARY .................................................................................................................... 13 
1. 
BACKGROUND AND RATIONALE ......................................................................................... 19 
1.1. 
Burden of Disease .................................................................................................................. 19 
1.2. 
Pathogen and Clinical Disease ............................................................................................... 19 
1.3. 
Pneumococcal Epidemiology in Africa and The Gambia ...................................................... 19 
1.4. 
Licensed Pneumococcal Conjugate Vaccines ........................................................................ 20 
1.5. 
Rationale for PNEUMOSIL® Development .......................................................................... 20 
1.6. 
Introduction to PNEUMOSIL ................................................................................................ 21 
1.7. 
Summary of Nonclinical Studies............................................................................................ 21 
1.7.1. 
Pharmacology ................................................................................................................. 22 
1.7.2. 
Toxicology ...................................................................................................................... 22 
1.8. 
Summary of Clinical Studies.................................................................................................. 23 
1.8.1. 
Safety .............................................................................................................................. 24 
1.8.2. 
Immunogenicity .............................................................................................................. 28 
1.9. 
Clinical Development Plan for PNEUMOSIL ....................................................................... 31 
1.10. Study Rationale ...................................................................................................................... 31 
2. 
HYPOTHESES, OBJECTIVES AND ENDPOINTS................................................................... 34 
2.1. 
Study Hypotheses ................................................................................................................... 34 
2.1.1. 
Primary Hypotheses: ....................................................................................................... 34 
2.1.2. 
Secondary Hypotheses: ................................................................................................... 34 
2.2. 
Study Objectives .................................................................................................................... 35 
2.2.1. 
Primary Objectives: ........................................................................................................ 35 
2.2.2. 
Secondary Objectives: .................................................................................................... 35 
2.2.3. 
Supplemental Objectives: ............................................................................................... 35 
2.3. 
Study Endpoints ..................................................................................................................... 36 

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2.3.1. 
Primary Endpoints: ......................................................................................................... 36 
2.3.2. 
Secondary Endpoints: ..................................................................................................... 36 
2.3.3. 
Supplemental Endpoints: ................................................................................................ 37 
3. 
STUDY DESIGN.......................................................................................................................... 37 
4. 
STUDY POPULATION ............................................................................................................... 40 
4.1. 
Description of Study Population ............................................................................................ 40 
4.2. 
Inclusion Criteria .................................................................................................................... 41 
4.3. 
Exclusion Criteria ................................................................................................................... 41 
5. 
STUDY PRODUCTS ................................................................................................................... 43 
5.1. 
PNEUMOSIL ......................................................................................................................... 43 
5.1.1. 
Product Description ........................................................................................................ 43 
5.1.2. 
Manufacturer ................................................................................................................... 43 
5.1.3. 
Presentation and Formulation ......................................................................................... 43 
5.1.4. 
Storage ............................................................................................................................ 43 
5.1.5. 
Potential Safety Risks ..................................................................................................... 43 
5.2. 
Synflorix ................................................................................................................................. 44 
5.2.1. 
Product Description ........................................................................................................ 44 
5.2.2. 
Manufacturer ................................................................................................................... 44 
5.2.3. 
Presentation and Formulation ......................................................................................... 44 
5.2.4. 
Storage ............................................................................................................................ 44 
5.2.5. 
Potential Safety Risks ..................................................................................................... 44 
5.3. 
Vaccine Storage, Transport, and Temperature Monitoring .................................................... 45 
5.4. 
Dose Preparation and Administration .................................................................................... 46 
5.5. 
Accountability and Disposal .................................................................................................. 46 
6. 
STUDY PROCEDURES .............................................................................................................. 47 
6.1. 
Recruitment and Informed Consent ...................................................................................... 47 
6.1.1. 
Community and Individual Sensitization........................................................................ 47 
6.1.2. 
Initial and Continuing Informed Consent ....................................................................... 48 
7. 
Study Visits ................................................................................................................................... 49 
7.1.1. 
Screening (Visit 1) .......................................................................................................... 49 
7.1.2. 
Randomization and Vaccination Visits (Visit 1, 2, 3, and 5) ........................................ 50 
7.1.3. 
Post-Vaccination Visits (Visit 4, 6, 7 and Unscheduled Visits) ..................................... 52 

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7.1.4. 
Interim Contacts and Visits ............................................................................................. 55 
7.2. 
Refusing of Procedures, Missed Visits, Withdrawal, and Early Termination ....................... 56 
7.3. 
Concomitant Medications and Treatments ............................................................................. 57 
7.4. 
Blinded and Unblinded Study Personnel ............................................................................... 58 
7.5. 
Unblinding Procedure ............................................................................................................ 59 
8. 
LABORATORY EVALUATIONS .............................................................................................. 59 
8.1. 
Sample Collection, Distribution, and Storage ........................................................................ 59 
8.2. 
Clinical Laboratory Assays .................................................................................................... 60 
8.3. 
Immunological Assays ........................................................................................................... 60 
8.4. 
Assay Qualification, Standardization, and Validation ........................................................... 61 
8.5. 
Biohazard Containment .......................................................................................................... 61 
9. 
SAFETY ASSESSMENT AND REPORTING ............................................................................ 62 
9.1. 
Collection of Safety Events .................................................................................................... 62 
9.2. 
Definitions .............................................................................................................................. 62 
9.2.1. 
Adverse Event or Medical Event .................................................................................... 62 
9.2.2. 
Severity (Intensity) of Adverse Event............................................................................. 63 
9.2.3. 
Causal Relationship of an Adverse Event ....................................................................... 63 
9.2.4. 
Assessment of Outcome of Adverse Event ..................................................................... 64 
9.2.5. 
Unexpected Adverse Event / Drug Reaction .................................................................. 64 
9.2.6. 
Serious Adverse Event .................................................................................................... 64 
9.2.7. 
Adverse Event Recording and Reporting ....................................................................... 65 
9.2.8. 
Serious Adverse Event Reporting ................................................................................... 66 
9.3. 
Unanticipated Problems ......................................................................................................... 66 
9.4. 
Medication Errors ................................................................................................................... 66 
10. SAFETY MONITORING ............................................................................................................. 66 
10.1. Protocol Safety Review Team ................................................................................................ 66 
10.2. Data Safety Monitoring Board ............................................................................................... 67 
10.3. Protocol Deviation and Protocol Violation ............................................................................ 68 
11. DATA MANAGEMENT .............................................................................................................. 68 
11.1. Case Report Form Development and Completion ................................................................. 69 
11.2. Record Archival ..................................................................................................................... 69 
11.2.1. Archiving Data at Study Site .......................................................................................... 69 

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11.2.2. Data Storage and Archival .............................................................................................. 69 
11.3. Posting of Information on Clinicaltrials.gov .......................................................................... 70 
11.4. Confidentiality ........................................................................................................................ 70 
11.5. Publication .............................................................................................................................. 70 
12. STATISTICAL DESIGN AND ANALYSIS ............................................................................... 70 
12.1. Study Populations ................................................................................................................... 71 
12.2. Conduct of the Analyses ........................................................................................................ 71 
12.2.1. Handling of Dropouts or Missing Data ........................................................................... 72 
12.3. Statistical Methods ................................................................................................................. 72 
12.3.1. Immunogenicity Analysis ............................................................................................... 72 
12.3.2. Safety Analysis ............................................................................................................... 74 
12.3.3. Multiple Comparisons/Multiplicity ................................................................................ 74 
12.4. Sample Size and Power Calculations ..................................................................................... 75 
13. STUDY MONITORING .............................................................................................................. 78 
13.1. Independent Auditing ............................................................................................................. 79 
13.2. Regulatory Agency Auditing ................................................................................................. 79 
14. OBLIGATIONS AND ROLES OF THE SPONSOR, PI AND STUDY PERSONNEL ............. 79 
15. ETHICAL CONSIDERATIONS AND INFORMED CONSENT ............................................... 80 
15.1. Institutional Review Board/Ethics Review Committee ......................................................... 80 
15.2. Informed Consent Process ...................................................................................................... 80 
15.3. Research Involving Children .................................................................................................. 81 
15.4. Insurance and Indemnity ........................................................................................................ 81 
15.5. Risk/Benefit ............................................................................................................................ 81 
15.6. Subject Confidentiality ........................................................................................................... 82 
15.7. Reimbursement ....................................................................................................................... 82 
15.8. Storage of Specimens ............................................................................................................. 82 
15.8.1. Use of Specimens during the Study ................................................................................ 82 
15.8.2. Future Use of Stored Specimens ..................................................................................... 83 
16. APPENDICES .............................................................................................................................. 84 
16.1. Appendix 1:  Solicited Local and Systemic Reactions Toxicity Grading Table.................... 84 
16.2. Appendix 2:  Vital Signs Toxicity Grading Table ................................................................. 86 
16.3. Appendix 3:  References ........................................................................................................ 87 

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LIST OF ABBREVIATIONS AND ACRONYMS 
ABBREVIATION/ 
ACRONYM 
DEFINITION 
ADR 
adverse drug reaction 
AE 
adverse event 
Alum 
aluminum phosphate 
AMC 
Advance Market Commitment 
BHDSS 
Basse Health and Demographic Surveillance System 
BLQ 
below limit of quantitation 
CAPA 
corrective action and preventive action 
CBER 
Center for Biologics Evaluation and Research 
CDAP 
1-cyano-4-dimethylaminopyridinium tetrafluoroborate 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CRF 
case report form 
CRM197 
Cross Reactive Material 197 
CRO 
contract research organization 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
DT 
diphtheria toxoid 
DTwP-HepB-Hib 
Pentavalent – diphtheria, tetanus, whole-cell pertussis, hepatitis B, and 
Haemophilus influenzae type b combined vaccine 
EC 
ethics committee 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
End of Study 
EPI 
Expanded Program on Immunization 
FDA 
US Food and Drug Administration 
FIP 
Full Immunogenicity Population 
FSFV 
first subject first visit 
Gambian 
subjects enrolled from the MRC field sites in The Gambia 
GCLP 
Good Clinical Laboratory Practice 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 

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GMC 
Geometric Mean Concentration 
GMP 
Good Manufacturing Practice 
GMT 
geometric mean titer 
GSK 
GlaxoSmithKline 
HbsAg 
hepatitis B surface antigen 
HBV 
Hepatitis B virus 
Hib 
Haemophilus influenzae type b 
HIV 
human immunodeficiency virus 
IATA 
International Air Transport Association 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ID 
identification 
IgG 
immunoglobulin G 
IM 
intramuscular 
IME 
Important Medical Event 
IP 
investigational product 
IPD 
invasive pneumococcal disease 
IPP 
Immunogenicity Persistence Population 
IPV 
inactivated poliovirus vaccine 
IRB 
Institutional Review Board 
IV 
intravenous 
IWC 
Infant Welfare Card 
LSLV 
last subject last visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOPA 
multiplexed opsonophagocytic assay 
MRCG 
Medical Research Council, representing Medical Research Council Unit 
The Gambia 
NMRA 
National Medicines Regulatory Authority 
NRA 
national regulatory authority 
NTF 
Note to File 
OPA 
opsonophagocytic assay 
OPV 
oral poliovirus vaccine 
PATH 
PATH Vaccine Solutions 
PCV 
pneumococcal conjugate vaccine 
PE 
physical examination 
PFS 
pre-filled syringe 

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PI 
Principal Investigator (the term is used throughout to indicate PI or 
designee) 
PP IMM 
Per Protocol Immunogenicity Population 
PSRT 
Protocol Safety Review Team 
RC 
research clinician 
RCD 
reverse cumulative distribution 
RDT 
rapid diagnostic test for malaria 
RE 
reactogenicity event 
REC 
Research Ethics Committee (PATH) 
RRF 
reactogenicity record form 
RV 
rotavirus vaccine (Rotarix)  
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SCC 
Scientific Coordinating Committee 
SD 
standard deviation 
SIDS 
sudden infant death syndrome 
SIIPL 
Serum Institute of India Pvt. Limited 
SOC 
system organ class 
SOP 
standard operating procedure 
SSP 
study specific procedure 
SST 
Serum Separator Tube 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
treatment-emergent adverse event 
TEN 
toxic epidermal necrolysis 
TMF 
Trial Master File 
TPN 
total parenteral nutrition 
TPP 
Target Product Profile 
TRS 
Technical Report Series 
TT 
tetanus toxoid 
WHO 
World Health Organization 
WIRB 
Western Institutional Review Board 
 
 
 

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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46) 
 
International Conference on Harmonisation (ICH) Guidance for GCP (E6) 
 
World Medical Association (WMA) Declaration of Helsinki – Ethical Principles for Research 
Involving Human Subjects (Oct 2013 or subsequent amendments) 
All key personnel (all individuals responsible for the design and conduct of this study) have completed 
Human Subjects Protection Training and ICH-GCP training. 
 
 
 

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PROTOCOL SIGNATURE PAGE 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements and ICH-GCP guidelines as outlined in the ‘Statement of Compliance.’ 
 
Principal Investigator: 
Signed: 
 
Date: 
 
 
Name: 
Title: 
 
 
Sponsor’s Representative: 
Signed: 
 
Date: 
 
 
Name: 
Title: 
 
 
 

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KEY ROLES AND CONTACT INFORMATION 
Sponsor 
PATH Vaccine Solutions (PATH) 
2201 Westlake Avenue 
Suite 200 
Seattle, WA 98121 
USA 
PATH Study Director / Clinical Lead 
Steve Lamola, MD 
Clinical Trial Center 
Medical Research Council Unit The Gambia at the London 
School of Hygiene and Tropical Medicine 
Atlantic Road, Fajara 
PO Box 273, Banjul 
The Gambia, West Africa 
Tel: (+220) 4495442/6 
Principal Investigator 
Ed Clarke, MB ChB, PhD 
Vaccine Manufacturer 
Serum Institute of India Pvt. Limited (SIIPL) 
212/2, Off Soli Poonawalla Road 
Hadapsar, Pune – 411028, India 
Tel: + 91-20-26993900 
Fax: + 91-20-26993921 
Contract Research Organization 
_______________ 
_______________ 
_______________ 
_______________ 
 
Immunology Laboratories 
Pneumococcal serology: 
_______________ 
_______________ 
_______________ 
_______________ 
Diphtheria, tetanus, pertussis, and Haemophilus 
influenzae type b  serology:  
_______________ 
_______________ 
_______________ 
_______________ 
Hepatitis B, measles, and rubella serology: 
_______________ 
_______________ 
_______________ 
_______________ 
Polio serology: 
_______________ 
_______________ 
_______________ 
_______________ 

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_______________ 
_______________ 
_______________ 
Rotavirus serology: 
_______________ 
_______________ 
_______________ 
_______________ 
Yellow fever serology: 
_______________ 
_______________ 
_______________ 
_______________ 
 
Clinical Laboratory 
_______________ 
_______________ 
_______________ 
_______________ 
 
Ethics Committees 
The Gambia Government/MRC Joint Ethics Committee 
c/o MRC Unit, The Gambia, Fajara, PO Box 273, Banjul, 
The Gambia, West Africa 
 
Western Institutional Review Board 
1019 39th Avenue SE Suite 120 
Puyallup, WA  98374-2115, United States 
The Gambia National Medicines 
Regulatory Agency 
The Medicines Control Agency 
 
 
 

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PROTOCOL SUMMARY 
TITLE 
A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety, 
Tolerability, Lot-to-Lot Consistency, Immunogenicity, and Non-
Interference with Concomitant Vaccinations of Serum Institute of 
India’s 
10-Valent 
Pneumococcal 
Conjugate 
Vaccine 
(PNEUMOSIL®) in Healthy Infants in The Gambia 
STUDY NUMBER 
VAC-056 
SCC NUMBER 
1517 
PROJECT PHASE 
Phase 3 
INVESTIGATIONAL 
PRODUCT(S) 
Investigational Vaccine: 
Pneumococcal 10-valent conjugate vaccine (PNEUMOSIL) at a dosage 
of 2 μg for each serotype polysaccharide, except 4 μg for 6B serotype, 
conjugated to a carrier protein (CRM197), with adjuvant (aluminum 
phosphate [alum]) and preservative (thiomersal). 
Active Comparator Vaccine: 
Pneumococcal 
conjugate 
vaccine 
(Non-Typeable 
Haemophilus 
influenzae (NTHi) protein D, diphtheria or tetanus toxoid conjugates) 
adsorbed (Synflorix®; GlaxoSmithKline) 
STUDY HYPOTHESES 
Primary Hypotheses: 
Immunogenicity: 
 
The immune responses to the 10 serotypes in PNEUMOSIL® (1, 5, 
6A, 6B, 7F, 9V, 14, 19A, 19F, 23F) induced by 3 different lots of 
PNEUMOSIL will be equivalent after a 3-dose primary series. 
 
The immune responses to at least 7 of the 10 serotypes in 
PNEUMOSIL will be non-inferior to the immune responses induced 
by the matched serotype (for 1, 5, 6B, 7F, 9V, 14, 19F, 23F) or 
serotype with the lowest seroresponse rate (for 6A, 19A) in 
Synflorix, after a 3-dose primary series. 
 
The immune responses induced by pentavalent, polio and rotavirus 
vaccines co-administered with PNEUMOSIL during a 3-dose 
primary series will be non-inferior to the immune responses observed 
when these vaccines are co-administered with Synflorix. 
Safety, Tolerability: 
 
PNEUMOSIL administered as a 3-dose primary series, and co-
administered with routine pediatric vaccines, will be safe and well 
tolerated. 
 
PNEUMOSIL administered as a booster dose to primed infants at 9 
months of age when co-administered with routine pediatric vaccines, 
will be safe and well tolerated. 

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Secondary Hypotheses: 
Immunogenicity: 
 
The immune responses induced by PNEUMOSIL for serotypes 6A 
and 19A will be superior to the cross-reactive responses to these 
serotypes induced by Synflorix after a 3-dose primary series. 
 
PNEUMOSIL will induce a measurable booster response to each of 
the 10 serotypes when administered as a 4th dose at 9 months of age. 
 
The immune responses induced by measles-rubella and yellow fever 
vaccines administered at 9 months of age concomitantly with a 
PNEUMOSIL booster dose will be non-inferior to those observed 
when the vaccines are co-administered with a Synflorix booster dose.
STUDY OBJECTIVES 
Primary Objectives: 
Immunogenicity: 
1. To demonstrate that the immune responses to the 10 pneumococcal 
serotypes in PNEUMOSIL (1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, 23F) 
induced by 3 different lots of PNEUMOSIL are equivalent when 
measured 4 weeks after a 3-dose primary series 
 
2. To demonstrate non-inferior immune responses for at least 7 of the 
10 serotypes in PNEUMOSIL in comparison to matched serotypes 
(for 1, 5, 6B, 7F, 9V, 14, 19F, 23F) or the lowest responder (for 6A, 
19A) in Synflorix based on (a) % IgG response ≥ 0.35 μg/mL or (b) 
IgG GMCs measured 4 weeks after a 3-dose primary series 
 
3. To demonstrate that the immune responses induced by routine 
pediatric vaccines (pentavalent, polio and rotavirus) when co-
administered with a 3-dose primary series of PNEUMOSIL are non-
inferior to those induced by these vaccines when co-administered 
with Synflorix (subset of subjects) 
Safety, Tolerability: 
1. To demonstrate an acceptable safety and tolerability profile for 
PNEUMOSIL administered as a 3-dose primary series and booster 
dose, and when co-administered with routine pediatric vaccines 
through 4 weeks after a booster dose (subset of subjects for 
tolerability) 
Secondary Objectives: 
Immunogenicity: 
1. To demonstrate that the immune responses to serotypes 6A and 19A 
in PNEUMOSIL are superior to the cross-reactive responses to these 
serotypes induced by Synflorix based on (a) % IgG response ≥ 0.35 
μg/mL or (b) IgG GMCs measured 4 weeks after a 3-dose primary 
series 
2. To evaluate the functional serotype-specific antibody responses 
induced by PNEUMOSIL in comparison to Synflorix, as measured 

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by OPA at 4 weeks post 3-dose primary series (subset of subjects)
3. To evaluate the booster responses (antibody concentrations and 
functional responses) to PNEUMOSIL in comparison to Synflorix, 
from 4 weeks after a 3-dose primary series to 4 weeks after a booster 
dose (subsets of subjects) 
4. To demonstrate that the immune responses induced by measles-
rubella and yellow fever vaccines when co-administered with a 
booster dose of PNEUMOSIL are non-inferior to those induced by 
these vaccines when co-administered with a booster dose of 
Synflorix (subset of subjects) 
Supplemental Objective: 
Immunogenicity: 
1. To evaluate the persistence of immune responses (antibody 
concentrations and functional responses) induced by PNEUMOSIL 
in comparison to Synflorix, 1 year after administration of a booster 
dose (subset of subjects) 
Safety: 
1. To assess the safety of 3-dose primary series and booster dose of 
PNEUMOSIL co-administered with routine pediatric vaccines in 
regards to serious adverse events occurring 4 weeks after the booster 
dose through 12 months after the booster dose (subset of subjects) 
STUDY ENDPOINTS 
Primary Endpoints: 
Immunogenicity: 
For Primary Objective 1 (lot consistency): 
 
Serotype-specific immunoglobulin G (IgG) geometric mean 
concentration (GMC) measured 4 weeks post dose 3 
For Primary Objective 2 (non-inferiority): 
 
Percentage of subjects with serotype-specific IgG concentrations ≥ 
0.35 µg/mL measured 4 weeks post dose 3 
 
Serotype-specific IgG GMC measured 4 weeks post dose 3 
For Primary Objective 3 (non-interference): 
 
Percentage of subjects with anti-diphtheria toxoid IgG concentration 
≥ 0.1 IU/mL measured 4 weeks post dose 3 
 
Percentage of subjects with anti-tetanus toxoid IgG concentration ≥ 
0.1 IU/mL measured 4 weeks post dose 3 
 
Percentage of subjects with anti-Hepatitis B surface antigen 
(HBsAg) IgG concentration ≥ 10 mIU/mL measured 4 weeks post 
dose 3 
 
Percentage of subjects with anti-Haemophilus influenzae type b 

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(PRP) IgG concentration ≥ 0.15 µg/mL measured 4 weeks post dose 
3 
 
Anti-pertussis toxoid and fimbriae IgG GMCs measured 4 weeks 
post dose 3 
 
Percentage of subjects with anti-poliovirus types 1, 2 and 3 
neutralizing antibody titers ≥ 1:8 measured 4 weeks post dose 3 
 
Percentage of subjects with anti-rotavirus IgA concentration ≥ 20 
U/mL measured 4 weeks post dose 3 
Safety, Tolerability: 
 
Number and severity of solicited local and systemic adverse events 
(reactogenicity events [REs]) through Day 6 post each 
vaccination 
 
Number, severity and relatedness of all AEs and serious adverse 
events (SAEs) during the entire study period through 4 weeks post 
last dose for the cohort 
Secondary Endpoints: 
Immunogenicity: 
For Secondary Objective 1 (superiority): 
 
Percentage of subjects with serotype-specific IgG concentrations ≥ 
0.35 µg/mL measured 4 weeks post dose 3 
 
Serotype-specific IgG GMC measured 4 weeks post dose 3 
Secondary Objective 2 (functional response): 
 
Percentage of subjects with OPA titer ≥ 1:8 measured 4 weeks post 
dose 3 
 
OPA geometric mean titer (GMT) measured 4 weeks post dose 3 
Secondary Objective 3 (boostability): 
 
Ratio of IgG GMCs measured 4 weeks post dose 4 to IgG GMCs 
measured 4 weeks post dose 3 
 
Ratio of OPA GMTs measured 4 weeks post dose 4 to OPA GMTs 
measured 4 weeks post dose 3 
Secondary Objective 4 (non-interference): 
 
Percentage of subjects with anti-measles IgG concentration ≥ 150 
mIU/mL measured 4 weeks post dose 4 
 
Percentage of subjects with anti-yellow fever neutralizing antibody 
titers ≥ 1:8 measured 4 weeks post dose 4 
 
Percentage of subjects with anti-rubella IgG concentration ≥ 4 
IU/mL measured 4 weeks post dose 4 

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Supplemental Endpoints: 
Immunogenicity: 
For Supplemental Objective 1 (immune persistence): 
 
Percentage of subjects with serotype-specific IgG concentrations ≥ 
0.35 µg/mL measured 1 year post dose 4 
 
Serotype-specific IgG GMC measured 1 year post dose 4 
 
Percentage of subjects with OPA titer ≥ 1:8 measured 1 year post 
dose 4 
 
OPA geometric mean titer (GMT) measured 1 year post dose 4 
For Supplemental Objective 2 (Safety): 
 
Number, severity and relatedness of all serious adverse events 
(SAEs) 4 weeks after the booster dose through 12 months after the 
booster dose (subset of subjects) 
STUDY DESIGN 
This prospective, single center, randomized, active-controlled, double-
blind, Phase 3 study in healthy Gambian PCV-naïve infants (6 to 8 weeks) 
will be conducted in 3 phases. In the initial priming phase, 2,250 subjects 
will be randomized (2:2:2:3) to receive 3 doses of either PNEUMOSIL 
(3 groups receiving vaccine from different lots) or Synflorix (1 group) at 
6, 10, and 14 weeks of age. In the second booster phase, the first 675 
randomized subjects will receive a booster dose of either PNEUMOSIL 
or Synflorix at 9 months of age that matches the treatment assignment for 
the priming phase. Standard EPI vaccinations in The Gambia will be 
given concomitantly with all 4 doses of the study vaccines. The third 
phase will include subjects from the booster phase whose parent provides 
additional consent to evaluate immune persistence at 1 year post booster 
vaccination.  
After parent(s) sign an informed consent form, prospective subjects will 
be assessed for eligibility to participate in the study, including assessment 
of medical history, vital signs and physical examination, and will receive 
the first vaccination (V1) at 6-8 weeks of age. Two subsequent primary 
vaccination visits will take place at 4 (+2) weeks after the prior 
vaccination. A follow-up visit (V4) will take place at 4 (+2) weeks after 
the third vaccination, during which blood will be collected for 
immunological assessments. This visit will serve as the end-of-study 
(EOS) visit for subjects not included among the first 675 subjects to be 
randomized (n=1,575).  
The first 675 subjects will continue on study and be asked to return for a 
booster vaccination (V5) at 9 (+1) months of age, followed 4 (+2) weeks 
later by a follow-up visit (V6), during which blood will be collected for 
immunological assessments. This visit will serve as the EOS visit for 
subjects whose parent does not provide consent for assessment of 
immune persistence 1 year after the booster vaccination.  

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After the last subject in the booster cohort completes V6, the database 
will be closed and the study unblinded (only the Sponsor, statistical 
personnel and medical monitor will be unblinded) in order to analyze and 
report primary and secondary endpoints. Those subjects (maximum 
n=675) whose parent provides additional consent to participation will 
return for a final visit (EOS, V7) at 12 (+1) months after the booster 
vaccination, during which blood will be collected for immunological 
assessment of immune persistence. 
STUDY SCHEMA 
w = weeks; m = months 
X = vaccination (+ EPI vaccines); B = blood sample for immunogenicity testing 
*Age ranges indicated for V1/V5. Other vaccination/follow up visits will be at 4 weeks post prior visit + 2 week window, 
except for V7, which will be at 12 months post V5 + 1 month window. 
# The total number of subjects assessed for immune persistence at V7 will depend on number of subjects whose parent 
provides additional informed consent. 
Groups 
Priming Phase 
Booster Phase 
Immune 
Persistence 
Phase 
N 
Visits* 
N 
Visits* 
Visit* 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
6-8 w 
V1+4 (+2) w 
V2+4(+2) 
w 
V3+4(+2)
w 
9-10 m 
V5+4(+2) 
w 
V5+12(+1) m 
PNEUMOSIL
Lot 1 
500 
X 
X 
X 
B 
150# 
X 
B 
B 
PNEUMOSIL
Lot 2 
500 
X 
X 
X 
B 
150# 
X 
B 
B 
PNEUMOSIL
Lot 3 
500 
X 
X 
X 
B 
150# 
X 
B 
B 
Synflorix 
750 
X 
X 
X 
B 
225# 
X 
B 
B 
STUDY POPULATION 
2,250 healthy, male and female PCV-naïve infants residing in The 
Gambia who are from 6 up to 8 weeks of age at enrollment (V1). 
STUDY DURATION 
All subjects will be followed for approximately 121 weeks after 
randomization (4 weeks after the third primary vaccination). A subgroup 
(n=675) will be followed for approximately 341 weeks after 
randomization (4 weeks after the booster dose). Those subjects in this 
subgroup whose parents provide consent will return for an additional 
blood draw at approximately 121 months after the booster dose 
(approximately 19 months after randomization). 
1Excluding any additional time due to visit windows 
 

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1. 
BACKGROUND AND RATIONALE 
1.1. 
Burden of Disease 
The bacterium Streptococcus pneumoniae kills a half million children annually before their fifth 
birthday, mostly in low-resource areas of the world.1 The most common cause of childhood morbidity 
and mortality due to the bacterium is pneumonia, which in 2013 was estimated to be the cause of 
roughly 900,000 (or 15% of all) under-five deaths worldwide, making it the most deadly infectious 
disease of young children today.2 Although pneumonia has multiple bacterial and viral etiologies, S. 
pneumoniae is the leading cause of severe pneumonia. In addition to pneumonia, S. pneumoniae also 
causes a number of other serious invasive pneumococcal diseases (IPD), including sepsis and 
meningitis, which collectively result in tremendous morbidity and mortality. The highest incidence of 
IPD is seen at the extremes of age, in the elderly and children less than 2 years old.3 Public health 
leaders agree that vaccines are the best way to address the enormous burden of pneumococcal disease, 
particularly in Africa and Asia, where 95% of all pneumococcal deaths occur.4 
1.2. 
Pathogen and Clinical Disease 
S. pneumoniae is a Gram-positive encapsulated bacterium that is commonly carried as a commensal in 
the human nasopharynx. More than 90 serotypes of the bacterium have been identified based on 
differences in the composition of its polysaccharide capsule, which is an essential virulence factor. 
Pneumococci are transmitted by direct contact with respiratory secretions from infected individuals 
and healthy carriers. Nearly all children harbor one or more strains, and become carriers during the first 
few years of life.5 Carriage is typically asymptomatic; however, it is believed to be a precondition for 
invasive pneumococcal infection. 
The signs and symptoms of IPD depend on the type of pneumococcal infection, but may be nonspecific. 
The most common signs and symptoms in adults include fever, chills, sweating, aches, pain, malaise, 
and headache. An individual with pneumococcal pneumonia may additionally complain of cough, chest 
pain, shortness of breath, and rapid breathing. 
1.3. 
Pneumococcal Epidemiology in Africa and The Gambia 
Although documentation of pneumococcal disease in children is limited in low-resource countries, 
several studies have estimated the extent of disease in Africa generally, and in The Gambia specifically. 
The studies conducted prior to the introduction of pneumococcal conjugate vaccine (PCV) have 
estimated rates of IPD to be as much as 10-fold higher in The Gambia and other African countries than 
in the developed world.6,7,8 Based on 2 studies conducted during the period 1988 through 1994, the 
incidence of invasive pneumococcal disease in The Gambia was estimated to be at least 500 per 100,000 
in children in their first year of life, and 250 per 100,000 in children less than 5 years of age.9  The 
importance of IPD in The Gambia was also highlighted in a randomized, placebo-controlled, double-
blind trial of a 9-valent PCV conducted in the Upper and Central River Divisions of the country 
between 2000 and 2004: the incidence of IPD due to all serotypes in the placebo arm of the study was 
380 per 100,000, versus 190 per 100,000 in the vaccine arm.10 A recently published population-based 
surveillance study conducted in the Upper River Region of The Gambia between May 2008 and 
December 2014 found that, after the introduction of PCV, the incidence of IPD decreased from 253 
to 113 cases per 100,000 population among children aged 2-23 months old.11 
Though there are more than 90 serotypes of S. pneumoniae, a small percentage are responsible for the 
large majority of cases of IPD. There are important regional differences in the dominant disease-

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causing serotypes (or serogroups); in particular, serotypes 1 and 5 account for a much larger percentage 
of IPD in the developing world. Serogroups 14, 6, 19, 18, 9, 23, and 7 are responsible for roughly 85% 
of IPD in the developed world, whereas the dominant serotypes causing IPD in Africa, Asia, and Latin 
America are 1, 2, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F (Table 1).12 
Table 1. 
Proportion (Percent) of Invasive Pneumococcal Disease in Children Less Than 5 
Years of Age due to Serotype by Region 
Region
1
2
4
5
6A
6B
7F
9V
14
18C
19A
19F
23F
Africa
11.7
1.9
2.3
10.7
9.4
8.5
0.8
2.2
13.0
1.4
3.9
5.4
6.5
Asia
9.5
2.6
1.6
6.7
3.5
11.5
2.0
3.1
11.6
2.4
2.6
8.1
9.7
LAC
8.4
0.3
1.6
8.5
4.5
9.4
2.5
2.7
26.5
4.3
2.9
3.6
5.3
Abbreviation: LAC = Latin America and the Caribbean 
1.4. 
Licensed Pneumococcal Conjugate Vaccines 
In 1983, Pneumovax® 23, a pneumococcal polysaccharide vaccine covering 23 serotypes developed by 
Merck, was first approved for use in older adults and the elderly to prevent pneumococcal disease. This 
vaccine contains capsular polysaccharide from serotypes 1, 2, 3, 4, 5, 6b, 7F, 8, 9N, 9V, 10A, 11A, 
12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F. While Pneumovax 23 has been shown to be 
effective against IPD in immunocompetent adults,13 it is poorly immunogenic in children less than 2 
years old.14 
The first effective pneumococcal vaccine for children less than 2 years old and infants was developed 
based on the success of the Haemophilus influenzae type b (Hib) conjugate vaccine, which elicits an 
enhanced immune response when the polysaccharide is conjugated to a carrier protein. Prevenar®, a 7-
valent pneumococcal conjugate vaccine, contains the capsular antigens from serotypes 4, 6B, 9V, 14, 
18C, 19F, and 23F individually conjugated to Cross Reactive Material 197 (CRM197, a non-toxic 
diphtheria toxoid protein). Developed by Wyeth (now Pfizer), Prevenar was first approved and 
introduced in the US for use in infants and young children in the year 2000. By the end of the decade, 
overall and serotype-specific IPD in the US were reduced by 45% and 94% respectively.15 However, 
given the limited coverage offered by Prevenar, two second-generation PCVs, Synflorix® 
(GlaxoSmithKline [GSK] Biologicals) and Prevenar 13® (Wyeth, now Pfizer) were subsequently 
developed and approved for infants and young children, both expanding on Prevenar’s 7 serotypes to 
offer protection against 10 and 13 serotypes, respectively. By adding serotypes 1, 5, and 7F in the case 
of Synflorix, and serotypes 1, 3, 5, 6A, 7F, and 19A in the case of Prevenar 13, the second-generation 
PCVs offer additional protection against common serotypes in Africa and Asia, most notably against 
serotypes 1 and 5. 
1.5. 
Rationale for PNEUMOSIL® Development 
More than 15 years after their introduction, the most significant barriers to global access to PCVs 
remain their cost and complex manufacturing process. The price of the vaccine is the critical factor that 
determines whether PCV introduction is considered cost-effective in a low resource setting. This reality 
has underscored the importance of developing an affordable PCV tailored against the specific serotypes 
causing pneumococcal disease in the developing world. 

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21 
Because of the high cost of PCV, introduction of the vaccine into low resource countries has depended 
on considerable external financial assistance. In 2009, Rwanda and The Gambia became the first low 
resource countries to introduce Prevenar, with assistance from Gavi and other international partners.16 
Since 2010 a global roll-out of Synflorix and Prevenar 13 has been underway in Gavi-eligible countries 
with the help of the pneumococcal Advance Market Commitment (AMC), a financing mechanism 
whereby donors commit funds to guarantee the price of future vaccines, creating incentives for 
producers and catalyzing competition to supply vaccines at long-term lower prices.17 Fifty-four low-
resource countries have now introduced PCV into their routine immunization programs with Gavi 
assistance.18 In April 2011, Prevenar 13 replaced Prevenar in the Gambian EPI schedule. As these 
lifesaving vaccines continue to make their way into the developing world with external assistance, the 
rapid development of less expensive PCVs is also needed if countries in the developing world will be 
able to independently afford them over the long term. To this end, enhancing the participation of 
emerging-market manufacturers in PCV production is a critical factor in achieving a sustainable, 
affordable, and accessible supply of vaccine for countries with limited resources. Development of 
effective and more affordable PCVs is aligned with the Sustainable Development Goal of ending 
preventable deaths of newborns and children under 5 years of age by 2030.19 
1.6. 
Introduction to PNEUMOSIL 
The Serum Institute of India (SIIPL), a manufacturer of multiple WHO-prequalified vaccines, in 
collaboration with PATH, has been working since 2006 to develop a multivalent PCV designed to 
prevent pneumococcal disease and to be affordable for use in low resource countries. PNEUMOSIL*, 
SIIPL’s 10-valent candidate pneumococcal conjugate vaccine incorporates prevalent serotypes in 
Africa, Asia, and Latin America (serotypes 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, and 23F), thus offering 
comparable coverage to currently licensed PCVs in these settings.  
In addition to selecting serotypes based on prevalence in low resource countries, SIIL has optimized 3 
critical components of the manufacturing practice – carrier protein production, polysaccharide 
production, and conjugation efficiency – that together substantially lower the cost of manufacturing a 
high-quality multivalent PCV. As a result, it will be possible to provide PNEUMOSIL at a price that is 
significantly lower than that of the currently licensed PCVs. If it becomes available under the AMC, 
PNEUMOSIL would provide significant cost savings to Gavi and to the Gavi-supported countries that 
have introduced pneumococcal vaccines procured through the AMC. This cost savings would result 
not only from a price substantially below the $3.05-$3.10 per dose contributed by Gavi and Gavi-
supported countries to the manufacturers of the 2 existing AMC-eligible PCVs (GlaxoSmithKline’s 
Synflorix and Pfizer’s Prevenar 13), but also from price pressure that PNEUMOSIL’s AMC eligibility 
would place on these vaccines. Finally, availability of PNEUMOSIL would address any potential long-
term supply constraints for pneumococcal vaccine. 
1.7. 
Summary of Nonclinical Studies 
PNEUMOSIL has been made in compliance with Good Manufacturing Practice (GMP), and this 
candidate vaccine has been tested in multiple preclinical pharmacology and Good Laboratory Practice 
(GLP) studies to assess immunogenicity, toxicity and local tolerance, in compliance with Schedule Y 
of the Drugs and Cosmetics Rules of India, ICH Harmonized Tripartite Guideline S6, and WHO 
recommendations.20,21,22 
                                                 
* Prior to trademark registration, SIIPL’s candidate PCV was referred to as “SIILPCV10”. 

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1.7.1. 
Pharmacology 
A pharmacology study was conducted in New Zealand White rabbits using the GMP lot of 
PNEUMOSIL (#4193001) used in the Phase 1/2 clinical trial in The Gambia (VAC-017). Eight (8) 
animals (4 per sex) were immunized intramuscularly (IM) with a human dose-volume of 
PNEUMOSIL on study Day 1, 15, and 29. Serum was collected at baseline, at Day 29 (pre-dose, 2 
weeks post second dose), and at Day 43 (2 weeks post the third and last dose). A second group of 8 
animals was treated with Prevenar13 (human dose-volume), and served as a comparator. Serum 
samples were assessed individually for their humoral, serotype-specific immune response using 2 test 
methods: 1) a direct ELISA to quantitate serotype-specific IgG; and 2) a multiplexed 
opsonophagocytic assay (MOPA) to estimate the amount of functional antibodies (able to induce 
phagocytosis and killing) elicited in the blood of the rabbits by the vaccination. The assay results 
indicated that the total IgG and the functional antibody responses elicited by IM immunization with 
GMP lot #4193001 and measured in the blood of the animals 2 weeks post 2nd and 3rd dose were 
equivalent to those elicited by the Prevenar13 comparator, across all vaccine serotypes. It should also 
be noted that the same analyses were performed after a 3-dose schedule of immunization on multiple 
lots of PNEUMOSIL after 1 year of manufacture, and the IgG and OPA antibody titers achieved were 
comparable to the titers achieved on the lots at the time of manufacture. 
1.7.2. 
Toxicology 
A total of 7 preclinical toxicology studies of PNEUMOSIL have been conducted either in Sprague- 
Dawley rats or New Zealand white rabbits, 4 of which have been single-dose and 3 repeat-dose 
studies (Table 2). 
Table 2. 
Summary of PNEUMOSIL Nonclinical Studies 
Study 
No. 
Animal 
Route 
Treatment Groups* 
Doses 
Sacrifice 
Day(s) 
Recovery 
(Days) 
Additional 
Assessmentsǂ 
G7628 
Rat 
IM 
G1, G2, G3, G4, G5, G6 
1 
D15 
14 
A1, A2 
G7629 
Rat 
SC 
G1, G2, G3, G4, G5, G6 
1 
D15 
14 
A1, A2 
G7630 
Rabbit 
IM 
G1, G2, G3, G4, G5, G6 
1 
D15 
14 
A1, A2 
G7631 
Rabbit 
SC 
G1, G2, G3, G4, G5, G6 
1 
D15 
14 
A1, A2 
G7557 
Rat 
IM 
G1, G2, G3, G4, G5, G6 
5 
D58, D86 
28 
A1, A2, A3, A5 
G7558 
Rabbit 
IM 
G1, G2, G3, G4, G5, G6 
5 
D58, D86 
28 
A1, A2, A3, A5 
12976 
Rabbit 
IM 
G2, G3, G4 
4 
D44, D72 
28 
A1, A2, A3, A4, A5 
Abbreviations: IM, intramuscular; SC, subcutaneous 
*G1: negative control (saline), G2: vehicle control (alum), G3: Prevenar 13 (1x), G4: PNEUMOSIL (1x), G5: 
PNEUMOSIL (10X), G6: PNEUMOSIL (20x). 
ǂA1: safety labs, A2: histopathology of injection sites, A3: histopathology of select organs/tissues; A4: limited male fertility, A5: 
immunogenicity (IgG and OPA). 
In 6 of these studies, groups of animals were administered PNEUMOSIL at doses of 1, 10, and 20 
times the expected human dose; in addition, concurrent control groups were administered Prevenar 
13, saline, and aluminum phosphate (alum) adjuvant. In Study 12976, groups of animals (rabbits) 
were administered alum, Prevenar 13, and PNEUMOSIL with or without preservative (thiomersal) at 

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the expected human dose. In the case of all studies, the test and control articles were administered via 
the intended clinical route (intramuscularly) or subcutaneously. In the repeat-dose studies, the animals 
were administered either 5 doses of vaccine or control at 2-week intervals, or 4 doses at 2-week 
intervals in the case of Study 12976, and were followed by a 28-day recovery period. Blood was 
collected from all animals prior to vaccination and at termination. Blood was analyzed for standard 
safety laboratory parameters in all studies, and for immunogenicity (IgG and OPA) against the 
vaccine serotypes in the repeat-dose studies. These latter analyses demonstrated a significant increase 
from baseline in both total IgG and functional antibody titers in the vaccinated animal sera against all 
the pneumococcal serotypes included in PNEUMOSIL. The immunizations with buffer and vehicle 
control did not give rise to any major changes in the antibody titers against any of the vaccine 
serotypes. 
In the single-dose rat studies (G7628, G7629), visual (edema) and microscopic evidence of local 
inflammation was seen in all treatment groups at a similar magnitude – indicating that the alum 
adjuvant was most likely the cause of these changes. Recovery was noted 14 days after 
administration, and therefore the effects were considered transient in nature. Increases in gamma- 
glutamyl transpeptidase (GGT) were observed in all treatment groups in the single intramuscular 
(IM)-dose study (G7628) but were not seen in the single subcutaneous (SC)-dose study (G7629) or 
the multi-dose study (G7557). Liver enzymes (alanine transaminase [ALT]/ aspartate 
aminotransferase [AST]) were not altered and liver weights were normal at time of sacrifice. 
In the multi-dose rat study (G7557), the albumin/globulin (A:G) ratio was decreased (as a result of 
an increase in globulin level) and the white blood cell count increased in the Prevenar 13 and 
SIILPCV13 treatment groups. These effects are commonly observed in vaccine animal testing, as 
they are expected pharmacological effects of stimulating the immune system. Coagulation 
parameters, prothrombin time (PT) and activated partial thromboplastin time (APTT), were within 
normal limits. Transient increases in serum fibrinogen, likely indicative of immune activation, were 
observed in Prevenar 13 and PNEUMOSIL treatment groups in the rat studies. Significant increases 
in serum creatinine were observed in all treatment groups of the multi-dose rat study (G7557), 
including the negative and vehicle control groups; while its cause is unclear, the consistency of the 
creatinine increase across groups suggests that it is unlikely to be an adverse effect of PNEUMOSIL 
and Prevenar 13. Microscopic examination of the kidneys at sacrifice showed that the organs were 
healthy. 
In the rabbit, erythema was seen at the injection site in all treatment groups in the single SC-dose 
study (G7631) but not with IM administration. Microscopic evidence of local inflammation of a 
similar magnitude was seen at the injection site in all treatment groups in the 4 rabbit studies. 
Subsequently it was concluded that these alterations were due to alum administration. Substantial 
recovery was noted at the end of the recovery period, suggesting a transient local inflammatory 
phenomenon. Based on assessment in the third repeat-dose study (12976), there was no effect of 
treatment on sperm motility and morphology. 
In summary, single- and repeat-dose administration of PNEUMOSIL to rats and rabbits was well 
tolerated, and resulted in observed changes that were not adverse but rather a consequence of the 
pharmacological activity of PNEUMOSIL and the comparator Prevenar 13, or were seen across all 
treatment groups and not associated with the test product only. 
1.8. 
Summary of Clinical Studies 
Three clinical trials of PNEUMOSIL have been conducted: 

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1) A Phase 1, randomized, active-controlled, double-blind trial (PCV10-001) evaluating the safety and 
tolerability of PNEUMOSIL in healthy young Indian adults (n=34) has been completed. Eligible 
subjects were randomized 1:1 to receive a single dose of PNEUMOSIL or Pneumovax 23 and were 
followed through 28 days post vaccination.  
2) A Phase 1/2, randomized, active-controlled, double-blind age de-escalation trial (VAC-017) 
evaluating the safety, tolerability and immunogenicity of PNEUMOSIL in 34 PCV-naïve adults, 
112 PCV (Prevenar 13)-primed toddlers (12-15 months of age), and 200 PCV-naïve infants in The 
Gambia has been completed through the infant primary series. Eligible subjects were randomized 
1:1 to receive a single dose of PNEUMOSIL or either Pneumovax 23 in adults or Prevenar 13 in 
toddlers, and a 3-dose primary series of PNEUMOSIL or Prevenar 13 (at 6, 10, and 14 weeks of 
age) in the infant cohort. EPI vaccines were concomitantly administered to infants, including 
pentavalent vaccine (diphtheria, tetanus, whole-cell pertussis, hepatitis B, and Haemophilus 
influenzae type b [DTwP-HepB-Hib]). Adults and toddlers were followed for 28 days post 
vaccination, and infants for 84 days post final vaccination. A Data Safety Monitoring Board 
(DSMB) granted approval to advance to the toddler and infant cohorts following the adult and 
toddler cohorts respectively. Following database lock and unblinded data review, the decision was 
made to extend the study to evaluate a matched booster dose of PNEUMOSIL or Prevenar 13 in 
infants. 
3) A Phase 2, randomized, active-controlled, double-blind trial (PCV10-002) evaluating the safety, 
tolerability and immunogenicity of a 2-dose regimen of PNEUMOSIL in 114 PCV-naïve Indian 
toddlers (12-15 months of age) is ongoing. A DSMB formally recommended advancing to this 
Phase 2 ‘catch-up’ trial in toddlers after review of results of the PCV10-001 trial post database lock. 
All toddlers have completed the final follow-up visit 28 days after the 2nd vaccination.  
PNEUMOSIL was well tolerated in all 3 trials, and no safety concerns were identified (based only on 
blinded review of safety data in the case of PCV10-002). PNEUMOSIL was also shown in the VAC-
017 study to be immunogenic for all 10 serotypes contained in the vaccine. A summary of safety and 
immunogenicity results follows. Please refer to the Investigator’s Brochure (IB) for additional details 
on the methodology and results of the PCV10-001 and VAC-017 trials. 
1.8.1. 
Safety 
Laboratory Assessments: 
In all 3 clinical studies blood samples were collected for safety hematology, clinical chemistry, and 
organ function tests; a coagulation panel was also evaluated in adult subjects. Laboratory assessments 
were only performed at baseline for infants in the VAC-017 study. There were no notable trends from 
baseline to post vaccination in any laboratory parameter in the adult subjects in the PCV10-001 and 
VAC-017 studies, or in the toddler subjects in the VAC-017 study. 
Reactogenicity:  
Solicited local and systemic reactogenicity were assessed daily in all subjects for the first 7 days post 
vaccination in all 3 clinical studies by means of a subject diary (PCV10-001 and PCV10-002) or daily 
home visits by field workers (VAC-017). When observed, reactogenicity after vaccination with 
PNEUMOSIL in all studies and age cohorts was generally mild or moderate and of limited duration. 
In adults, the most common local reactogenicity event (RE) after a single dose of PNEUMOSIL was 
pain, reported in 70.6% and 58.8% of adults in the PCV10-001 and VAC-017 studies respectively. 
Only 1 Grade ≥ 2 local RE was reported in the PNEUMOSIL group in either trial (Grade 3 

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tenderness). Headache was the most common systemic RE after vaccination and was reported for 
17.6% of adults who received PNEUMOSIL in both trials. No Grade ≥ 2 systemic RE was reported 
in adults who received PNEUMOSIL. 
In the VAC-017 toddler cohort, the most common local RE post vaccination was tenderness (21.5% 
PNEUMOSIL, 21.4% Prevenar 13). A higher proportion of toddlers in the PNEUMOSIL group vs 
the Prevenar 13 group had Grade 1 or 2 induration/swelling at the injection site (10.7% 
PNEUMOSIL; 1.8% Prevenar 13). No severe (Grade ≥ 3) tenderness or other local RE was reported 
in toddlers in either the VAC-017 or PCV10-002 studies. Fever (axillary temperature ≥ 37.5°C) was 
the most common systemic RE (16.1% PNEUMOSIL, 19.6% Prevenar 13 in VAC-017). Grade 3 
fever was reported in 2 toddlers who received the PNEUMOSIL booster and 1 toddler who received 
the Prevenar 13 booster. A higher proportion of toddlers in the PNEUMOSIL group vs the Prevenar 
13 group had Grade 1 or 2 drowsiness (10.7% PNEUMOSIL; 0% Prevenar 13). Most REs were 
transient and resolved within 24 hours. 
Table 3 presents the highest grade (Grade ≥ 1) of selected REs occurring over the first 7 days 
following primary vaccination of infants in the VAC-017 study. 
Table 3. 
Highest Grade ≥ 1 of Selected Reactogenicity Events in Infants – Primary Series 
(VAC-017) 
Reactogenicity Event 
Grade 
Vaccination 1 
Vaccination 2 
Vaccination 3 
PNEUMOSIL Prevenar 
13 
PNEUMOSIL Prevenar 
13 
PNEUMOSILPrevenar
13 
N = 100 
N = 100 
N = 100 
N = 100 
N = 100 
N = 100
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Temperature 
 
 
 
 
 
 
Grade 1: ≥ 37.5 to ≤ 38.0 
29 (29.0) 
34 (34.0) 
11 (11.0) 
13 (13.0)
15 (15.0) 
16 (16.0)
Grade 2: > 38.0 to ≤ 39.0 
11 (11.0) 
7 (7.0) 
7 (7.0) 
6 (6.0) 
4 (4.0) 
4 (4.0) 
Grade 3: > 39.0 to ≤ 40.0 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (1.0) 
1 (1.0) 
0 (0.0) 
Irritability 
 
 
 
 
 
 
Grade 1: Crying more than usual/no 
effect on normal activity 
33 (33.0) 
29 (29.0) 
35 (35.0) 
30 (30.0)
33 (33.0) 
37 (37.0)
Grade 2: Crying more than 
usual/interferes with normal activity 
4 (4.0) 
2 (2.0) 
5 (5.0) 
3 (3.0) 
3 (3.0) 
4 (4.0) 
Grade 3: Crying that cannot be 
comforted/prevents normal activity 
0 (0.0) 
0 (0.0) 
0 (0.0) 
0 (0.0) 
1 (1.0) 
0 (0.0) 
Drowsiness 
 
 
 
 
 
 
Grade 1: Drowsiness easily tolerated 
8 (8.0) 
1 (1.0) 
6 (6.0) 
1 (1.0) 
2 (2.0) 
3 (3.0) 
Grade 2: Drowsiness that interferes 
with normal activity 
0 (0.0) 
1 (1.0) 
0 (0.0) 
1 (1.0) 
0 (0.0) 
0 (0.0) 
Decreased appetite 
 
 
 
 
 
 
Grade 1: Eating less than usual/no 
effect on normal activity 
10 (10.0) 
1 (1.0) 
9 (9.0) 
8 (8.0) 
6 (6.0) 
9 (9.0) 
Grade 2: Eating less than 
usual/interferes on normal activity 
0 (0.0) 
0 (0.0) 
1 (1.0) 
0 (0.0) 
1 (1.0) 
2 (2.0) 
Tenderness at injection site 
 
 
 
 
 
 
Grade 1: Mild reaction to touch 
15 (15.0) 
12 (12.0) 
18 (18.0) 
26 (26.0)
21 (21.0) 
19 (19.0)
Grade 2: Cries/protests on touch 
4 (4.0) 
5 (5.0) 
2 (2.0) 
1 (1.0) 
0 (0.0) 
2 (2.0) 

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Reactogenicity Event 
Grade 
Vaccination 1 
Vaccination 2 
Vaccination 3 
PNEUMOSIL Prevenar 
13 
PNEUMOSIL Prevenar 
13 
PNEUMOSILPrevenar
13 
N = 100 
N = 100 
N = 100 
N = 100 
N = 100 
N = 100
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Erythema/redness at injection site 
 
 
 
 
 
 
Grade 1: Erythema present but ≤ 2.5 
cm diameter 
1 (1.0) 
8 (8.0) 
0 (0.0) 
4 (4.0) 
3 (3.0) 
3 (3.0) 
Grade 2: Erythema > 2.5 cm diameter 
but < 50% surface area of the extremity 
segment 
0 (0.0) 
1 (1.0) 
1 (1.0) 
1 (1.0) 
0 (0.0) 
0 (0.0) 
Induration/Swelling at Injection Site 
 
 
 
 
 
 
Grade 1: Induration/Edema present but 
≤ 2.5 cm diameter 
4 (4.0) 
8 (8.0) 
7 (7.0) 
16 (16.0)
11 (11.0) 
13 (13.0)
Grade 2: Induration/Edema > 2.5 cm 
diameter but < 50% surface area of the 
extremity segment 
0 (0.0) 
2 (2.0) 
1 (1.0) 
2 (2.0) 
2 (2.0) 
1 (1.0) 
Source: VAC-017 CSR Table IS7A. 
In the VAC-017 infant cohort, the most common local RE after a primary dose of study vaccine was 
tenderness (19-21% PNEUMOSIL, 17-27% Prevenar 13). No Grade ≥ 3 local RE was reported. A 
lower proportion of infants in the PNEUMOSIL group had Grade 1 or 2 erythema/redness (1.0% 
PNEUMOSIL; 5.0-9.0% Prevenar 13) and induration/swelling (4.0-8.0% PNEUMOSIL; 10.0-18.0% 
Prevenar 13) after vaccinations 1 and 2. Fever (axillary temperature ≥ 37.5°C) was the most common 
systemic RE after the first vaccination (40.0% PNEUMOSIL, 41% Prevenar 13). The proportion of 
cases of fever was lower after vaccinations 2 and 3 (18.0-20.0% PNEUMOSIL; 20% Prevenar 13). 
One event of Grade 3 fever was reported in both treatment groups, and 1 episode each of Grade 3 
irritability and cutaneous rash in the PNEUMOSIL group. A higher proportion of infants in the 
PNEUMOSIL group compared with infants in the Prevenar 13 group had Grade 1 or 2 vaccine-related 
drowsiness (6.0% to 8.0% PNEUMOSIL; 2.0% Prevenar 13) and decreased appetite (10.0% 
PNEUMOSIL; 1.0% to 8.0% Prevenar 13) after vaccinations 1 and 2. Most REs were transient and 
resolved within 24 to 48 hours. 
The highest grades (Grade ≥ 1) of selected reactogenicity events (REs) after a booster dose of study 
vaccine in infants are presented in Table 4. When observed, reactogenicity in infants was generally 
mild or moderate. Overall, there were no notable differences in RE frequency or severity between 
infants receiving PNEUMOSIL and infants receiving Prevenar 13. Two (4.1%) infants in the 
PNEUMOSIL group and 1 (2.1%) infant in the Prevenar 13 group had Grade 3 fever. All other REs 
were mild or moderate in severity. Fever and irritability were the most common systemic REs, both 
occurring in a total of 12% of subjects (fever: 12.2% PNEUMOSIL, 12.7% Prevenar 13, irritability: 
10.2% PNEUMOSIL, 14.9% Prevenar 13). Tenderness at the injection site was the most common 
local RE (18.3% PNEUMOSIL, 23.4% Prevenar 13). Most REs were transient and resolved within 
24 to 48 hours. 
Table 4 
Highest Grade (≥ 1) Reactogenicity Post Booster Vaccination – Infant Booster 
Population (VAC-017) 

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Reactogenicity Event 
Grade 
PNEUMOSIL
(N = 49) 
n (%) 
Prevenar 13 
(N = 47)  
n (%) 
Total 
(N = 96)  
n (%) 
Systemic 
Temperature (oC) 
 
 
 
Grade 1: ≥ 37.5 to ≤ 38.0 
3 (6.1) 
4 (8.5) 
7 (7.3) 
Grade 2: > 38.0 to ≤ 39.0 
1 (2.0) 
1 (2.1) 
2 (2.1) 
Grade 3: > 39.0 to ≤ 40.0 
2 (4.1) 
1 (2.1) 
3 (3.1) 
Cutaneous rash 
 
 
 
Grade 1: Localized macular rash 
1 (2.0) 
3 (6.4) 
4 (4.2) 
Grade 2: Diffuse 
macular/maculopapular/morbilliform rash or 
target lesions 
0 (0.0) 
2 (4.3) 
2 (2.1) 
Irritability 
 
 
 
Grade 1: Crying more than usual/no effect on 
normal activity 
5 (10.2) 
7 (14.9) 
12 (12.5) 
Drowsiness 
 
 
 
Grade 1: Drowsiness easily tolerated 
0 (0.0) 
1 (2.1) 
1 (1.0) 
Grade 2: Drowsiness that interferes with normal 
activity 
1 (2.0) 
0 (0.0) 
1 (1.0) 
Decreased appetite 
 
 
 
Grade 1: Eating less than usual/no effect on 
normal activity 
2 (4.1) 
5 (10.6) 
7 (7.3) 
Local 
Tenderness at injection site 
 
 
 
Grade 1: Mild reaction to touch 
8 (16.3) 
11 (23.4) 
19 (19.8) 
Grade 2: Cries/protests on touch 
1 (2.0) 
0 (0.0) 
1 (1.0) 
Erythema/redness at injection site 
 
 
 
Grade 1: Erythema present but ≤ 2.5 cm 
diameter 
1 (2.0) 
1 (2.1) 
2 (2.1) 
Induration/Swelling at Injection Site 
 
 
 
Grade 1: Induration/Edema present but ≤ 2.5 cm 
diameter 
4 (8.2) 
4 (8.5) 
8 (8.3) 
Grade 2: Induration/Edema > 2.5 cm diameter 
but < 50% surface area of the extremity segment 
2 (4.1) 
0 (0.0) 
2 (2.1) 
Note: Highest toxicity grade experienced across all observations from 30 minutes through 6 days post vaccination for 
each subject is summarized. May include unscheduled visits. 
Source: Table IBS7A. 

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Adverse Events: 
In all 3 clinical studies subjects were monitored for AEs from enrollment to final clinic visit, and any 
AE was assessed by the investigator with regards to severity, relatedness, and duration. No deaths, 
related serious adverse events (SAEs), or AEs leading to subject withdrawal were reported following 
vaccination in the 3 studies. In the 2 studies that have unblinded results (PCV10-001 and VAC-017), 
there are no concerning trends in the frequency of any grade of treatment-emergent AEs (TEAEs), 
vaccine-related TEAEs, or treatment-emergent SAEs. 
No adult in either the PCV10-001 or VAC-017 studies experienced a Grade >1 TEAE or serious 
adverse event (SAEs). The only related TEAE in the PCV10-001 study was Grade 1 postvaccination 
injection-site paraesthesia (1 event in both groups), and in the VAC-017 adult cohort was Grade 1 
injection-site pain (1 event in both groups). 
In the VAC-017 toddler cohort, there were only 2 related TEAEs were reported in the PNEUMOSIL 
group (Grade 1 diarrhea, Grade 2 morbilliform/papular rash) and 1 related TEAE in the Prevenar 
group (Grade 1 pruritus). Two (2) treatment-emergent SAEs were reported, one in each treatment 
group and neither deemed related to study vaccine. 
In the VAC-017 infant cohort, the most common TEAEs reported in both treatment groups through 
12 weeks post final primary vaccination included upper respiratory tract infection (64.0% 
PNEUMOSIL, 48.0% Prevenar 13), tinea infection (31.0% PNEUMOSIL; 21.0% Prevenar 13), 
diarrhea (29.0% PNEUMOSIL; 19.0% Prevenar 13), and conjunctivitis (27.0% PNEUMOSIL; 
19.0% Prevenar 13). The most common TEAE after the booster vaccination through 4 weeks of 
follow up was upper respiratory tract infection (28.6% PNEUMOSIL, 12.8% Prevenar 13), dermatitis 
(8.2% PNEUMOSIL, 6.4% Prevenar 13), and diarrhea (4.1% PNEUMOSIL, 10.6% Prevenar 13). 
The differences in the frequency of these TEAEs between the treatment groups were within the 
expected range for this early-stage clinical study. The only vaccine-related TEAE for more than 1 
infant was Grade 1 vaccination site swelling (2.0% PNEUMOSIL, 6% Prevenar 13), and the only 
severe TEAE reported for > 1 infant was bronchiolitis (2% PNEUMOSIL, 0% Prevenar 13).  
Six (6.0%) infants in the PNEUMOSIL group and 2 (2.0%) infants in the Prevenar 13 group had a 
treatment-emergent SAE through 12 weeks post primary vaccination, and one (2.0%) infant in the 
PNEUMOSIL group had a treatment-emergent SAE after the booster vaccination through 4 weeks of 
follow up. There was an imbalance in serious cases of bronchiolitis (4 in the PNEUMOSIL group, 1 
in the Prevenar 13 group) but no imbalance in overall TEAEs of bronchiolitis. No treatment-emergent 
SAE was considered to be related to study vaccine, and there was no temporal relationship to any 
vaccination.  
1.8.2. 
Immunogenicity 
In the VAC-017 study, serum samples were collected 28 days after vaccination in the adult and 
toddler cohorts, and 28 days after completion of the primary vaccination series and prior to and 28 
days post booster vaccination in the infant cohort, for evaluation by ELISA to determine the IgG 
concentration to each of the 10 serotypes contained in PNEUMOSIL. In the case of toddlers, a 
random subset was selected for this analysis (n=34), and this subset of toddlers also had serotype-
specific IgGs determined from sera collected at baseline. In the infant cohort, the IgG concentration 
was determined for each component of the co-administered pentavalent vaccine (DTwP-HepB-Hib). 
The functional activity of the IgG response to the 10 serotypes contained in PNEUMOSIL was also 
determined in randomly selected subsets of infants (n=40) and toddlers (n=34), and in all adults using 

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the same serum samples collected 28 days after vaccination (only after primary vaccination in the 
case of infants). 
PNEUMOSIL was shown to be immunogenic for all 10 serotypes contained in the vaccine in all 3 
age cohorts, and, in toddlers and infants, the level of responses to each serotype was comparable to 
the responses observed in the Prevenar 13 control group. The percentage of infants achieving an IgG 
concentration of 0.35 µg/mL (the reference concentration for assessment of vaccine efficacy against 
IPD defined by the WHO23) at 28 days post final primary series vaccination was substantial across 
all serotypes in both treatment groups, with seroresponse rates of 91% or higher achieved in all cases 
except for serotypes 6A (79.0%) and 6B (89.0%) in the PNEUMOSIL group (Table 5). While they 
were generally higher in the Prevenar 13 group, IgG GMCs were > 1 µg/mL for all 10 serotypes in 
both treatment groups. 
Table 5. 
Percentage of IgG Seroresponders in the Infant Cohort – Primary Series 
 
PNEUMOSIL 
(N = 100) 
Prevenar 13 
(N = 100) 
PNEUMOSIL vs 
Prevenar 13 
Serotype 
n (%)a 
90% CIb 
n (%)a 
90% CIb 
Difference (90% CI)c 
IgG ELISA type 1 
99 (99.0) 
95.34 - 99.95 
100 (100) 
97.05 - 100.00 
-1.0 (-5.13- 2.66) 
IgG ELISA type 5 
100 (100) 
97.05 - 100.00 
97 (97.0) 
92.43 - 99.18 
3.0 (-1.10- 7.95) 
IgG ELISA type 6A 
79 (79.0) 
71.19 - 85.48 
91 (91.0) 
84.82 - 95.22 
-12.0 (-20.94- -2.97) 
IgG ELISA type 6B 
89 (89.0) 
82.45 - 93.71 
93 (96.9) 
92.12 - 99.14 
-7.9 (-15.00- -1.01) 
IgG ELISA type 7F 
97 (97.0) 
92.43 - 99.18 
100 (100) 
97.05 - 100.00 
-3.0 (-7.95- 1.10) 
IgG ELISA type 9V 
94 (94.0) 
88.50 - 97.36 
97 (97.0) 
92.43 - 99.18 
-3.0 (-9.17- 2.90) 
IgG ELISA type 14 
98 (98.0) 
93.84 - 99.64 
96 (97.0) 
92.35 - 99.17 
1.0 (-4.00- 6.27) 
IgG ELISA type 19A 
92 (92.0) 
86.03 - 95.96 
94 (97.9) 
93.59 - 99.63 
-5.9 (-12.38- 0.17) 
IgG ELISA type 19F 
99 (99.0) 
95.34 - 99.95 
97 (99.0) 
95.25 - 99.95 
0.0 (-4.22- 4.33) 
IgG ELISA type 23F 
91 (91.0) 
84.82 - 95.22 
97 (97.0) 
92.43 - 99.18 
-6.0 (-12.77- 0.40) 
Abbreviations: CI = confidence interval, ELISA = enzyme-linked immunosorbent assay, IgG = immunoglobulin G. 
a 
Number of responders (IgG ≥ 0.35 µg/mL). 
b 
Exact CIs based on Clopper-Pearson method. 
c 
Exact CIs around treatment group differences were calculated based on Newcombe score. 
Source: VAC-017 CSR Table I12. 
Similarly, while the functional immune response to multiple serotypes (types 6A, 7F, 9V, and 19A) 
was superior for the Prevenar 13 group as measured by OPA GMTS (and as illustrated in divergent 
reverse cumulative distribution [RCD] curves), the percentage of infants with a functional IgG 
response (OPA titer ≥ 1:8) was substantial across all serotypes for both treatment groups -- and was 
numerically higher for the PNEUMOSIL group for more serotypes (4 vs 1) (Table 6). The small 
number of subjects with OPA data in all 3 cohorts limits what can be meaningfully concluded from 
these analyses. 
 
 

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Table 6. 
Percentage of OPA Seroresponders in the Infant Cohort – Primary Series 
 
PNEUMOSIL 
(N = 20) 
Prevenar 13 
(N = 20) 
PNEUMOSIL vs 
Prevenar 13 
Seroresponders on OPA 
Titers 
n (%)a 
90% CIb 
n (%)a 
90% CIb 
Difference (90% CI)c 
OPA - Pn 1 
15 (93.8) 
73.60 - 99.68 
11 (84.6) 
58.99 - 97.19 
9.1 (-15.55 - 36.11) 
OPA - Pn 5 
19 (95.0) 
78.39 - 99.74 
19 (95.0) 
78.39 - 99.74 
0.0 (-18.56 - 18.56) 
OPA - Pn 6A 
20 (100) 
86.09 - 100.00 
19 (100) 
85.41 - 100.00 
 
OPA - 6B 
19 (100) 
85.41 - 100.00 
19 (95.0) 
78.39 - 99.74 
5.0 (-12.35 - 22.97) 
OPA - 7F 
20 (100) 
86.09 - 100.00 
20 (100) 
86.09 - 100.00 
 
OPA - 9V 
20 (100) 
86.09 - 100.00 
20 (100) 
86.09 - 100.00 
 
OPA - 14 
19 (100) 
85.41 - 100.00 
18 (94.7) 
77.36 - 99.73 
5.3 (-12.15 - 24.01) 
OPA - 19A 
16 (94.1) 
74.99 - 99.70 
20 (100) 
86.09 - 100.00 
-5.9 (-26.41 - 11.01) 
OPA - 19F 
20 (100) 
86.09 - 100.00 
19 (95.0) 
78.39 - 99.74 
5.0 (-11.64 - 22.97) 
OPA - 23F 
20 (100) 
86.09 - 100.00 
20 (100) 
86.09 - 100.00 
 
Abbreviations: CI = confidence interval, OPA = opsonophagocytic assay. 
a 
Number of responders (OPA titers ≥ 1:8). 
b 
Exact CIs based on Clopper-Pearson method. 
c 
Exact CIs around treatment group differences were calculated based on Newcombe score. Calculation of 
difference and CI around the difference was not possible when all subjects in both groups were responders. 
Source: VAC-017 CSR Table II5. 
IgG GMCs decreased substantially from 4 weeks post Vaccination 3 to just prior to the booster 
vaccination in both the PNEUMOSIL and Prevenar 13 groups. While GMCs were generally higher in 
the Prevenar 13 group at 4 weeks post Vaccination 3, pre booster vaccination GMCs were generally 
comparable between groups due to the more substantial reduction in IgG concentrations in the Prevenar 
13 group for serotypes that were significantly higher in the Prevenar 13 group post primary series. Both 
PNEUMOSIL and Prevenar 13 demonstrated a substantial booster effect across serotypes, indicating 
that the initial 3-dose series of both vaccines effectively ‘primed’ infants for boosting of immune 
responses. 
In the toddler cohort, there was a substantial booster response for all serotypes in both treatment groups. 
No meaningful conclusions can be drawn from the generally higher Geometric Mean Fold Rise 
(GMFR) response after boosting with Prevenar 13 given the small number of boosted subjects, higher 
baseline GMCs in the PNEUMOSIL group, and the potential immunologic advantage of boosting with 
the homologous vaccine (Prevenar 13) that was used for priming. Additionally, OPA GMTs were 
similar in toddlers boosted with Prevenar 13, and there was no divergence in RCD curves of OPA titers 
in favor of Prevenar 13. Results of the supplemental infant booster phase of the VAC-017 study will 
be more informative, given that a booster dose of PNEUMOSIL will be evaluated in PNEUMOSIL-
primed infants (in comparison to a booster dose of Prevenar 13 in Prevenar 13-primed infants).  
In the adult cohort, the IgG GMC and functional (OPA GMT) immune responses were generally similar 
4 weeks after administration of a single dose of PNEUMOSIL or Pneumovax 23. The consistent 
exceptions were serotypes 6A and 6B in favor of PNEUMOSIL and serotype 1 in favor of Pneumovax 
23. The small number of adults evaluated, and expected high levels of naturally acquired immunity, 
limit what can be meaningfully concluded from these analyses. 

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Based on review of seroprotection rates and GMCs to component antigens (as well as RCD curves of 
IgG levels), there is no evidence from this early-stage study that administration of PNEUMOSIL 
interferes with the immune response to any component of the pentavalent vaccine when these vaccines 
are given concomitantly as a 3-dose primary series to infants. 
1.9. 
Clinical Development Plan for PNEUMOSIL 
The ultimate goal of PNEUMOSIL clinical development is to achieve licensure through a WHO-
recognized national regulatory authority (NRA), followed by prequalification by WHO to support 
product acquisition by Gavi and UNICEF for its distribution to low- and middle-resource countries. 
The product specifications detailed in Part C of the WHO Technical Report Series (TRS) 977 Annex 
3 (2013)23 and the associated Target Product Profile (TPP) for the Advance Market Commitment 
(AMC) for Pneumococcal Conjugate Vaccines (2008)24 – which establishes additional essential 
criteria for the AMC for PCVs – are a critical guide for the PNEUMOSIL clinical development plan, 
to ensure that planned trials serve to evaluate the vaccine on the basis of the essential attributes for a 
PCV deemed suitable for use in Gavi-eligible countries. As was the case for the second-generation 
PCVs, the path to WHO prequalification and Gavi eligibility for PNEUMOSIL is to conduct a Phase 
3 pivotal trial in infants to demonstrate the following: 1) vaccine efficacy based on immunologic non-
inferiority to a licensed and prequalified comparator vaccine post a 3-dose primary series, 2) 
manufacturing quality demonstrated by post-primary lot-to-lot consistency, 3) non-interference with 
co-administered EPI vaccines, 4) immunologic memory as indicated by boostability, and 5) an 
adequate safety and tolerability profile after primary series and booster vaccination. An additional TPP 
requirement is that the first dose of the vaccine must be shown to be administrable at 6 weeks of life 
or earlier. 
The current Phase 3 non-inferiority trial of PNEUMOSIL in healthy infants in The Gambia (n = 2,250) 
is designed to provide the data necessary to demonstrate each of these critical attributes of a licensed 
and prequalified PCV. Conducting such a large Phase 3 trial in infants is warranted based on the 
observed safety, tolerability, and immunogenicity results of VAC-017. Phase 3 trials will also be 
conducted in India to demonstrate the safety and immunogenicity of PNEUMOSIL administered at 6 
weeks, 10 weeks and 14 weeks of age, as well as at 6 weeks, 14 weeks and 9 months of age.  
1.10. Study Rationale 
Given that vaccine efficacy will be demonstrated based on immunologic non-inferiority (NI), a key 
element in the design of this Phase 3 pivotal trial is the choice of licensed PCV comparator. After 
much consideration Synflorix has been selected as the active comparator for the trial. Since its initial 
licensure and WHO prequalification in 2009, Synflorix has been introduced in 30 countries 
worldwide -- including 13 Gavi-eligible countries through the AMC framework --, and has been 
given to more than 70 million children.25 The safety profile of Synflorix that led to licensure and 
prequalification was established in clinical trials in which 63,905 doses of the vaccine were 
administered to 22,429 healthy children as primary vaccination, and 19,466 doses were administered 
as a booster dose in the second year of life.26 
One of the key factors for selecting Synflorix as the comparator in this Phase 3 pivotal trial is that 
Synflorix is the only licensed and WHO-prequalified 2nd generation PCV that has been evaluated in 
randomized controlled trials for both efficacy and effectiveness against IPD and pneumonia in 
infants and children. In a large (n= 47,366) Phase 3/4, double-blind, cluster-randomized, controlled, 
clinical trial conducted in Finland (FinIP), effectiveness of Synflorix against culture-confirmed 

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vaccine-type IPD in both 3+1 (3, 4, 5 + 11 mo) and 2+1 (3, 5 + 11 mo) schedules was 100% (95% 
CI: 91-100; 0 vs 11 cases) and was 93.0% (95% CI: 75-99; 2 vs 14 cases) for culture-confirmed IPD 
irrespective of serotype.27 Synflorix also was shown in the FinIP trial to be effective in reducing 
pneumonia rates: rates of hospital-diagnosed pneumonia were reduced by 26.7% (95% CI: 4.9; 43.5) 
and 29.3% (95% CI: 7.5; 46.3) in the 3+1 and 2+1 clusters, respectively.25 In a large (n=23,821) 
Phase 3, randomized, double-blind clinical trial conducted in Argentina, Panama and Colombia 
(COMPAS), vaccine efficacy against culture-confirmed IPD was 66.7% (95% CI: 21.8-85.9; 7 vs 
21 cases), and efficacy against likely bacterial community-acquired pneumonia was 22.0% (95% 
CI: 7.7, 34.2) in infants who received Synflorix in a 3+1 schedule (2, 4, 6 mo + booster at 15-18 
mo).28 Given these robust results from randomized controlled studies of Synflorix, determining that 
PNEUMOSIL is immunologically non-inferior to Synflorix will provide an indication of the 
expected efficacy of PNEUMOSIL against IPD and pneumonia. 
It is important to note that Synflorix has been shown to be effective against IPD and pneumonia 
despite evidence that serotype-specific IgG antibody responses induced by the vaccine are generally 
lower than those induced by Prevenar 13 when measured 1 month after a 3-dose primary series – 
the timepoint specified in the TRS guidelines (Section C.2.2.3) for the primary NI analysis.29,30 The 
fact that Synflorix has proven that a PCV can be highly effective while inducing somewhat lower 
post-primary antibody responses compared with Prevenar 13 is an important consideration in the 
selection of Synflorix as comparator in this Phase 3 pivotal trial. 
Synflorix and PNEUMOSIL have 8 serotypes in common: serotypes 1, 5, 6B, 7F, 9V, 14, 19F, and 
23F. Serotypes 6A and 19A are contained in PNEUMOSIL, but not in Synflorix. In accordance with 
TRS guidelines (Section C.2.2.3), non-inferiority of the immune response after primary vaccination 
with PNEUMOSIL will be demonstrated for any of the 8 matched serotypes if the difference in the 
percentage of subjects with serotype-specific IgG concentration ≥ 0.35 µg/mL (percentage 
responding after Synflorix vaccination minus percentage responding after PNEUMOSIL) is less 
than the standard† NI margin of 10%, or if the serotype-specific IgG GMC ratio (Synflorix GMC 
divided by PNEUMOSIL GMC) is less than 2 (the same standard 2-fold criterion for comparing 
serotype-specific IgG GMC ratios will be the basis for demonstrating equivalence of the 3 
productions lots of PNEUMOSIL). Again in accordance with TRS guidance, the approach for 
serotypes 6A and 19A will be to assume that the response rate with Synflorix is the lowest observed 
rate among the 10 serotypes in Synflorix, and the GMC is the GMC of the serotype with the lowest 
response rate. Since the TRS guidance does not require non-inferiority to be met for each of the 
serotypes in the candidate vaccine, it is prespecified that the primary NI objective will be met if at 
least 7 of the 10 serotypes in PNEUMOSIL are shown to be non-inferior to Synflorix. 
Of note, a secondary immunogenicity objective of this study is to demonstrate that the post-primary 
immune responses to serotypes 6A and 19A in PNEUMOSIL are superior to the responses to these 
serotypes induced by Synflorix, based on either the proportion with IgG antibody concentration ≥ 
0.35 µg/mL or GMC ratio. Due to cross-reactivity from serotypes 6B and 19F, immune responses 
to 6A and 19A induced by Synflorix are not only measurable, but have been shown to provide 
statistically significant cross-protection in surveillance studies of vaccine effectiveness for 
individual serotypes against IPD (also, Synflorix is indicated for protection against serotype 19A 
disease in Europe, Canada and other countries).31,32,33 Demonstrating superiority to the immune 
responses to these serotypes induced by Synflorix – especially superiority based on a margin of 
                                                 
† A NI margin of 10% was used in the pivotal Phase 3 trials of both Prevenar 13 and Synflorix for comparison of 
seroresponse rates.29, 30 

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>10% higher seroresponse rate or >2-fold GMC ratio – will indicate expected effectiveness of 
PNEUMOSIL against IPD due to serotypes 6A and 19A. 
It is also important to emphasize that surveillance data from the Basse Health and Demographic 
Surveillance System (BHDSS) in the Upper River Region of The Gambia provide reassurance that 
this Phase 3 trial, in which infants will receive PNEUMOSIL or Synflorix, instead of Prevenar 13, 
can be safely conducted in the country. Because of the early and successful introduction of 7-valent 
Prevenar and then Prevenar 13 in the national EPI schedule, the incidence of IPD due to serotypes 
included in Prevenar 13, and prevalence of nasopharyngeal carriage of vaccine-type 
pneumococci, have decreased significantly in Gambian children since PCV introduction.11,31 In 
fact, since 2013 the BHDSS has not detected a single case of IPD in children aged 2-59 months 
that was due to a serotype contained in Prevenar 13 but not PNEUMOSIL (serotypes 3, 4, and 
18C) (G. Mackenzie, personal communication). These data, together with BHDSS surveillance data 
showing numerical reduction in serotype-specific IPD in adults,11 suggest robust indirect (herd) 
protection against Prevenar 13 vaccine-type disease in The Gambia.  
Given the TPP requirement regarding dosage schedule (‘The first dose must be shown to be 
administrable at 6 weeks of life or earlier’), study vaccine (PNEUMOSIL or Synflorix), and all other 
EPI vaccines normally administered at 2, 3, and 4 months of age in The Gambia (DTwP-HepB-Hib, 
OPV, RV and IPV‡), will be administered to infants enrolled in this Phase 3 trial at 6, 10, and 14 
weeks of age. This schedule is approved by the WHO and is common in EPI programs.22,34 
Administering these infant EPI vaccines at this earlier schedule as part of the clinical trial ensures 
that all subjects are fully vaccinated, and avoids complications of missed vaccinations, and over-
vaccination in the case of PCV. It is also required in order to evaluate whether concomitant 
administration of PNEUMOSIL interferes with the immune responses to these EPI vaccines. For 
the same reason, the booster dose of study vaccine will be administered at 9 months of age, to be 
aligned with the EPI schedule (see the Gambian EPI schedule in  
Table 7). Seroprotection rates for DTwP-HepB-Hib and polio vaccine (type 1 and 3) after the 3-
dose primary series, and for measles-rubella and yellow fever vaccines after the booster dose, will 
be measured in a subset of infants enrolled in the trial to demonstrate that the immune responses 
induced by these EPI vaccines are not inferior to those induced by these vaccines when co-
administered with Synflorix. If, after completion of the trial, the immune response proves to not be 
comparable for an EPI vaccine when co-administered with PNEUMOSIL, infants who failed to 
seroconvert will be offered a booster dose of the vaccine. 
 
Table 7. 
Gambian EPI Schedule for Children 0 to 18 Months Old§ 
Age at Immunization 
Antigen 
At birth 
BCG, OPV, HepB 
2 months 
OPV, DTwP-HepB-Hib, PCV, RV 
3 months 
OPV, DTwP-HepB-Hib, PCV, RV 
4 months 
OPV, DTwP-HepB-Hib, PCV, IPV* 
                                                 
 
 

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9 months 
OPV, measles-rubella, yellow fever 
18 months 
OPV, measles-rubella, DTwP, Vitamin A 
 
Abbreviation: BCG, Bacillus Calmette–Guérin;  
 *Only a single dose of IPV is given alongside the third infant priming vaccines in line with the national EPI program 
recommendations. 
* Should any changes to the EPI schedule in the Gambia occur before or during the study the vaccines given alongside the 
study vaccines will be modified accordingly to reflect the current programme unless this is considered to interfere with the 
assessment of the study endpoints in any way. 
2. 
HYPOTHESES, OBJECTIVES AND ENDPOINTS 
2.1. 
Study Hypotheses 
2.1.1. 
Primary Hypotheses: 
Immunogenicity: 
 The immune responses to the 10 serotypes in PNEUMOSIL (1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, 
23F) induced by 3 different lots of PNEUMOSIL will be equivalent after a 3-dose primary series. 
 The immune responses to at least 7 of the 10 serotypes in PNEUMOSIL will be non-inferior to 
the immune responses induced by the matched serotype (for 1, 5, 6B, 7F, 9V, 14, 19F, 23F) or 
serotype with the lowest seroresponse rate (for 6A, 19A) in Synflorix, after a 3-dose primary 
series. 
 
The immune responses induced by pentavalent, polio and rotavirus vaccines co-administered with 
PNEUMOSIL during a 3-dose primary series will be non-inferior to the immune responses 
observed when these vaccines are co-administered with Synflorix. 
Safety, Tolerability: 
 PNEUMOSIL administered as a 3-dose primary series, and co-administered with routine pediatric 
vaccines, will be safe and well tolerated. 
 PNEUMOSIL administered as a booster dose to primed infants at 9 months of age will be safe 
and well tolerated when co-administered with routine pediatric vaccines. 
2.1.2. 
Secondary Hypotheses: 
Immunogenicity: 
 The immune responses induced by PNEUMOSIL for serotypes 6A and 19A will be superior to 
the cross-reactive responses to these serotypes induced by Synflorix after a 3-dose primary series. 
 PNEUMOSIL will induce a measurable booster response to each of the 10 serotypes when 
administered as a 4th dose at 9 months of age. 
 The immune responses induced by measles-rubella and yellow fever vaccines administered at 9 
months of age concomitantly with a PNEUMOSIL booster dose will be non-inferior to those 
observed when the vaccines are co-administered with a Synflorix booster dose. 

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2.2. 
Study Objectives 
2.2.1. 
Primary Objectives: 
Immunogenicity: 
1. To demonstrate that the immune responses to the 10 pneumococcal serotypes in PNEUMOSIL 
(1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, 23F) induced by 3 different lots of PNEUMOSIL are 
equivalent when measured 4 weeks after a 3-dose primary series 
2. To demonstrate non-inferior immune responses for at least 7 of the 10 serotypes in PNEUMOSIL 
in comparison to matched serotypes (for 1, 5, 6B, 7F, 9V, 14, 19F, 23F) or the lowest responder 
(for 6A, 19A) in Synflorix based on (a) % IgG response ≥ 0.35 μg/mL or (b) IgG GMCs measured 
4 weeks after a 3-dose primary series 
3. To demonstrate that the immune responses induced by routine pediatric vaccines (pentavalent, 
polio and rotavirus) when co-administered with a 3-dose primary series of PNEUMOSIL are non-
inferior to those induced by these vaccines when co-administered with Synflorix (subset of 
subjects) 
Safety, Tolerability: 
1. To demonstrate an acceptable safety and tolerability profile for PNEUMOSIL administered as a 
3-dose primary series and booster dose, and when co-administered with routine pediatric vaccines 
through 4 weeks after a booster dose (subset of subjects for tolerability) 
2.2.2. 
Secondary Objectives: 
Immunogenicity: 
1. To demonstrate that the immune responses to serotypes 6A and 19A in PNEUMOSIL are superior 
to the cross-reactive responses to these serotypes induced by Synflorix based on (a) % IgG 
response ≥ 0.35 μg/mL or (b) IgG GMCs measured 4 weeks after a 3-dose primary series 
2. To evaluate the functional serotype-specific antibody responses induced by PNEUMOSIL in 
comparison to Synflorix, as measured by OPA at 4 weeks post 3-dose primary series (subset of 
subjects) 
3. To evaluate the booster responses (antibody concentrations and functional responses) to 
PNEUMOSIL in comparison to Synflorix, from 4 weeks after a 3-dose primary series to 4 weeks 
after a booster dose (subsets of subjects) 
4. To demonstrate that the immune responses induced by measles-rubella and yellow fever vaccines 
when co-administered with a booster dose of PNEUMOSIL are non-inferior to those induced by 
these vaccines when co-administered with a booster dose of Synflorix (subset of subjects) 
2.2.3. 
Supplemental Objectives: 
Immunogenicity: 
1. To evaluate the persistence of immune responses (antibody concentrations and functional 
responses) induced by PNEUMOSIL in comparison to Synflorix, 1 year after administration of a 
booster dose (subset of subjects) 

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Safety: 
1. To assess the safety of a 3-dose primary series and booster dose of PNEUMOSIL co-administered 
with routine pediatric vaccines in regards to serious adverse events occurring 4 weeks after the 
booster dose through 12 months after the booster dose (subset of subjects) 
2.3. 
Study Endpoints 
2.3.1. 
Primary Endpoints: 
Immunogenicity: 
For Primary Objective 1 (lot consistency): 
 Serotype-specific immunoglobulin G (IgG) geometric mean concentration (GMC) measured 4 
weeks post dose 3 
For Primary Objective 2 (non-inferiority): 
 Percentage of subjects with serotype-specific IgG concentrations ≥ 0.35 µg/mL measured 4 weeks 
post dose 3 
 Serotype-specific IgG GMC measured 4 weeks post dose 3 
For Primary Objective 3 (non-interference): 
 Percentage of subjects with anti-diphtheria toxoid IgG concentration ≥ 0.1 IU/mL measured 4 
weeks post dose 3 
 Percentage of subjects with anti-tetanus toxoid IgG concentration ≥ 0.1 IU/mL measured 4 weeks 
post dose 3 
 Percentage of subjects with anti-Hepatitis B surface antigen (HBsAg) IgG concentration ≥ 10 
mIU/mL measured 4 weeks post dose 3 
 Percentage of subjects with anti-Haemophilus influenzae type b (PRP) IgG concentration ≥ 0.15 
µg/mL measured 4 weeks post dose 3 
 Anti-pertussis toxoid and fimbriae IgG GMCs measured 4 weeks post dose 3 
 Percentage of subjects with anti-poliovirus types 1, 2 and 3 neutralizing antibody titers ≥ 1:8 
measured 4 weeks post dose 3  
 Percentage of subjects with anti-rotavirus IgA concentration ≥ 20 U/mL measured 4 weeks post 
dose 3 
Safety, Tolerability: 
 Number and severity of solicited local and systemic adverse events (reactogenicity events [REs]) 
through Day 6 post each vaccination 
 Number, severity and relatedness of all AEs and serious adverse events (SAEs) during the entire 
study period through 4 weeks post last dose for the cohort 
2.3.2. 
Secondary Endpoints: 

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Immunogenicity: 
For Secondary Objective 1 (superiority): 
 Percentage of subjects with serotype-specific IgG concentrations ≥ 0.35 µg/mL measured 4 weeks 
post dose 3 
 Serotype-specific IgG GMC measured 4 weeks post dose 3 
Secondary Objective 2 (functional response): 
 Percentage of subjects with OPA titer ≥ 1:8 measured 4 weeks post dose 3 
 OPA geometric mean titer (GMT) measured 4 weeks post dose 3 
Secondary Objective 3 (boostability): 
 Ratio of IgG GMCs measured 4 weeks post dose 4 to IgG GMCs measured 4 weeks post dose 3 
 Ratio of OPA GMTs measured 4 weeks post dose 4 to OPA GMTs measured 4 weeks post dose 3 
Secondary Objective 4 (non-interference): 
 Percentage of subjects with anti-measles IgG concentration ≥ 150 mIU/mL measured 4 weeks 
post dose 4 
 Percentage of subjects with anti-yellow fever neutralizing antibody titers ≥ 1:8 measured 4 weeks 
post dose 4 
 Percentage of subjects with anti-rubella IgG concentration ≥ 4 IU/mL measured 4 weeks post 
dose 4 
2.3.3. 
Supplemental Endpoints: 
Immunogenicity: 
For Supplemental Objective 1 (immune persistence): 
 Percentage of subjects with serotype-specific IgG concentrations ≥ 0.35 µg/mL measured 1 year 
post dose 4 
 Serotype-specific IgG GMC measured 1 year post dose 4 
 Percentage of subjects with OPA titer ≥ 1:8 measured 1 year post dose 4 
 OPA geometric mean titer (GMT) measured 1 year post dose 4 
For Supplemental Objective 2 (Safety): 
 Number, severity and relatedness of all serious adverse events (SAEs) 4 weeks after the booster 
dose through 12 months after the booster dose (subset of subjects) 
3. 
STUDY DESIGN 
This is a prospective, single center, randomized, active-controlled, double-blind, Phase 3 study in 
healthy Gambian PCV-naïve infants (6 to 8 weeks). The study will be conducted in 3 phases: an initial 
priming phase, in which all (n=2,250) eligible subjects will participate, and a second booster phase, in 
which only the first 675 randomized subjects will participate. In the third phase out of the 675 booster 
subjects, additionally consented subjects will participate to evaluate immune persistence. The study 
schema is presented in Table 8. 
Screening: After parental informed consent is obtained, prospective subjects will be considered 
enrolled in the trial, and will be screened to determine eligibility. While informed consent may occur 
as early as 4 weeks of age, the screening window will be 6 to 8 weeks of age. Randomization will take 

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place only after a subject has satisfied all eligibility criteria, including confirmation of 1) no acute 
illness that precludes vaccination; 2) a negative rapid diagnostic test (RDT) for malaria; and 3) normal 
vital signs. These same criteria will need to be satisfied prior to administration of any subsequent 
vaccination. 
Priming Phase: Subjects (n=2,250) deemed eligible to participate in the study by the Principal 
Investigator (PI) will be randomized in a 2:2:2:3 ratio based on a pre-established randomization scheme, 
to receive the first dose of either PNEUMOSIL (3 groups receiving vaccine from different lots) or 
Synflorix (1 group) at 6-8 weeks of age (V1). Treatment assignment will be stratified by field site. 
Subsequent primary vaccination visits will take place at 4 (+2) weeks after the previous vaccination.  
Table 8. 
Study Schema 
Groups 
Priming Phase 
Booster Phase 
Immune 
Persistence 
Phase 
N 
Visits* 
N 
Visits* 
Visit* 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
6-8 w 
V1+4(+2)w
V2+4(+2)w
V3+4(+2)w
9-10 m 
V5 
+4(+2)w 
V5+12(+1)m 
PNEUMOSIL 
Lot 1 
500 
X 
X 
X 
B 
150# 
X 
B 
B 
PNEUMOSIL 
Lot 2 
500 
X 
X 
X 
B 
150# 
X 
B 
B 
PNEUMOSIL 
Lot 3 
500 
X 
X 
X 
B 
150# 
X 
B 
B 
Synflorix 
750 
X 
X 
X 
B 
225# 
X 
B 
B 
w = weeks; m = months 
X = vaccination (+ EPI vaccines); B = blood sample for immunogenicity testing 
*Age ranges indicated for V1/V5. Subsequent vaccinations/follow up visits at 4 weeks post prior visit + 2 week 
window except for V7, which will be at 12 months post V5 + 1 month window. 
#The total number of subjects assessed for immune persistence at V7 will depend on number of subjects whose parent 
provides additional informed consent. 
(V2, V3). Standard EPI vaccinations based on the Gambian EPI schedule (See Table 7) will be given 
concomitantly with all 3 doses of the study vaccine. A follow-up visit (V4) will take place at 4 (+2) 
weeks after the third vaccination visit, during which blood will be collected for immunological 
assessments. This visit will serve as the end-of-study (EOS) visit for subjects not included among the 
675 subjects to be randomized (n=1,575). 
Infants who are only enrolled in the priming phase of the study will be offered a booster dose of 
Prevenar 13 outside the study, at 9 to 12 months to ensure all recruited infants gain maximal long term 
pneumococcal protection.  Prevenar 13 is used as the vaccine routinely in the EPI schedule in The 
Gambia.   
Booster Phase: The first 675 randomized subjects will continue on study and be asked to return to 
clinic at 9 (+1) months of age for a booster vaccination of study vaccine that matches the original 
treatment assignment (V5). Standard EPI vaccinations based on the Gambian EPI schedule (measles-
rubella, yellow fever vaccine, OPV) will be co-administered with the booster dose of study vaccine. 

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Subjects will be evaluated at a follow-up visit 4 (+2) weeks later (V6), during which a blood sample 
will be collected for immunological assessments. This visit will serve as the EOS visit for boosted 
subjects whose parent does not provide consent to continue on study for assessment of immune 
persistence 1 year after the booster vaccination (V7). Initial database closure and unblinding of only 
the Sponsor, statistical personnel and medical monitor will occur after the last subject in the booster 
cohort completes V6 in order to analyze and report primary and secondary endpoints. Those subjects 
(maximum n=675) whose parent provides additional consent to participation will return for a final visit 
(EOS, V7) at 12 (+1) months after the booster vaccination, during which blood will be collected for 
assessment of immune persistence. 
Safety Monitoring: Planned safety assessments will provide the data for active monitoring of vaccine 
safety during conduct of the trial through 4 weeks post the final (booster) vaccination, and for the 
primary safety and tolerability endpoints. For subjects who are included in the third phase for immune 
persistence evaluation, serious adverse events will be monitored from 4 weeks post the booster 
vaccination to 12 months after booster vaccination. 
Immediate solicited reactogenicity and vital signs will be assessed at 30 (+/- 10) minutes following 
vaccination in all subjects. Severity of solicited reactions will be assessed by toxicity grading scale (see 
Section 9.2.2). The solicited local reactions assessed will include tenderness, erythema/redness, and 
induration/swelling at the study vaccine injection site. The solicited systemic reactions will include 
cutaneous rash, fever (based on axillary temperature), irritability, drowsiness, and decreased appetite.  
Half of the subjects assigned to each treatment group (n = 1,125 subjects total) will be randomly 
selected to be included in the “primary reactogenicity cohort.” These subjects will be monitored daily 
at home by field workers for assessment of local and systemic reactogenicity during the 6 days after 
each primary series vaccination. In addition, all 675 infants who receive the booster vaccination 
(“booster cohort”) will be monitored daily at home by field workers during the 6 days after the booster 
vaccination. Reactogenicity scoring will be reviewed by a research clinician (RC) prior to being entered 
into the electronic data capture (EDC) system. 
Subjects who are enrolled in the priming phase of the study will be monitored for adverse events (AEs) 
at each clinic visit until the End-of-Study (EOS) visit. Subjects in the booster cohort will be monitored 
for AEs at each clinic visit through the follow-up visit at 4 weeks post the booster vaccination (V6).  
Additionally, for subjects who are included in the third phase for immune persistence evaluation, 
serious adverse events will be monitored from 4 weeks post the booster vaccination to 12 months after 
booster vaccination. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) (version 19.1 or 
later) and assessed by the PI with regards to severity, relatedness, and duration. Any serious adverse 
event (SAE) ongoing at the time of the subject’s EOS visit, will be attempted to be followed until it is 
resolved, assessed as resolved with sequelae by the PI, or until last subject last visit (LSLV) in the trial 
(ie last subject completes V7). Any SAE deemed related to study vaccine that is ongoing at the time of 
LSLV will continue to be followed until it is resolved, assessed to be resolved with sequelae, or assessed 
to be stable/chronic. SAEs deemed not related to study vaccine that are unresolved at the time of LSLV 
will be classified as ongoing for the purposes of data lock but will continue to be followed by the 
investigator team or referred on if appropriate according to good practice in The Gambia. 
To facilitate rigorous safety monitoring, data captured on case report forms (CRFs) at each visit will 
be entered into the EDC system within 3 business days from the date of the clinic visit. Home visit 

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data (Day 1-6 following vaccination) will be entered in the EDC system within 3 days of the Day 6 
home visit.  
The Protocol Safety Review Team (PSRT), including the PI, RCs, PATH Study Director, and CRO 
staff, will review blinded safety data and clinical trial conduct weekly throughout the trial, until the 
last subject completes V6. During this time, data will be aggregated for routine review by the PSRT. 
In addition, an independent Data Safety Monitoring Board (DSMB) will monitor conduct of the trial 
and vaccine safety; this will include a formal, unblinded review of all safety data accrued during the 
trial when approximately one-quarter of the infants in the primary reactogenicity cohort have received 
their first vaccination. The need for additional meetings to review unblinded safety data will be 
determined by the DSMB following this initial review or may be specifically requested by the PSRT. 
Immunogenicity Testing: Serum samples collected 4 weeks after completion of the 3-dose primary 
series (V4), 4 weeks after the booster dose (V6) and 1 year after the booster dose (V7) will be analyzed 
by ELISA to determine the IgG concentration and seroresponse rates (≥0.35 µg/mL) to each of the 10 
serotypes included in PNEUMOSIL. Comparisons for primary objectives 1 (lot-consistency) and 2 
(non-inferiority), secondary objectives 1 (superiority) and 3 (boostability) and supplemental objective 
1 (immune persistence) will be based on these endpoints. Serum samples collected at Visits 4, 6 and 7 
will also be analyzed by OPA to determine the functional immune response to the 10 serotypes included 
in PNEUMOSIL. Serotype-specific OPA titers and seroresponse rates are secondary immunogenicity 
endpoints for objectives 2 (functional response) and 3 (boostability) and supplemental immunogenicity 
endpoints for objective 1 (immune persistence). 
Serum collected 4 weeks after the primary series (V4) and after the booster dose (V6) will also be 
analyzed by ELISA and by neutralization assays (for poliovirus types 1, 2 and 3 and yellow fever) to 
determine immune responses to antigenic components of co-administered EPI vaccines. Seroprotection 
rates and GMCs calculated on the basis of these data are primary and secondary endpoints for 
assessment of primary objective 3 and secondary objective 4 (non-interference). Should these analyses 
post database lock reveal evidence of PNEUMOSIL interference to an EPI vaccine (i.e. failure to 
demonstrate non-inferiority to the immune response to the vaccine when co-administered with 
Synflorix), the PI will offer a booster dose to subjects who failed to seroconvert to the EPI vaccine. 
4. 
STUDY POPULATION 
4.1. 
Description of Study Population 
The study population will consist of healthy, Gambian male and female, PCV-naïve infants from 6 up 
to 8 weeks of age, to be recruited, screened, and qualified by the site staff (under the direction of the 
PI) at the MRC Unit The Gambia. 
Since 1947, the MRC Unit The Gambia has been conducting medical research focused on infectious 
diseases of significance to people of The Gambia and other African countries, with the goal of reducing 
the burden of illness and death in the country and throughout the developing world. The MRC Unit, 
The Gambia has conducted seminal vaccine trials, in particular against H. influenzae type b and S. 
pneumoniae, that have resulted in important benefits to The Gambia as a result of early vaccine 
introduction and disease surveillance. The VAC-017 study was also conducted at the MRC Unit The 
Gambia. 
Clinical vaccine trials at the MRC are conducted at field sites based within the compounds of government 
urban health centers or at other facilities within the vicinity of the respective health centers if space at the 

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health center itself is insufficient.  These field sites are within a short distance of the main MRC 
administrative and laboratory site in Fajara, which includes a ward and clinical unit for subject inpatient 
treatment, as well as clinical laboratories. The present trial will be conducted at multiple field sites. 
4.2. 
Inclusion Criteria 
Prospective subjects will only be eligible for randomization if all of the following inclusion criteria, and 
none of the exclusion criteria, are met at the time of screening: 
 They are healthy infants. Subjects are deemed healthy if, based on medical history and clinical 
assessment, they are determined to be without acute or chronic, clinically significant pulmonary, 
cardiovascular, hepatobiliary, gastrointestinal, renal, neurological, or hematological functional 
abnormality or illness that requires medical therapy.  
 They are between 6 and 8 weeks (ie 42 to 56 days) old, inclusive. Subjects will be eligible from 
the day they reach 6 weeks until the day they reach 8 weeks only. 
 Subject’s parent must provide voluntary written/thumb-printed informed consent for the subject 
to participate in the study. As local languages in The Gambia are non-written, informed consent 
may be obtained from an English-illiterate parent but will require an English-literate impartial 
witness who is also fluent in the relevant local language (and who is not an employee of MRC) 
to be present for consenting and to co-sign the informed consent form (ICF) to confirm that the 
information in the ICF has been provided in full and that the subject’s parent is consenting for 
their infant to take part in the trial having had any questions answered to the parent’s apparent 
satisfaction. 
 Subject’s parent must be able to comprehend and comply with study requirements and 
procedures and must be willing and able to return for all scheduled follow-up visits. 
 Subjects must have been born full-term, have a weight-to-height Z score of ≥ -2 (WHO child 
growth standard), and be ≥ 3.5 kg at randomization. 
  
Note: Subjects with borderline z-score or weight at initial screening may be rescreened if within 
the age window.  
 Subject’s parents must have a readily identifiable place of residence in the study area, be 
available for the duration of trial participation, and have a means of telephone contact. 
Note: A telephone and/or telephone credit will be provided to subjects enrolled in the trial to 
ensure they are always able to contact a member of the field team in the case of illness/adverse 
event. 
4.3. 
Exclusion Criteria 
 Use of any investigational medicinal product prior to randomization or planned use of such a 
product during the period of study participation. 
 Previous vaccination against S. pneumoniae. 
 History of S. pneumoniae infection confirmed by culture from a normally sterile site. 
 History of allergic disease or history of a serious reaction to any prior vaccination or known 
hypersensitivity to any component of the study vaccines. This includes such reactions in older 
siblings and also includes all components of the EPI vaccines. 
 History of anaphylactic shock. 

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 Any abnormal (Grade ≥ 1) vital sign. 
 
Note: An abnormal vital sign, including fever (axillary temperature of ≥ 37.5°C), may be 
repeated to determine whether a subject is eligible for randomization. A minimum of 48 hours 
following a documented fever must pass before the subject can be reassessed for eligibility. The 
last vital sign measurement must be used as the baseline value for the study. 
 Any moderate or severe (Grade ≥ 2) acute illness.  
Note: Infants with a Grade 1 acute illness may be enrolled at the discretion of the PI. 
 
Note: Subjects with moderate or severe acute illness may return for clinical re-assessment; if the 
illness has sufficiently resolved, they may still qualify for randomization. 
 A positive RDT (or blood film) for malaria. 
 
Note: Subjects with a positive RDT may be retested post treatment. A RDT for malaria will be 
undertaken on the day of each vaccination to ensure a subject is not vaccinated with a concurrent 
malaria infection. 
 History of administration of a non-study vaccine within 30 days prior to administration of study 
vaccine or during the course of study participation, other than EPI vaccinations, and any 
campaigns administered through The Gambian EPI office and Ministry of Health and Social 
Welfare.  
Note: BCG administered to subjects who did not receive BCG at birth must be given at least 7 
days prior to study vaccine. 
 Chronic administration (defined as more than 14 consecutive days) of immunosuppressant or 
other immune modifying drugs prior to the administration of the study vaccine, including the use 
of glucocorticoids. The use of topical and inhaled glucocorticoids will be permitted. 
 Administration of immunoglobulins and/or any blood products or anticipation of such 
administration during the study period. 
 History of known disturbance of coagulation or blood disorder that could cause anemia or excess 
bleeding (eg, thalassemia, coagulation factor deficiencies, severe anemia at birth). Any clearly 
documented history in a first-degree relative (eg, parent, sibling) of the same is also exclusionary. 
  History of suspected primary immunodeficiency. Any clearly documented history in a first-
degree relative of the same is also exclusionary. 
 Subject had a sibling die of likely sudden infant death syndrome (SIDS) or die suddenly and 
without apparent other cause or preceding illness in the first year of life. 
 Evidence of a clinically significant congenital abnormality as judged by the PI. 
 History of meningitis, seizures or any neurological disorder. 
 Evidence by history taking alone of exposure to an HIV-positive individual through maternal 
fetal transmission, breast milk, or other blood-borne mechanisms. 
 Subject is a direct descendant (child or grandchild) of any person employed by the Sponsor, the 
CRO, the PI, study site personnel, or site.  

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 Any medical or social condition that in the opinion of the PI may interfere with the study 
objectives, pose a risk to the subject, or prevent the subject from completing the study follow-
up. 
Note that specific exclusion criteria (eg, abnormal vital sign, acute illness, positive RDT) will be 
reassessed at all vaccination visits. Any subject who cannot be vaccinated due to an acute abnormality 
assessed at the 2nd or 3rd primary vaccination visit (V2 or V3), or at the booster vaccination visit (V5), 
may return once the acute issue has resolved. A minimum of 48 hours must have passed after a 
documented fever before a subject can be vaccinated. This safety requirement will not be deemed a 
protocol deviation should the visit fall outside the vaccination window; however, it will be encouraged 
to maintain the vaccination window whenever possible in these situations. 
Note that there is no further screening once initial randomization has taken place.  All subjects enrolled 
in the booster cohort will be eligible to continue into the cohort for immune persistence if informed 
consent is obtained.   
5. 
STUDY PRODUCTS 
5.1. 
PNEUMOSIL 
5.1.1. 
Product Description 
PNEUMOSIL consists of 10 individually fermented and purified pneumococcal polysaccharides that 
have been subsequently conjugated to CRM197, a detoxified diphtheria toxin, using 1-cyano-4-
dimethylaminopyridinium tetrafluoroborate (CDAP) conjugation chemistry. 
One single 0.5mL dose of PNEUMOSIL contains 2μg of polysaccharide for serotypes 1, 5, 9V, 14, 
19A, 19F, 23F, 7F and 6A, and 4μg for serotype 6B. It is formulated with aluminum phosphate 
(0.125mg Al3+ per dose) as an adjuvant in an appropriate buffer, and the multi-dose presentation used 
in this trial contains thiomersal (25µg per dose) as a preservative. The vaccine is a turbid white 
suspension. 
5.1.2. 
Manufacturer 
PNEUMOSIL is manufactured and supplied by SIIPL. 
5.1.3. 
Presentation and Formulation 
PNEUMOSIL will be supplied in a 5-dose (multi-dose) vial, in cartons containing 50 labeled vials 
and 1 product leaflet. Each vial label will include the following information: name of the medicinal 
product, composition, dose and fill volume, route of administration, lot number, manufacturing date, 
retest dates, storage condition, and a cautionary statement (“For Clinical Trial Use Only”). 
5.1.4. 
Storage 
PNEUMOSIL is stored at between 2°C and 8°C. It must not be frozen. 
5.1.5. 
Potential Safety Risks 
As with any vaccine, severe allergic reaction is a potential rare event. Known hypersensitivity to any 
component of the vaccine (including diphtheria toxoid and CRM197) is a contraindication to 
vaccination. 

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In the VAC-017 study, the most commonly reported solicited adverse reactions in infants (n = 100) 
after any of the 3 primary doses of PNEUMOSIL administered at 6, 10, and 14 weeks of age, and co-
administered with DTwP-HepB-Hib vaccine, were irritability (69%), fever (53%), injection site 
tenderness (45%), injection site induration/swelling (21%), and decreased appetite (20%). Reported 
Grade 3 solicited adverse reactions in infants after any of the 3 primary doses of PNEUMOSIL were 
fever (1%), rash (1%) and irritability (1%).  
The most commonly reported solicited adverse reactions in subjects from the infant cohort of the 
VAC-017 study (n = 49) after a booster dose of PNEUMOSIL administered at 10-13 months of age 
were injection site tenderness (18.3%), injection site induration/swelling (12.3%), fever (12.2%) and 
irritability (10.2%). The only reported Grade 3 solicited adverse reaction in these subjects was fever 
(4.1%; >39.0  ≤40.0◦C).  
The most commonly reported solicited adverse reactions in subjects from the toddler cohort (n = 56) 
in the VAC-017 study after a booster dose of PNEUMOSIL at 12-15 months of age were injection 
site tenderness (21.5%), fever (16.1%), decreased appetite (12.5%), drowsiness (10.7%), and 
injection site induration/swelling (10.7%). The only reported Grade 3 solicited adverse reaction in 
toddlers was fever (3.6%). Refer to Section 1.8.1 and to the IB for additional details on adverse 
reactions reported in clinical trials of PNEUMOSIL. 
5.2. 
Synflorix 
5.2.1. 
Product Description 
Synflorix consists of 10 individually fermented and purified pneumococcal polysaccharides that have 
been subsequently conjugated to non-typeable Haemophilus influenzae protein D (serotypes 1, 4, 5, 
6B, 7F, 9V, and 14), tetanus toxoid (serotype 18C), or diphtheria toxoid (serotype 19F) using CDAP 
conjugation chemistry.  
One single 0.5 mL dose of Synflorix contains 1μg of polysaccharide for serotypes 1, 5, 6B, 7F, 9V, 
14, and 23F, and 3μg of serotypes 4, 18C, and 19F. It is formulated with aluminum phosphate (0.5mg 
Al3+ per dose) as an adjuvant. The vaccine is a turbid white suspension. 
5.2.2. 
Manufacturer 
Synflorix is manufactured and supplied by GSK Biologicals. 
5.2.3. 
Presentation and Formulation 
Synflorix may be supplied in a pre-filled syringe (PFS) or in a single- or multi-dose vial. Each 
PFS/vial will be labeled with the following minimum information: name of the medicinal product, 
route of administration, expiry date, lot number, dose volume, and a cautionary statement (“For 
Clinical Trial Use Only”). 
5.2.4. 
Storage 
Synflorix should be stored at between 2°C and 8°C. It must not be frozen. 
5.2.5. 
Potential Safety Risks 
As with any vaccine, severe allergic reaction is a potential rare event. Synflorix should not be 
administered to subjects with known hypersensitivity to any component of the vaccine. 

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The most relevant clinical data for identifying potential solicited adverse reactions in infants who 
receive Synflorix in the current trial are from a Phase 3 study evaluating the safety and tolerability of 
Synflorix administered to Filipino infants (n = 300) as a 3-dose primary series at 6, 10, and 14 weeks 
of age, and co-administered with DTwP-HepB-Hib vaccine.35 The most commonly reported solicited 
adverse reactions after any of the 3 primary doses of Synflorix were injection site tenderness (67.2%), 
irritability (66.2%), fever (60.9%), injection site erythema (47.0%), drowsiness (38.8%), injection 
site swelling (36.4%), and decreased appetite (25.9%). Reported Grade 3 solicited adverse reactions 
after any of the 3 primary doses of Synflorix were injection site tenderness (9.4%), fever (6.1%; >39.0 
 ≤40.0◦C), irritability (2.9%), drowsiness (1.0%), and decreased appetite (0.2%). Injection site 
swelling > 30mm was reported in 9.3% of infants, and injection site erythema > 30 mm was reported 
in 2.4%.  
A Phase 3 trial evaluating the safety and tolerability of a booster dose of Synflorix administered to 
toddlers aged 12-18 months (n = 737), and co-administered with INFANRIX hexa® (combined 
diphtheria and tetanus toxoids, acellular pertussis, hepatitis B (recombinant), inactivated poliomyelitis 
and adsorbed conjugated Haemophilus influenzae type b vaccine), was conducted in Finland, France 
and Poland.33 The most commonly reported solicited adverse reactions after the booster dose of 
Synflorix were irritability (59.6%), drowsiness (41.2%), decreased appetite (31.3%), fever (33.3%), 
injection site tenderness (61.5%), injection site erythema (61.4%), and injection site swelling 
(46.0%). Grade 3 solicited adverse reactions after the booster dose of Synflorix were injection site 
tenderness (6.4%), fever (3.3%; >39.0  ≤40.0◦C), irritability (2.0%), drowsiness (0.7%), and 
decreased appetite (0.5%). Injection site swelling > 30mm was reported in 9.1% of toddlers, and 
injection site erythema > 30 mm was reported in 13.1%. Grade 4 fever (>40.0◦C) was reported in 
0.1% of toddlers.  
In both Phase 3 trials the incidence of solicited reactions reported after each vaccination dose was 
within the same range as after vaccination with the comparator, 7-valent Prevenar. Refer to the 
Summary of Product Characteristics for Synflorix (2014)25 for additional information on adverse 
reactions that have been reported in clinical trials and post-marketing surveillance. 
5.3. 
Vaccine Storage, Transport, and Temperature Monitoring 
The temperature of study vaccines will be monitored during shipment, storage and transportation to the 
field sites to ensure that temperature deviations do not occur. 
The temperature of all vaccine shipments will be monitored throughout transit using a continuous 
temperature monitoring system. Vaccines will not be used until the temperature of the vaccines 
throughout transit has been confirmed to be within acceptable limits. 
Upon receipt at MRC Fajara, all vaccines will be stored at 2°C to 8°C in dedicated refrigerators that are 
safe, locked, and not accessible to unauthorized personnel – including study team personnel blinded for 
study conduct purposes. The refrigerators will be under continuous temperature monitoring with 
maintenance of daily temperature logs, and connected to a power source with a reliable back-up system. 
Vaccine needed for a particular day will be transported from the main MRC site at Fajara to the field 
site in a cold box with continuous temperature monitoring. Any unused vaccines at the end of clinic will 
be returned to MRC Fajara for storage. 
It is the responsibility of designated unblinded site personnel to ensure that vaccine has not been 
exposed to temperatures outside the allowed range during transport or storage at the facility prior to 
being dispensed for vaccination. Should there be a deviation outside the allowed temperature range, 
the affected vaccine(s) will be quarantined. The temperature deviation will be reported to the CRO who 

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will advise the unblinded investigator team of the action to be taken based on the magnitude and 
duration of the temperature deviation. All drug accountability procedures, including cold chain 
monitoring will be documented and are the responsibility of the unblinded study personnel. 
5.4. 
Dose Preparation and Administration 
A limited number of appropriately trained, unblinded study personnel (herein referred to as unblinded 
personnel) will be responsible for preparing study vaccine doses in accordance with the randomly 
determined assignment, administering the study and other EPI vaccines, and handling all drug 
accountability procedures. The number of unblinded personnel will remain limited, and these personnel 
will not participate in the other aspects of the clinical trial, to help ensure the integrity of the blind at 
the site. The unblinded personnel will not reveal subjects’ randomization assignments to the subjects’ 
parents, or staff associated with the Sponsor, CRO, or site. Unblinded personnel will retrieve a subject’s 
randomization assignment after being informed by the PI that a subject is eligible for randomization. 
They will prepare the study vaccine based on the subject’s randomization assignment in a setting 
distinct from the clinic staff, and then the unblinded study nurse will administer study vaccine to a 
subject in a separate clinic setting. To be prepared for the highest level of possible medical risk, 
vaccination will take place in a clinical setting in which there is immediate access to the medical 
personnel (certified in pediatric life support), equipment and medications required for emergency 
resuscitation. 
Since both PNEUMOSIL and Synflorix are suspensions containing an alum adjuvant, study vaccine 
must be shaken gently immediately prior to use, in order to obtain a uniform homogenous white 
suspension. Inspection of each vial/PFS will occur immediately prior to use. If a vial/PFS or its contents 
appear unusual in any way, the vial/PFS will not be used, and procedures detailed in the Study Specific 
Procedures (SSP) for documentation and disposal will be followed. 
Only a single dose of study vaccine (PNEUMOSIL and Synflorix) will be drawn from each vial. EPI 
vaccines will be administered in an unblinded manner. Unblinded nursing staff will administer vaccines 
based on WHO best practices.36 Vaccination of EPI and PCV will be documented on the subject’s 
Infant Welfare Card (IWC). A detailed account of procedures related to preparation and administration 
of study vaccine will be included in the SSP. 
 PNEUMOSIL or Synflorix will be administered as an IM injection into the anterolateral aspect 
of the left thigh, using a 23G x 25mm needle. 
 Injectable EPI vaccines (DTwP-HepB-Hib, IPV, measles-rubella, and yellow fever vaccines) 
will be administered as an IM injection into the anterolateral aspect of the  right thigh. 
 RV and OPV vaccines will be administered orally according to standard local procedures. 
Injectable vaccines may be given at other sites if there is a good reason to do so (eg, local infection, 
or pre-existing swelling). In exceptional circumstances this could mean administering up to three 
vaccines, including study vaccine, into the same leg. Such decisions will be made on a case by case 
basis by the PI, and the reasons documented clearly in the clinical notes. When more than one vaccine 
is administered into the same leg, the leg may be temporarily marked with a pen to ensure local 
reactogenicity is assessed accurately. The site at which study vaccine is administered will be 
documented in the CRF for all subjects. 
5.5. 
Accountability and Disposal 

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Following vaccination, the vaccine vials/PFS will be labeled with the screening number of the subject 
to which the vaccine has been administered using prepared stickers. The person who administered the 
vaccine and the time and date of vaccine administration will also be documented in an appropriate drug 
accountability log on the day of vaccination. All used vials/PFS will be stored in a dedicated space that 
is accessible only to the unblinded site personnel and the unblinded CRO monitor (and ultimately 
disposed of after completion of the study). 
In case a vial/PFS of vaccine is broken or unusable, the unblinded site personnel will promptly inform 
the unblinded monitor and store the vial/PFS for accountability, following all safety precautions. In 
case a broken vial/PFS cannot be stored safely for accountability, appropriate discard and 
documentation will be followed after consultation with the unblinded monitor. Study product prepared 
but not administered to subjects, and all unused study product, will likewise be documented per drug 
accountability processes and discarded after the study is completed or terminated after notification by 
the CRO study drug monitor. 
The designated unblinded site personnel will maintain a complete and accurate inventory of study 
vaccines received (including the quantity of vaccines received, date of receipt, condition at receipt, 
temperature noted during transit), those administered, and any broken or destroyed.  
The unblinded CRO monitor will visit the site (including field sites) periodically throughout the trial 
to review and verify vaccine accountability records, as well as to ensure compliance with all trial 
procedures by the unblinded site personnel. After final drug accountability is completed by the 
unblinded CRO monitor, any used or unused vials/PFS of study vaccine will be destroyed at the site 
under the supervision of the unblinded site personnel. Due to the need to maintain blinding, no drug 
accountability records will be sent to the Sponsor or included in the trial master file (TMF) until after 
database lock. 
6. 
STUDY PROCEDURES 
6.1. 
Recruitment and Informed Consent 
This will be a single-center study to be conducted at the MRC Unit The Gambia, with prospective 
subjects to be recruited and consented at multiple field sites. 
6.1.1. 
Community and Individual Sensitization 
Recruitment for the trial will take place at MRC clinical trial facilities (field sites) based in or close to 
the compounds of a number of government health centers in the peri-urban coastal region of The 
Gambia. The health centers provide antenatal and obstetric services as well as inpatient care. They are 
also the sites through which the national EPI vaccine program is delivered to infants and children. 
Prior to commencing any trial-related activities a process of ‘community sensitization’ will take place. 
A series of ‘kola nut’** meetings with the Alkalo (community leader) and other senior members of the 
local community including representatives of women’s and mother’s groups will take place.  During 
these meetings, the PI and other members of the clinical trial team will explain the purpose of the trial, 
as set out in the ICF, and a chance for the attendees at the meeting to ask any questions they may have 
will be given. Following these meetings, information regarding the trial is disseminated throughout the 
                                                 
** Kola nuts (the seeds of Cola nitida and Cola acuminata) are given to members of the community at the end of the 
meeting as a sign of thanks and respect. 

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local community through well-established community networks. The aim here is that the community 
as a whole is aware of the trial and that any concerns or misunderstandings are avoided.   
Information regarding the trial may also be provided to mothers attending antenatal clinics to raise 
awareness of the trial in advance and to give them further time to consider and discuss possible 
participation. 
Potentially eligible infants will subsequently be identified by members of the clinical trial team in the 
early post-natal period at around the time that the newborn vaccines (BCG, OPV and hepatitis B) are 
administered and ‘individual sensitization’ of the parents will be undertaken. Sensitization at this age 
is necessary as the first set of primary EPI vaccines is recommended in The Gambia at 8 weeks of age, 
so recruitment at this visit is too late to catch infants in the 6 to 8 week eligibility window. 
During individual sensitization, parents will be approached and, if interested, the details of the study, 
as outlined in the ICF, will be explained to them by the study staff. Having had a chance to ask initial 
questions, they will then be given a copy of the ICF and encouraged to discuss the study with other 
close family members. It will be important to ensure that the subject’s father is also aware of the study. 
According to the mother’s preference a field worker may visit the home to provide information to the 
father or may provide such information by telephone. Contact details are taken from any parent who 
remains potentially interested following individual sensitization. The family will then be given a 
minimum of an overnight period to consider the information in the ICF before informed 
consent/enrollment can take place – ie, individual sensitization and consent cannot take place on the 
same day. However, in most cases the interval will be significantly longer than this given most 
sensitization will occur in the post-natal period and consent will not take place before an infant reaches 
4 weeks of age and will generally occur at 6 week of age. Of note, neither community nor individual 
sensitization alter the later process of consent during which the ICF is reviewed again line by line on a 
one-to-one basis.    
6.1.2. 
Initial and Continuing Informed Consent 
Informed consent is the process of ensuring that study subjects’ parent(s) fully understand the purpose 
of the study and what will and may happen during participation in the research study and what the 
risks are. The informed consent process continues throughout the study. Key study concepts will be 
reviewed with the study subjects’ parent(s) at designated times and as needed; this review process 
will be fully documented. Additionally, if any new information becomes available that, in the 
judgment of PATH and/or the PI, may affect parents’ decision to have their infant continue in the 
trial, such information will be shared, and may be the basis for requiring a new consent form to be 
signed.  
A separate informed consent procedure will be undertaken following V6 in the booster cohort only 
to include the additional blood draw one year after the booster vaccination (i.e. at V7) and to allow 
for the interim reporting of SAEs.  
If interested following individual sensitization, a subject’s parent(s) will be invited to one of the field 
sites, at which point documented informed consent can be obtained. Prior to initiation of this process 
at the site, parents must provide study staff with the IWC to confirm their infant’s identity and age. 
Copies of IWCs will be retained as a part of the source documents for the trial.  
A prospective subject may be as young as 4 weeks old on the day of consent. The parent providing 
consent must be 18 years or over on the day consent was provided. Consent from grandparents or 
guardians will not be accepted. 

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Parents who are literate in English will be provided with all the information in the ICF again by the 
PI or designee in English. English literacy will be confirmed in this case by asking the parent to read 
and explain a section of the consent form. Parents who are not literate in English (this is common 
in The Gambia) will have all the information in the ICF explained to them verbally in their local 
language by a member of the study team who is documented to be fluent in the language in question 
(all members of the team are English literate). Of note, the tribe to which a parent belongs is not 
necessarily the same as the first language spoken. If consent is obtained in this way, an impartial 
witness, who is fluent in English and the local language, must be present throughout the process of 
informed consent and is required to attest that all the information in the ICF has been given to the 
parent. They must also confirm that the parent has had the chance to ask questions and that these have 
been answered to the parent’s apparent satisfaction. 
After understanding all aspects of the study and having all questions answered, the parent will be 
required to undertake an ‘Assessment of Understanding’ – a series of questions to check that key 
elements of the study have been fully understood. If understanding is confirmed (according to 
predefined criteria) the parent is required to sign or provide a thumb print confirming agreement to 
have the parent’s infant participate in the study. Some parents may mark or sign the ICF rather than 
thumb-printing even though they are not English literate. This is acceptable according to the parent’s 
preference. If the consent has been undertaken in a language other than English the impartial witness 
must also sign and date the ICF to confirm the information has been given (as above). The language 
of consent and the relationship of the person providing consent for their child (eg, mother or father) 
will also be documented on the ICF. The PI or designee who has taken consent will also sign and date 
the form. 
A copy of the ICF will be provided to the parent and the original ICF will be filed with other subject 
records by the site team. 
The ICF will only be completed once at the time of enrollment and prior to screening for subjects 
enrolled only in the priming phase of the study (and unless new information necessitating repeat 
consent is required). As indicated, for subjects in the booster cohort, a second ICF will be completed 
at or after V6 to include an additional blood draw at 1 year post booster vaccination (V7) and to allow 
for the interim reporting of SAEs. 
Regardless of duration on study, ongoing willingness of subjects to participate will be documented 
in the source documents at each visit.   
7. 
STUDY VISITS 
7.1.1. 
Screening (Visit 1) 
Once informed consent has been documented the subject will be considered to be enrolled in the trial, 
and may be screened to determine study eligibility. The screening period may encompass more than 
1 day to allow for resolution of an exclusionary acute illness and/or abnormal vital sign. All 
inclusion/exclusion criteria must be assessed from data obtained within the screening period, unless 
otherwise specified in the eligibility criteria. After informed consent has been obtained, the following 
screening procedures will be performed: 
1. Screening identification (ID) number will be assigned. 
2. Demographic and contact information will be obtained including address (with adequate 
detail for another individual to identify the residence), telephone number(s), and email 
(if applicable). 

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3. Complete medical history of relevance to study eligibility will be obtained from the subject’s 
parent. 
4. A history of medications taken that are of specific relevance to study eligibility (eg, 
immunosuppressant medications) will be obtained from the subject’s parent. The IWC 
will also be reviewed for this purpose. 
5. Vaccination history will be obtained from the IWC, which will represent the source 
document for this information. 
6. Height/length and weight will be measured. The weight-for-height Z score will be 
calculated. 
7. A PE will be performed, including vital signs (temperature, pulse rate, and respiratory rate) 
and assessment of the major organ systems. Any subject with a > Grade 1 vital sign based on 
the toxicity grading tables in Appendix 1 and 2 will not be eligible for randomization (note: 
toxicity scores for pulse rate and > Grade 1 respiratory rate are based on severity of clinical 
manifestations of bradycardia/tachycardia and respiratory distress, respectively). Infants may 
return for repeat assessments once during the screening period to be reassessed for eligibility. 
The last measurement will be taken as the baseline for purposes of analysis. 
The PI will use good clinical judgment in considering an infant’s overall eligibility. Infants who are 
not eligible will be recorded as screen failures, along with the basis for this determination, on the 
appropriate CRF. An infant deemed a screen failure may not be rescreened. Any infant who fails 
screening due to an abnormal clinical finding will receive counseling from the PI, may receive initial 
care from the clinical trial team, and will be referred for further medical management as indicated 
according to normal practice in The Gambia. 
7.1.2. 
Randomization and Vaccination Visits (Visit 1, 2, 3, and 5) 
In most cases, eligibility will be determined in a single clinic visit, and no additional assessments 
will be needed prior to randomization and first study vaccination, when these are completed on the 
same day. If the screening period encompasses more than 1 day to allow for resolution of an acute 
illness, abnormal vital sign and / or borderline z-score or baseline weight<3.5 kg, or due to time or 
logistic constraints, the following procedures will need to be performed prior to randomization and 
first vaccination. These procedures will also be performed prior to subsequent vaccinations during 
the priming phase of the trial for all subjects, and prior to booster vaccination for those subjects 
included in the booster phase of the trial. 
1. Ongoing willingness to participate in the study will be documented. 
2. Interval medical and medication history will be obtained and eligibility confirmed based on 
review of inclusion/exclusion criteria. No moderate or severe acute illness may be noted, and 
no vital sign may be ≥ Grade 1 based on toxicity score (see Appendix 1 and 2). Randomized 
subjects may return to clinic to receive the 2nd (V2), 3rd (V3) or booster (V5) vaccination after 
resolution of an acute illness (or other cause of abnormal vital signs), without this resulting in 
a protocol deviation. Ideally this vaccination visit will occur within the allowable visit window 
(+2 weeks). A minimum of 48 hours must be allowed after a documented fever (axillary 
temperature of ≥ 37.5°C) before a subject may receive a study vaccination. 
3. If not already recorded, unsolicited AEs will be documented and graded for severity.  
4. If not already recorded, the occurrence of any SAE will be documented – inclusive of 
location, duration, severity, relatedness and clinical summary – and will result in 

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notification, based on guidelines set forth by the NRA and Investigational Review Boards 
(IRBs) pertaining to both reporting timelines and processing of related forms. Submission 
to the Sponsor will occur within a 24-hour time frame, from the time the event is first 
documented by the PI. 
5. Negative malaria parasitemia will be confirmed by RDT/blood film for malaria (generally a 
capillary sample will be used for this purpose). 
6. Targeted PE will be performed, to confirm absence of exclusionary acute illness or abnormality 
of the extremities (skin and lymph nodes) targeted for vaccination. 
7. After assessment of items 1-6 above any basis for determining that an infant is a screen failure, 
or for withholding re-vaccination in the case of subjects returning for the 2nd (V2), 3rd (V3) or 
booster (V5) vaccination, will be documented. Any subject who is not randomized will be 
referred back to their normal clinic for routine EPI vaccination. 
The PI must approve the randomization of the subject, based on confirmation that the subject meets 
all eligibility criteria. Randomization will occur at Visit 1 using a predefined randomization scheme, 
with allocations occurring in a 2:2:2:3 ratio to PNEUMOSIL (3 groups receiving vaccine from 
different lots) or Synflorix (1 group) and with stratification by field site. A subject’s allocation will 
be selected in numeric order from a set of sealed randomization envelopes. The assignment will be 
associated with a unique randomization ID. Following assignment, the unblinded study personnel 
will maintain a list documenting the vaccine assigned and administered to given randomization IDs 
in a secure location that is not accessible to blinded study personnel. The subject will be referred to 
by screening ID for the remainder of the study. The randomization ID will be required on select 
CRFs. 
Once eligibility has been confirmed and randomization has taken place -- or it has been determined 
that a subject returning for a vaccination at Visits 2, 3 or 5 may be re-vaccinated --, unblinded study 
personnel will perform the following procedures in an area of the clinic that is not readily accessible 
to blinded study personnel: 
1. Subject randomization ID will be recorded. 
2. The assigned study vaccine will be administered and documented on the CRF as to timing and 
location of administration (see Section 5.4 for details). 
3. The EPI vaccines due at the given vaccination visit will be administered and documented on 
the IWC and CRF (see Section 5.4 for details). It will also be noted on the IWC that a 
pneumococcal conjugate vaccine has been given. 
 
4. All subjects will be provided with a study ID card documenting their screening ID, the fact that 
they are enrolled in the clinical trial, and that they have received a study vaccine. It will also 
include telephone contact details for study personnel, and state that, should the subject become 
unwell, a member of the clinical trial team should be contacted immediately. This card will be 
attached to the IWC. 
 
5. All subjects will also be provided with a photo ID card confirming their randomization in the 
study. 
After vaccination is complete, the subject will be observed by blinded study personnel for the 
remainder of that visit and for all subsequent non-vaccination-related trial conduct. Immediately 
following vaccination the following will occur: 
1. Subjects will be monitored for vital signs and solicited reactogenicity with recording of all these 

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events at 30 (+/-10) minutes post vaccination. See Appendices 1 and 2 for appropriate severity 
grading scales. 
2. Parents of subjects in the primary reactogenicity cohort or booster cohort will be reminded 
about daily home visits for the subsequent 6 days after vaccination, and place of residence and 
phone contact details will be reconfirmed. Note: inclusion in the primary reactogenicity cohort 
will be determined at the time of randomization. 
3. The date of the subsequent clinic visit will be established. 
Note: Study vaccination must occur on the day of randomization. Subjects who are discontinued from 
the study after vaccination will not be replaced. However, if a subject is discontinued after 
randomization but prior to vaccination, he or she will be replaced using a new randomization 
assignment for the replaced subject. 
Home Visits – Primary Reactogenicity and Booster Cohorts (Days 1 through 6 Post 
Vaccination) 
Half of the subjects assigned to each treatment group (n = 1,125 subjects total) will be randomly 
selected as part of the randomization scheme to be included in the “primary reactogenicity cohort.” 
These subjects will be monitored daily at home by field workers for assessment of local and systemic 
reactogenicity during the 6 days after each primary series vaccination. In addition, all 675 infants 
who receive the booster vaccination (“booster cohort”) will be monitored daily at home by field 
workers during the 6 days after the booster vaccination.  
Field workers will be provided with a reactogenicity record form (RRF) for recording of 
reactogenicity events. The RRF will be retained as part of the source documents in the subject’s file. 
The grading scales to be used for assessment of severity of local and systemic reactogenicity events 
are listed in Appendix 1 (Section 16.1). Any Grade 3 or higher reactogenicity assessed by a field 
worker will result in immediate clinic contact, and the subject will be seen in the clinic within 
24 hours of the event. Field workers will contact the site to assist with scheduling if subjects are 
noted to be experiencing any medical condition (ie, solicited or unsolicited AE) that needs to be 
evaluated by the PI at an unscheduled clinic visit. 
Independent of a clinic visit, a Research Clinician (RC) will review the reactogenicity scoring with 
the field worker at the end of the 6-day assessment period, and sign off to confirm that this review 
has occurred. Following this review, an anonymized copy of the RRF will be submitted for data entry. 
If the condition of the RRF is such that data entry could be difficult, the source RRF could be 
transcribed to a new RRF for copying and submission. In this case the reason for this will be explained 
in the clinical notes. If more than 1 measurement of a particular parameter is taken and recorded, the 
value corresponding to the greatest magnitude of the RE will be used as the basis for categorizing 
and recording the event on the CRF during the given period of assessment. Any local or systemic 
reactogenicity or other AE ongoing at the day 6 home visit will prompt a day 7 follow-up visit in 
clinic. If a solicited AE is ongoing on day 7 post vaccination, or occurs after 7 days post vaccination, 
the event will be recorded on the AE CRF and continued to be followed as per AE monitoring 
requirements. 
7.1.3. 
Post-Vaccination Visits (Visit 4, 6, 7 and Unscheduled Visits) 
All subjects will be seen in clinic at Visit 4 (4 weeks post completion of the 3-dose primary series), 
and subjects in the booster cohort will be seen in clinic at Visit 6 (4 weeks post booster vaccination). 
The following procedures will be completed at these visits, as well as at any required unscheduled 
visit before Visit 6:  

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1. Screening ID, address and telephone number(s) will be confirmed. 
 
2. Unsolicited AEs will be recorded, including assessment of relatedness to vaccination and 
severity grade. 
3. The occurrence of any SAE will be documented – inclusive of location, duration, severity, 
relatedness and clinical summary – and will result in notification as set forth by the NRA and 
IRBs pertaining to both reporting timelines and processing of related forms. Submission to the 
Sponsor will occur within a 24-hour time frame, from the time the event is first documented by 
the PI. 
a. Follow-up will be attempted on any SAE that is ongoing at the time of a subject’s last 
visit, until the event is resolved, assessed to be resolved with sequelae by the PI, or until 
the last subject exits the study (LSLV). Any SAE deemed related to study vaccine that 
is ongoing at the time of LSLV will continue to be followed until it is resolved, assessed 
to be resolved with sequelae, or assessed to be stable/chronic. SAEs deemed not related 
to study vaccine that are unresolved at the time of LSLV will be classified as ongoing. 
4. Concomitant medications will be recorded. 
5. Vital signs will be measured, recorded, and graded. See Appendix 1 and 2 for severity grading 
of abnormal vital signs. 
 
6. Targeted PE will be performed, including local examination of the vaccination site and for any 
clinically significant finding. 
 
7. Blood sample for immunologic testing will be obtained by venipuncture (Visit 4 and 6). 
 
8. Any follow-up visits will be scheduled. 
9. Exit from the study will occur after Visit 4 (following completion of the final disposition CRF) 
for any subject not participating in the booster phase of the study or after Visit 6 for subjects in the 
booster cohort. 
Parents of subjects in the booster cohort will be asked during Visit 6 whether they are interested in 
continuing in the immune persistence phase (i.e. they will be individually sensitized to the immune 
persistence phase at V6).  At the same visit or at a subsequent visit, those that are interested will then 
provide informed consent for the immune persistence phase based on the new informed consent 
document.  The procedures for informed consent will be the same as for the initial consent for the main 
trial. 
 The following procedures will be completed at Visit 7 for subjects from the booster cohort whose 
parent provides prior informed consent: 
1. Screening ID, and other identifiers (e.g.  mother’s name/father’s name) will be confirmed. 
2. Any unrecorded SAE will be captured and reported  
3. Record any specific medications (e.g. immunosuppressives), vaccines (e.g. additional 
pneumococcal vaccines) or other treatments (e.g. blood products) which could influence 
immune persistence and which may be accounted for in the final analysis subsets 
4. Blood sample for immunologic testing will be obtained by venipuncture. 
5. Exit from the immune persistence phase of the study. 

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Between V6 and V7 the study team will continue to provide medical care at the trial site, in line with 
good medical practice in The Gambia, for those participants enrolled in the immune persistence 
phase.  The ongoing provision of clinical care in this way is essential to ensure any SAE occurring 
in these participants are captured real-time.  In addition, for consistency purposes, the study team 
will generally offer the routine EPI vaccines and Vitamin A due within the schedule in The Gambia 
at around 18 months of age (DTwP, Measles and Rubella, OPV).  However, if a participant was away 
from the trial site at this point they would be encouraged to attend a nearby clinic rather than delaying 
these vaccines.  Data regarding these activities will be captured on clinical notes and other appropriate 
source documents by the clinical trial team but are not otherwise part of the clinical trial dataset.  The 
administration of the routine EPI vaccines will be documented in the IWC of the infant. 
The occurrence of any SAE will be documented and reported in the immune persistence cohort as for 
the primary and booster cohorts between V1 and V4 or V6 respectively.  The procedures will be set 
out in the safety management plan for the immune persistence phase. 
Follow-up will be attempted on any SAE that is ongoing at the time of a subject’s last visit, until the 
event is resolved, assessed to be resolved with sequelae by the PI, assessed to be stable  and the outcome 
unlikely to change (chronic) by PI or until the last subject exits the immune persistence phase (LSLV). 
Any SAE deemed related to study vaccine that is ongoing at the time of LSLV will continue to be 
followed until it is resolved, assessed to be resolved with sequelae, or assessed to be stable/chronic. 
SAEs deemed not related to study vaccine that are unresolved at the time of LSLV will be classified as 
ongoing. 
 
 

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Evaluations to be performed at each study visit are shown in Table 9 as follows: 
Table 9. 
Study Visits 
Step 
No. 
 
Evaluation 
V1* 
V2 
V3 
V4 
V5# 
V6# 
V7# 
6-8 weeks 
V1+4 (+2)
V2+4 (+2)
V3+4 (+2)
9-10 mos
V5+4 (+2)
V5+12 (+1)
1 
Signing of ICF and confirmation of ongoing 
informed consent (+) 
 
+ 
+ 
+ 
+ 
+$ 
+ 
2 
Assign screening ID and confirm (+) 
 
+ 
+ 
+ 
+ 
+ 
+ 
3 
Demographics 
 
4 
Record contact information – address and 
telephone number(s) – and confirm (+) 
 
+ 
+ 
+ 
+ 
+ 
+ 
5 
Full medical history (including concomitant 
medications) and vaccination history. 
 
~ 
~ 
~ 
~ 
~ 
 
6 
Vital signs and PE (targeted after screening)*
^
^
^

^


7 
Blood sample for immunogenicity testing 







8 
Rapid malaria diagnostic test* 







9 
Eligibility check* 

 

 

 
 
10 
Assign randomization ID  

 
 
 
 
 
 
11 
Study vaccination 

 

 

 
 
12 
EPI vaccination 

 

 

 
 
13 
Record local/systemic solicited reactions 







14 
Record adverse events (including SAE)* 






(only 
SAEs)
15 
Record concomitant medications* 






%
16 
Schedule/confirm next visit 



# 



17 
Exit study 
 
 
 
‡ 
 
‡ 

Age ranges indicated for V1/V5. Other vaccination/follow up visits to be scheduled at 4 weeks post prior visit + 2 week window, or 
at 12 months post booster dose + 1 month window in the case of V7. 
* If screening extends beyond 1 clinic visit assessments (*) need to be repeated on the day of randomization/1st vaccination. 
# Visits 5 and 6 will only be completed by subjects in the booster cohort. Visit 7 will only be completed by subjects in the booster 
cohort whose parent provides additional consent for this assessment. 
(~) Confirmation of medical history 
^ Evaluations will be conducted twice – before and after vaccination 
‡ V4 is the EOS visit for subjects who do not participate in the booster phase, and V6 is the EOS visit for subjects in the booster 
phase whose parent does not additionally consent for assessment at V7. 
$ Informed consent for subjects in the booster cohort to continue on study in order to be assessed at V7 will be obtained at or after 
V6. 
%- if relevant to immune persistence objectives 
7.1.4. 
Interim Contacts and Visits 
Interim unscheduled contacts and visits (eg, unscheduled visits) in between regularly scheduled 
follow-up visits may occur at any time at the request of the subject’s parent or as deemed necessary 
by the PI. Up to V6, all unscheduled interim contacts and visits will be captured in the subject’s study 
records and on applicable CRFs.   

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In the immune persistence phase, data for unscheduled contacts and visits will be captured in clinical 
notes and other source documents but not on CRF.  SAEs during this period will continue to be 
documented in the internet-based SAE database and on the AE CRF; this will be described in the 
safety management plan. 
7.2. 
Refusing of Procedures, Missed Visits, Withdrawal, and Early Termination 
Subjects’ parents may refuse procedures on behalf of subjects at any time during enrollment in the 
study and can withdraw consent at any time. The PI may also, at his discretion, withdraw the subject 
from participating in the study at any time if he considers it in the best interest of the subject, with 
clear documentation as to the reason.  
Minor protocol deviations (eg, a missed visit window for a follow up visit, but the subject is seen 
for the visit within a reasonable time frame) do not constitute grounds for withdrawal of the subject 
per se, though these will be clearly documented on a protocol deviation CRF and in the clinical notes. 
If a subject fails to come to clinic for a study visit, extensive follow-up will be undertaken to locate 
and recall him/her. If the subject still fails to present to clinic within the allowed window for the 
visit, then he or she may still be permitted to complete the visit and related procedures at a suitable 
later date on a case-by-case basis. The PI will use discretion regarding the window allowed, or if 
the visit will be deemed a “Missed Visit.” If a subject has exceeded the visit window for a 
vaccination visit, the PI, in consultation with the Sponsor, will have the discretion to determine 
whether the subject ought to be withdrawn from further study vaccinations and only be offered the 
routine EPI vaccines. For major protocol violations (eg, a subject receives a non-trial investigational 
medical product) a notification to the appropriate regulatory authorities may be required, and the 
subject may be withdrawn from the study. Such decisions will be made by the PSRT on a case-by-
case basis. However subjects will be withdrawn from the study if any of the following events occur 
after informed consent has been given: 
 The subjects’ parent requests that the subject be withdrawn. 
 The PI determines that the subject is unable to comply with the protocol. 
 The subject is lost to follow-up.  
Note: A subject will be considered lost to follow-up only after telephonic attempts to contact the 
subject’s parent have failed, and a visit to the home to attempt a contact has occurred and the 
subject still cannot be located. 
 The Sponsor decides to suspend or discontinue development of PNEUMOSIL. 
If a subject is withdrawn for a major protocol violation prior to V6, the subject may continue to be 
followed for safety monitoring if he/she has received a study vaccination.  
In the event of a subject’s withdrawal or early termination prior to V6, the following activities will be 
attempted to be performed and information recorded in the database: 
1. Contact information will be reviewed and updated. 
2. Results from prior visits will be reviewed and any outstanding data queries completed. 
3. Date of withdrawal will be recorded. The date of withdrawal will be designated as the date 
when the last contact with the subject occurred (telephone or face-to-face). 
4. The reason for withdrawal or early termination will be documented. 
5. PE will be performed if possible. 
6. New AEs since the last visit will be documented. 

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7. All previously documented AEs and SAEs will be updated in regards to classification (ongoing, 
resolved, etc.). 
8. Concomitant medications since last visit will be documented. 
9. The subject’s final study visit will be documented and the final disposition CRF completed. 
Efforts made to complete the final disposition CRF in the event that the subject’s parent cannot 
or is unwilling to be contacted will be documented. 
In the event of a subject’s withdrawal or early termination after V6, the following activities will be 
attempted to be performed and information recorded in the database: 
1. Contact information will be reviewed and updated. 
2. Any previously recorded SAEs will be updated if necessary with regard to outcome and 
unrecorded SAEs will be captured 
3. The final disposition CRF will be completed. The date of withdrawal will be the date when 
the last contact with the subject occurred (telephone or face-to-face) 
In the case of early subject withdrawal or early termination, samples already collected will be retained 
for appropriate immunogenicity measurements unless the parent asks that these samples not be tested 
or be destroyed. If immunogenicity testing has already been carried out the data will be retained within 
the final analysis set irrespectively. 
7.3. 
Concomitant Medications and Treatments 
Up to and including V6, all concomitant medications, therapies and procedures will be recorded in 
source documents during each clinic visit of the study as outlined above. Subjects may receive all 
medications and procedures deemed necessary based on good medical practice in The Gambia. To enable 
the PI to directly assess potential AEs, subjects’ parents will be encouraged to obtain initial medical care 
for subjects at the field site during their enrollment in the trial except in the event of an emergency 
situation in which another health facility is more readily accessible. Any necessary medical care will 
follow what is considered to represent good medical practice in The Gambia, and access to such 
medical therapies will be made available to all subjects during enrollment in the trial. Essential 
treatments and medications will be provided by the trial team within the scope of their clinical 
expertise, although referral to government facilities will be appropriate in some cases (eg surgical 
conditions or trauma). 
That said, certain medications will not be allowed according to the protocol (unless for clinical need 
which will always take priority); if a subject uses the following medications, the PSRT will 
determine whether to discontinue the subject from the study or from receiving further vaccinations: 
 Use of any investigational drug or vaccine other than the study vaccines. 
 Administration of a vaccine not part of the EPI, or not administered as part of a national 
campaign. 
 
Chronic administration (defined as more than 14 days) of immunosuppressant or other 
immune modifying agents during the vaccine period. For corticosteroids, this means 
prednisone or equivalent >10 mg per day; topical and inhaled steroids are allowed. 
 
Administration of immunoglobulins or any blood products during the study period. 
 Data regarding concomitant medications (other than those detailed in SAE reports) will not be 
routinely captured after V6. However, parents will be questioned at V7 regarding the administration of 
certain medications not permitted per protocol (listed above). Reported use of these specific 

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medications will be documented on the CRF, if possible, and will be taken into consideration regarding 
the participant's inclusion in the relevant analysis population. 
7.4. 
Blinded and Unblinded Study Personnel 
With the exception of the designated unblinded site personnel described below, all study site personnel, 
including the PI and the Sponsor, will remain blinded to subjects’ treatment assignments until first 
database closure and study unblinding.  All CRO personnel, with the exception of the unblinded 
monitor, clinical supplies manager, an administrator and statistician for the DSMB will remain blinded 
to the treatment assignments until this time. After the last subject completes V6, the study will be 
unblinded (only the Sponsor, statistical personnel and medical monitor will be unblinded) following 
closure of all data, at which time primary and secondary endpoints will be analyzed. Study unblinding 
will be conducted and documented in accordance with SOP. Personnel who had remained blind would 
be unblinded only at the end of the study (post V7).  The randomization scheme will be appended to 
the integrated clinical study report (CSR) for reporting of these endpoints, as well as to the CSR 
addendum reporting the supplemental immunogenicity and safety endpoints.  
During conduct of the study through completion of Visit 6 by the last subject in the booster cohort, a 
limited number of unblinded site personnel will be responsible for preparing and administering study 
vaccines, performing drug accountability, and maintaining the security of the treatment assignments. 
The unblinded site personnel will not be involved in the safety assessment of the subjects, or in any 
other aspect of the study. All other site personnel, including those who perform the clinical evaluations 
(such as but not limited to assessment of medical history, vital signs assessment, and PE), will be 
blinded with respect to the identity of the vaccine administered to the subjects. 
The CRO will assign blinded monitor(s) to visit the site (including all field sites) during the study 
period, in order to assess and verify activities of the blinded study personnel, review appropriate 
documentation, and provide a report to the CRO and Sponsor of ongoing activities and issues requiring 
resolution. The blinded monitor(s) will be responsible for all aspects of the clinical trial related to 
subjects, the blinded site staff, and regulatory and audit readiness. Monitoring can occur both at the site 
and remotely with standard reports and escalation as needed to the PI or PSRT. The CRO will also 
assign an unblinded study monitor, who will visit the site (including all field sites) during the study 
period to assess and verify activities of the unblinded site personnel, review appropriate documentation, 
and provide a report to the CRO and Sponsor of ongoing activities and issues requiring resolution. The 
unblinded study monitor will be responsible for review of treatment assignments, vaccine storage and 
accountability, and dosing-related matters. The unblinded monitor will be responsible for escalating 
issues to the PI or PSRT in a blinded manner. Any unblinding of additional project team personnel 
required to resolve issues will be clearly documented in the TMF. Of note, all reports to blinded 
personnel by the unblinded CRO monitor will be constructed in order to maintain the blind during the 
trial. No report that would break the blind will be released into the TMF until after database lock. 
 
 

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7.5. 
Unblinding Procedure 
In the event of a medical emergency, the PI may require that the blind be broken for the subject 
experiencing the emergency when knowledge of the subject’s treatment assignment may influence the 
subject’s clinical care. 
An identical set of sealed randomization envelopes will be available at the site for this purpose, and 
should unblinding be necessary the PI will access these envelopes and obtain the envelope 
corresponding to the randomization ID of the subject in question. 
Training surrounding such unblinding will be done during the site initiation visit. Documentation of 
the unblinding event (including the rationale and requestor) will be recorded and duly entered into the 
EDC system. Every effort will be made not to unblind the subject unless it is considered necessary for 
the welfare of the subject. Prior to unblinding, the PI must attempt (to the extent possible, without 
jeopardizing the subject’s health) to contact the Sponsor (or designee) to discuss the decision to break 
the blind. The PI will be expected to provide a rationale for the necessity of unblinding based on the 
expectation that knowledge of the subject’s treatment assignment will have a meaningful impact on the 
subject’s medical care in the short term. If a subject’s treatment assignment is unblinded, the subject 
will remain in the study and continue with protocol-defined study visits, but not receive further study 
vaccines. The decision to unblind will be communicated to the Gambian Government/MRC joint EC 
and all other regulatory bodies as required. At the end of the study, documentation of all unblinded 
subjects (and the rationale for unblinding) will be incorporated into the TMF. 
8. 
LABORATORY EVALUATIONS 
Blood samples will be collected from subjects for immunogenicity testing. 
8.1. 
Sample Collection, Distribution, and Storage 
Blood samples collected for the immunogenicity endpoints will be separated into aliquots by the 
MRC research laboratories as per study SSP and stored at -70°C or lower in the MRC biobank 
before being shipped to the central immunology laboratories (see Section 8.3). Continuous 
temperature monitoring and backup generators will be in place to ensure proper sample storage. 
Any blood samples obtained for clinical evaluations will be transported to the MRC clinical 
laboratory for testing, although for efficiency a blood film for malaria parasites may be undertaken 
in the government laboratory at the health center when deemed necessary. 
Volumes of blood required at different time points for immunogenicity testing are shown in 
Table 4. 

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Table 4. 
Total Blood Volume Required 
Immunogenicity Test: 
Visit 4 
Visit 6 
Visit 7 
Total 
Study Vaccine: 
ELISA IgG for 10 serotypes in 
PNEUMOSIL 
3.0 mL 
3.0 mL 
3.0 mL 
9.0 mL 
OPA for 10 serotypes in PNEUMOSIL  
EPI Vaccines: 
ELISA IgG for components of DTwP-
HepB-Hib  
2.0 mL 
- 
- 
2.0 mL 
Neutralization assay for poliovirus 1, 2 
and 3 
- 
- 
ELISA IgA for rotavirus 
- 
- 
ELISA IgG for measles and rubella 
- 
2.0 mL 
- 
2.0 mL 
Neutralization assay for yellow fever 
- 
- 
Total Blood Volume 
5.0 mL1 
5.0 mL 
3.0 mL 
13.0 mL2 
1Total volume for infants in priming phase only. 
2Total volume for infants assessed for immune persistence at V7.  Infants in the booster cohort whose parent 
does not consent to this assessment will require a total blood volume of 10.0 mL. 
8.2. 
Clinical Laboratory Assays 
Clinical laboratory tests obtained at the discretion of the PI and RCs will be performed at the Clinical 
Laboratories Services, MRC in Fajara. The Clinical Laboratories Services subscribes to proficiency 
testing programs, and operates based on the principles of Good Clinical Laboratory Practice (GCLP) 
and ISO15189. 
Additional investigations may also be undertaken on subjects for research and/or diagnostic purposes 
in order to more fully characterize particular AEs (eg, to identify respiratory viruses in the nasopharynx, 
or investigate the cause of focal chest findings on PE with a chest x-ray). The circumstances in which 
such additional investigations may be undertaken, beyond those required as part of routine clinical care, 
will be specified in study specific procedures for the trial.   
8.3. 
Immunological Assays 
The following immunological assays are to be undertaken: 
 ELISA IgG: The IgG concentration to each of the 10 serotypes contained in PNEUMOSIL will 
be measured by ELISA in serum samples collected at Visit 4 (all subjects), 6 (booster cohort) 
and 7 (immune persistence cohort). The IgG concentration to components of the co-administered 
pentavalent (DTwP-HepB-Hib) vaccine will also be determined in serum samples collected at 
Visit 4, and to measles and rubella antigens in serum samples collected at Visit 6 (subset of 
subjects for each assay). The IgA concentration to co-administered rotavirus vaccine will be 
measured by ELISA in serum samples collected at Visit 4 (subset of subjects). The ELISAs for 
the PCV vaccines will be performed at the ______________, using the WHO reference PCV 

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ELISA protocol. The ELISAs for pentavalent and measles-rubella vaccines will be performed by 
______________. The ELISA for rotavirus vaccine will be performed by the ______________. 
 OPA: The functional activity of the IgG response to the 10 serotypes contained in PNEUMOSIL 
will be determined in serum samples collected at Visit 4, 6  and 7 (subsets of subjects). This 
activity will be determined using the 4-fold multiplexed opsonophagocytic assay (MOPA) 
developed at the University of Alabama at Birmingham, also to be performed at ______________. 
 Neutralization assays: The immune responses to co-administered poliovirus and yellow fever 
vaccines will be determined in serum samples collected at Visit 4 and 6, respectively, by 
neutralization assays for poliovirus types 1, 2 and 3 and yellow fever (subset of subjects in both 
cases). The assay for poliovirus types 1, 2 and 3 will be performed by ______________, and for 
yellow fever by ______________. 
If there are limitations to blood volumes, appropriate subsets and priorities for immune testing will be 
established with the immunology laboratories to ensure measurements will be unbiased and be 
representative of the entire cohort. After the completion of immune testing, all remaining samples at 
the central laboratories will be destroyed.  
All study results will be shared with contributing laboratories at the conclusion of the study. In addition, 
subjects’ parents will be provided an overall summary of the findings of this study through a community 
meeting held at each recruitment site. 
8.4. 
Assay Qualification, Standardization, and Validation 
The ELISA IgG and MOPA assays that will be used to measure the magnitude and the functional 
activity of the polysaccharide antibody responses – constituting primary and secondary endpoints of 
the trial – are standardly used in the field to measure immunogenicity as a surrogate marker for efficacy 
of PCVs, and were validated at the ______________. A detailed description of these 2 standard assays 
can be found at: ______________.  
The ELISAs that will be used for pentavalent vaccine and for rotavirus vaccine and the neutralization 
(plaque reduction) assay for yellow fever have all been validated following ICH guidelines as specified 
in Q2 (R1) “Validation of Analytical Procedures: Text and Methodology.” The ELISAs that will be 
used for measles and rubella are commercially available kits (Enzygnost® anti-measles and anti-rubella 
virus IgG; Siemens, Munich, Germany). The neutralization assay for poliovirus will be undertaken at 
a ______________   
8.5. 
Biohazard Containment 
As transmission of blood-borne pathogens can occur through contact with contaminated needles, blood, 
and blood products, appropriate blood and secretion precautions will be employed by all personnel in 
the drawing of blood and processing of blood, and shipping and handling of all specimens for this study. 
The laboratory SOPs will ensure appropriate coverage of the needs for this trial. All biological 
specimens will be transported using packaging mandated by the site and CRO SOPs, and aligned with 
other applicable regulations. All dangerous goods materials, including diagnostic specimens and 
infectious substances, will be transported according to instructions detailed in the International Air 
Transport Association (IATA) Dangerous Goods Regulations. 
Biohazardous waste will be contained according to institutional, transportation/carrier, and all other 
applicable regulations. 

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9. 
SAFETY ASSESSMENT AND REPORTING 
The PI is responsible for the detection and documentation of events meeting the criteria and definition 
of an AE or SAE as provided in this protocol for the duration of the study period through Visit 6. In 
addition, for subjects in the immune persistence cohort, the PI is responsible for also detecting and 
documenting events meeting the criteria and definition of a SAE from Visit 6 through Visit 7. 
9.1. 
Collection of Safety Events 
AEs will be systematically collected at all clinic visits through Visit 6 and for subjects enrolled only 
in the primary phase of the study, through Visit 4. For subjects in the immune persistence cohort, 
SAEs will also be collected from Visit 6 through Visit 7. Reactogenicity events will be assessed in 
all subjects immediately (30 minutes) after vaccination and for subjects included in the primary 
reactogenicity cohort and/or booster cohort, at the daily home visits for the first 6 days following 
each vaccination. 
In addition, subjects’ parents will be instructed to contact the PI immediately should the subject 
manifest any signs or symptoms. Subjects’ parents will be provided with contact details for the field 
site team and will be provided with telephone credit for this purpose. Site staff will be available 24 
hours a day by telephone and in person for emergency needs and during clinic hours to assess subjects 
for the duration of the trial (FSFV to LSLV). 
9.2. 
Definitions 
9.2.1. 
Adverse Event or Medical Event 
 An AE is any untoward, undesired, or unplanned event in the form of signs, symptoms, disease, 
or laboratory or psychological/physiologic observations occurring in a subject enrolled in the 
clinical trial. This includes all subjects from whom consent has been obtained whether or not 
they have yet been randomized and received a study vaccine (PNEUMOSIL or Synflorix). The 
event does not need to be causally related to trial participation or receipt of a study vaccine. An 
AE is temporally related to participation in the study and will be documented as to whether or 
not it is considered to be related to vaccine. An AE includes, but is not limited to, the following: 
o An intercurrent illness or injury during the course of the study. 
o Any clinically significant worsening of a preexisting condition. 
 A protocol-related AE is one that occurs from the time of enrollment until the EOS visit for a 
particular cohort that is not considered to be related to receipt of the study vaccine, but is 
considered by the PI or the medical monitor (Sponsor or designee) to be related to the research 
conditions, ie, related to the fact that a subject is participating in the study. For example, a 
protocol-related AE may be an untoward event occurring during blood sampling or other 
protocol-specified activity. 
 A treatment-emergent AE is defined as an event that is not present prior to administration of the 
study medication, or, if present prior to the administration of the study medication, increases in 
intensity after administration of the study medication during the course of the study. 
 Reactogenicity events include local and systemic reactions noted immediately post vaccination, 
or during follow-up visits through 1 week after vaccination by field workers and confirmed by 
the PI. 
o Any solicited AE that is ongoing on day 7 post vaccination, or occurs after 7 days post 

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vaccination will be entered as an unsolicited AE and followed appropriately at subsequent 
visits until resolved or EOS visit. 
9.2.2. 
Severity (Intensity) of Adverse Event 
The severity of all solicited AEs will be graded from Mild (Grade 1) to Potentially Life Threatening 
(Grade 4), based on the criteria given in Appendix 1 (Section 16.1). All AEs leading to death are 
Grade 5 events. Adverse events are graded based on the worst severity grade during the 
illness/symptoms. The grading scales for solicited AEs in the Appendix have been derived from the 
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
(Version 2.0, November 2014), from the US National Institutes of Health. 
All other unsolicited AEs will be classified as an AE and graded based on the AE severity scale in 
Table 5 below. 
Table 5. 
Severity Grading 
Grade
Description
0 
No AE (or within normal limits). 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 
Moderate; minimal, local, or noninvasive intervention indicated. 
3 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling. 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE. 
Derived from  http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
9.2.3. 
Causal Relationship of an Adverse Event 
A suspected adverse drug reaction (ADR) means any AE for which there is a reasonable possibility 
that the study vaccine caused the AE. A reasonable possibility means there is evidence to suggest 
a causal relationship between the vaccine and the AE. All cases judged by either the PI or the 
Sponsor as having a reasonable suspected causal relationship to the study vaccine will qualify as 
ADRs. Medical judgment will be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, confounding factors such as 
concomitant medication, concomitant diseases, and relevant history. Assessment of causal 
relationship will be recorded on the CRFs and on the SAE form (in case of SAEs). 
The likelihood of the relationship of the AE to study vaccine is to be recorded as follows: 
 Related: There is a reasonable causal relationship between the vaccine administered and the AE. 
 Not Related: There is no reasonable causal relationship between the vaccine administered and 
the AE. 
Note: solicited reactogenicity events will not be judged for relatedness. 

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9.2.4. 
Assessment of Outcome of Adverse Event 
The outcome of the AE will be assessed and recorded as per the following categories: 
 Ongoing. 
 Recovered/resolved. 
 Recovered/resolved with sequelae. 
 Fatal. 
 Unknown. 
9.2.5. 
Unexpected Adverse Event / Drug Reaction 
An AE or suspected ADR is considered “unexpected” if it is not listed in the Investigator’s Brochure 
(IB) for PNEUMOSIL or if it is not listed at the severity that has been observed. "Unexpected," as 
used in this definition, also refers to AEs or suspected adverse reactions that are mentioned in the IB 
as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, 
but are not specifically mentioned as occurring with the particular drug under investigation. If the 
classification of an unexpected AE/ADR is serious and is thought to be related to the study vaccine, 
then it is classified as a suspected unexpected serious adverse reaction (SUSAR). 
9.2.6. 
Serious Adverse Event 
An SAE is a specific AE that: 
 Results in death. 
 Is life-threatening.* 
 Requires inpatient hospitalization or prolongation of an existing hospitalization.** 
 Results in a persistent or significant disability or incapacity.*** 
 Results in a congenital anomaly or birth defect. 
*Life-threatening refers to immediate risk of death as the event occurred per the reporter. A life-
threatening event does not include an event that, had it occurred in a more severe form, might have 
caused death but, as it actually occurred, did not create an immediate risk of death. 
For example, hepatitis that resolved without evidence of hepatic failure would not be considered life-
threatening, even though hepatitis of a more severe nature can be fatal. Similarly, an allergic reaction 
resulting in angioedema of the face would not be life-threatening, even though angioedema of the 
larynx, allergic bronchospasm, or anaphylaxis can be fatal. 
**Hospitalization is an admission to a health facility (eg, government health center, MRC clinical 
services department, Edward Francis Small Teaching Hospital) in the situation where there is an AE. 
A period of observation at a clinical trial site or government health facility is not considered to 
represent hospitalization for the purposes of SAE reporting. Hospitalization or prolongation of a 
hospitalization constitutes a criterion for an AE to be serious; however, it is not in itself considered 
an SAE. In absence of an AE, a hospitalization or prolongation of a hospitalization should not be 
reported as an SAE by the PI on a SAE form. Such situations include, but are not limited to, the 
following: 
 A hospitalization for a preexisting condition that has not worsened. 

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 Hospitalization for social reasons. 
***Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions. If there is any doubt about whether the information constitutes an SAE, the information is 
treated as an SAE. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events (IME) that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should also 
usually be considered serious. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, or blood dyscrasias or convulsions that do not result in 
hospitalization. 
9.2.7. 
Adverse Event Recording and Reporting 
Recording and reporting of all AEs will occur from signing of the ICF (enrollment) through the EOS 
visit for each study subject enrolled only in the primary phase of the study, and through Visit 6 for 
each study subject enrolled in the booster cohort. For subjects in the immune persistence cohort, 
SAEs will also be collected from Visit 6 through Visit 7.  In this case study staff will continue to 
see infants under follow-up between V6 and V7 with any illnesses but will document their 
assessment in the clinical notes only.  AEs that are not serious nor considered IMEs will not be 
formally reported as study-specific data. 
The PI must completely and promptly record each AE in the source documentation and on the AE 
CRF, regardless of relationship to the vaccine administered/procedure as determined by the PI. The 
PI will attempt, if possible, to establish a diagnosis based on the signs and symptoms. When a 
diagnosis for the reported signs or symptoms is known, the PI will report the diagnosis as the AE, not 
the signs and symptoms. Adverse events will be classified by MedDRA term and by 
severity/intensity, relatedness, and outcome. 
Enrolled subjects who subsequently screen fail (ie, who never underwent randomization) will have 
any AEs recorded from enrollment until the time they are determined to be ineligible for 
randomization. These AEs will be listed in separate appendices from those subjects randomized and 
vaccinated. For the purposes of data capture they will be closed at the point the subject is deemed 
ineligible. 
Reporting of AEs will follow the regulatory guidelines of the National Medicines Regulatory 
Authority (NMRA), the local EC in The Gambia, WIRB and the PATH Research Ethics Committee 
(REC) in the US, in regards to requirements, processes and forms. 
 
 

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9.2.8. 
Serious Adverse Event Reporting 
If an AE is classified as serious or an IME, an SAE form will be completed and submitted within 24 
hours of the PI becoming aware of the SAE, including information on the location, severity, 
relatedness, and clinical summary of the event to the Sponsor. This will initiate evaluation by the 
PSRT through V6 and any additional reporting requirements for the duration of the study. In addition, 
the SAE submission will follow the regulatory guidelines of the NMRA, the local EC in The Gambia, 
and WIRB in the US, in regards to requirements, processes and forms. It is the responsibility of the 
Sponsor to ensure that the manufacturer (SIIPL) is notified of SAEs. Any SAE deemed related to 
study vaccine that is ongoing at the time of LSLV will continue to be followed until it is resolved, 
assessed to be resolved with sequelae, or assessed to be stable/chronic. SAEs deemed not related to 
study vaccine that are unresolved at the time of LSLV will be classified as ongoing. 
9.3. 
Unanticipated Problems 
All unanticipated problems will be reported in the continuing review report submitted to the NMRA, 
the local EC, REC and WIRB per reporting requirements of each regulatory body. All serious 
unanticipated problems involving risk to participants or others will be promptly (within 48 hours) 
reported by telephone, by email, or by facsimile to the Sponsor. Follow-up reports will be submitted as 
soon as additional information becomes available. 
9.4. 
Medication Errors 
A medication error is any preventable event that may cause or lead to inappropriate investigational use 
or subject harm while the investigational product (IP) is in control of the healthcare professional, 
subject, or consumer. Examples of medication error that will require reporting to the Sponsor include 
the following: 
 Administration of unassigned treatment. 
 Administration of expired investigational material. 
 Injection by the wrong route. 
All AEs and SAEs will be handled as specified in this protocol whether or not they are associated with 
a medication error. 
10. SAFETY MONITORING 
The PI will be responsible for continuous monitoring of all study subjects’ safety through to their final 
EOS visit. In case of urgent need, subjects’ parents will have the means to get in contact with field site 
staff at any time (24 hours per day) – and the site will have the means to transport subjects to clinic (or 
another appropriate clinical setting) or will provide fares for this purpose – to allow for expeditious 
clinical evaluation of, and provision of medical care to subjects. The PI will also be available by cell 
phone 24-hours per day for medical emergencies. 
10.1. Protocol Safety Review Team 
Safety will be monitored routinely throughout the study by the PSRT, until the last subject of the 
booster cohort completes Visit 6. The PSRT will include the PI and clinical trial coordinators from 
the MRC, the PATH Study Director and Clinical Operations Lead, and CRO staff (including the 
Clinical Project Manager, and data management personnel). The Study Director will serve as the 
PSRT Chairman. The PSRT will review blinded safety data and clinical trial conduct weekly 

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throughout the trial until the last subject of the booster cohort completes Visit 6 and any individual 
case safety concerns thereafter as deemed necessary (in this case the PSRT is unblinded except for 
site staff). Blinded safety reports will be prepared routinely by the CRO for the PSRT that will include 
at a minimum the following: 
 Accrual data and subject status data with regard to completion of/discontinuation from the 
study, sorted by field site. 
 Visit windows expected, deviations, and completions, sorted by field site. 
 Summary of reactogenicity data by vaccination number (#1, #2, #3, boost), classified by 
severity. 
 AEs sorted by MedDRA term, severity, and relatedness to study vaccine. 
 Any new or updated AEs that have occurred in the interval from the previous report. 
 Data management summaries and status of missing data, missing CRFs and manual queries, 
sorted by field site. 
 Quality review of any site findings by blinded or unblinded monitors that are critical to the 
integrity of the study. These findings will be provided in a manner that maintains the blind. 
 All SAEs will be provided to the PSRT, with history and subsequent follow-up information as 
pertains to the SAE, within the first 24 hours following site awareness of the SAE (as per other 
SAE notification rules). 
 Site-specific performance issues with source data verification, inclusion/exclusion criteria, 
documentation practices and audit readiness. 
 Additional reports as required by ongoing conduct of the trial. 
The PSRT has the authority to implement a study pause based on review of safety findings, or if alerted 
to unexpected clinical findings by the PI. If the PSRT elects to implement a study pause, the study team 
will pause the study for randomization and vaccination purposes, until the DSMB approves lifting the 
pause. 
If a study pause is initiated, randomized subjects will continue with their scheduled follow-up visits 
(V4 and V6), but not vaccination visits. In that case, the visit will be on hold during the pause; when 
the study is resumed, the subject will still be considered to be within their vaccination window, and all 
future visits adjusted based on the date of resumed vaccination. Such a pause in the study would not 
constitute a protocol deviation in regards to subject visit windows, and the pause would be taken into 
consideration for restarting the assigned vaccination visit schedule. A NTF will be written to explain 
such an occurrence. If at any time a decision is made to permanently discontinue further vaccinations, 
the PI will notify The Gambia Government/MRC Joint EC and NMRA, and the Sponsor will notify 
WIRB expeditiously. In this case, those subjects already enrolled in the study who have received a 
vaccine in either phase of the study will complete the 4-week safety follow-up period. Such safety 
follow-up could be extended by the PSRT based, if necessary, on the advice of the DSMB if judged to 
be appropriate according to the reasons for study discontinuation. 
10.2. Data Safety Monitoring Board 
The DSMB will provide external monitoring of vaccine safety and clinical trial conduct. It will be 
comprised of independent experts in vaccines, infectious diseases, pediatrics and biostatistics. The 
DSMB will conduct a formal, unblinded review of all safety data accrued during the trial when 
approximately one-quarter of the infants in the primary reactogenicity cohort have received their first 

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vaccination. The need for additional meetings to review unblinded safety data will be determined by 
the DSMB following this initial meeting. The PSRT may also request additional guidance based on 
occurrence of certain events.  
During meetings the DSMB will not only review all accrued safety data, including all solicited and 
unsolicited AEs, but also the quality of data generated and any protocol violations and significant 
protocol deviations at the field site level, with specific attention to inclusion/exclusion criteria, 
AE/SAE documentation, unblinding, and EDC completion. The DSMB may also take into 
consideration factors external to the study such as scientific or therapeutic developments that may have 
an impact on subject safety or the ethical conduct of the study. 
DSMB reviews will indicate whether or not safety concerns were identified, and whether the trial 
should continue without change, be modified, or be terminated. The Sponsor will carefully consider 
the DSMB recommendations. If the Sponsor does not agree with these recommendations, a meeting 
will be held between the Sponsor, PI and DSMB to reach consensus on the appropriate action(s) to take 
in regard to the trial. However, if attempts to reach consensus fail, the Sponsor’s opinion will prevail. 
In such situation, the Sponsor will inform the regulatory authorities, The Gambia Government/MRC 
Joint ethics committee and WIRB of the DSMB findings, the Sponsor’s perspective, and any changes 
to the trial. 
10.3. Protocol Deviation and Protocol Violation 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or site SOP 
requirements. The noncompliance may be either on the part of the subject or the site team/PI. 
A protocol violation is a significant departure from processes or procedures required by the protocol. 
Violations often result in data that are not deemed evaluable for a per-protocol analysis, and may require 
that the subject(s) who violates the protocol be discontinued from the study.37 
When appropriate, corrective actions and preventive actions (CAPAs) will be developed by the site to 
address protocol violations and deviations, and will be implemented promptly. These practices will be 
consistent with ICH E6 Guidelines. 
11. DATA MANAGEMENT 
The Sponsor-designated CRO’s study monitors will visit the site at regular intervals (including field 
sites) as per the monitoring plan and perform pre-agreed source data verification of the data recorded 
in the paper CRF against the source documents available at the site. In addition, missing data forms 
and fields will be queried by daily electronic edit checks or through manual edits of the data by the 
data management team. Study monitors will closely evaluate pre-screening data, inclusion/exclusion 
criteria, informed consents, data entry timeliness, and visit dates and windows at each field site to 
ensure integrity of the study is maintained. 
Any data discrepancies generated by the system will be flagged in the EDC system for the PI to provide 
a satisfactory resolution within the EDC system. The data management team will review all the data 
discrepancy responses by the site to ensure the correctness of data. The AEs will be coded using 
MedDRA dictionary version 19.1 or later and the concomitant medications will be coded using standard 
nomenclature. After completion of data coding and resolution of all the queries in the database 
pertaining to subject visits through completion of Visit 6 by the last subject in the booster cohort, the 
database will be declared to be accurate and will be closed for statistical analysis of primary and 
secondary endpoints. A final database lock will occur after completion of data coding and resolution 

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of all the queries in the database following completion of Visit 7 by the last subject of the booster 
cohort (LSLV). 
11.1. Case Report Form Development and Completion 
Based on the final protocol of the study, a comprehensive set of paper CRFs will be prepared to capture 
all the relevant data required for analysis and reporting. This study will utilize an EDC system such that 
the entire study data can be maintained in a secure electronic system. No written or electronic data 
recorded prior to the study will be included in the paper CRFs or EDC system respectively. 
All study data will be collected by the clinical study staff using designated source documents, wherever 
applicable, and will be entered in the appropriate CRFs and EDC system in an anonymized form. In 
most cases, the CRF will be the source document. The study database will identify study subjects only 
by unique study identification numbers through screening (screening ID) and randomization 
assignments (randomization ID) and will not contain any identifying information such as name, address 
or personal contact information, or any other regional/state/national identification number. CRFs will 
be reviewed by the clinical team who are responsible for ensuring that they are accurate and complete.  
The data management activities will be performed as per the CRO’s SOPs. The appropriately trained 
site personnel will ensure double data entry of the study data recorded on the CRFs into the EDC 
system. To ensure that data are entered in a timely fashion so as to monitor safety of the study, it is 
expected that the site will maintain data entry with a minimal expectation of 3 business days from 
subject clinic visit or last home visit. The study monitor plan will include assessments of data entry 
timeliness.  
The study site will maintain the source documents for each study subject. The source documents and 
other supporting documents will be kept in a secure location. Source documentation will be available 
for review by the study monitor to ensure that the collected data are consistent with the CRFs. 
11.2. Record Archival 
11.2.1. Archiving Data at Study Site 
The study site will maintain appropriate medical and research records for this trial, in compliance 
with ICH-GCP, regulatory, sponsoring organization and institutional requirements for the protection 
of confidentiality of subjects. The site will permit authorized representatives of the Sponsor and 
regulatory agencies to examine (and when required by applicable law, to copy) clinical records for 
the purposes of quality assurance reviews, audits, and evaluation of the study safety and progress. 
The final database will be locked and transferred to the Sponsor for long-term storage. 
11.2.2. Data Storage and Archival 
The PI will maintain an Investigator Site File, which will be used to file the IB, protocol, drug 
accountability records, correspondence with the EC/IRB, Sponsor, CRO, and other study-related 
documents. The PI will maintain, and store securely, complete, accurate and current study records 
throughout the study. 
As required by ICH GCP guidelines, the PI will keep essential documents until at least 2 years after 
the last approval of a marketing application in an ICH region, and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IP. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by an agreement 

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with the Sponsor. The documents will be archived either in the MRC Archive or at any other secure 
location as agreed upon with the Sponsor. It is the responsibility of the Sponsor to inform the 
PI/institution as to when these documents no longer need to be retained. 
Following completion of the study, serum samples will be stored at an appropriate place in a 
designated freezer at the ______________ until it is determined whether the samples are to be retained 
or destroyed under the direction of PATH. During the informed consent procedures, additional 
consent for the use of any serum remaining at the end of the trial for other ethically approved 
research will be sought from subjects’ parents by the PI. Any such use must be with the 
consent/approval of PATH. When such additional consent has not been obtained the PI will destroy 
remaining serum samples based on the Sponsor’s instructions (with proper audit documentation, 
reconciliation, and certification). 
No data will be destroyed without the agreement of the Sponsor. The applicable records include 
source documents, site registration documents and reports, correspondence, ICFs, and notations of 
all contacts with the subject. The Sponsor will inform the PI in writing of the need for record retention 
and will notify the PI in writing when the trial-related records are no longer needed. Subjects’ medical 
records and other original data will be archived in accordance with the local regulations or facilities 
of the investigational site. 
11.3. Posting of Information on Clinicaltrials.gov 
Study information from this protocol will be posted on Clinicaltrials.gov. 
11.4. Confidentiality 
Documented evidence that the PI is aware and agrees to the confidential nature of the information 
related to the study must be obtained by means of a confidentiality agreement. 
All information provided by PATH and all data and information generated by the site as part of the 
study (other than a subject’s medical records) will be kept confidential by the PI and other site staff. 
This information and data will not be used by the PI or other site personnel for any purpose other than 
conducting the study. 
11.5. Publication 
PATH will work with the PI and other relevant personnel at MRC Unit The Gambia on the publication 
of the complete Phase 3 study outlined in this protocol in a timely fashion. Primary publication of the 
trial results will be shared between the MRC and PATH. Other individuals having input into the study 
justifying authorship from MRC Unit, The Gambia, from collaborators and from PATH will similarly 
be included in publication(s). Additional publications resulting from the analysis of the study data will 
be agreed between PATH and the MRC on a case-by-case basis but will generally include authors from 
both organizations. PATH will be acknowledged in all publications as the Sponsor of the trial. 
If a written contract for the conduct of the study, which includes publication provisions inconsistent 
with this statement, is executed between PATH and the study site, that contract’s publication provisions 
shall apply rather than this statement. 
12. STATISTICAL DESIGN AND ANALYSIS 
The planned statistical analyses for sizing and assessing this study are outlined below. A detailed 
Statistical Analysis Plan (SAP) for preparation of the final study report will be created and made final 

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prior to first database closure and unblinding of only the Sponsor, statistical personnel and medical 
monitor for primary and secondary endpoint analyses.  
AEs will be coded using the MedDRA Version 19.1 or later. The frequency count and percentage of 
subjects will be summarized according to the coded terms of system organ class (SOC) and preferred 
term (PT). Data listings will show AEs by subject.  
12.1. Study Populations 
All randomized subjects are expected to provide data for safety analyses. We estimate that data for at 
least 90% of randomized subjects will be available for immunogenicity analyses, with 10% loss of data 
because of withdrawal, loss to follow-up, problems with specimens, etc. 
The Enrolled Population includes all screened subjects who provide informed consent, regardless of 
whether the subject is randomized to receive a study treatment. This population will be used to account 
fully for subject disposition, starting with the informed consent. The enrolled population will not be 
analyzed as such but will be available in the clinical database. 
The Safety Population includes all subjects who were randomized, received a study vaccination, and 
provided at least some post-vaccination safety data. Treatment groups for safety analyses will be 
assigned according to the actual treatment received at Visit 1. This population will serve as the primary 
analysis population for demographics and study disposition as well as safety and is the basic population 
for all analyses except immunogenicity. 
The Full Immunogenicity Population (FIP) includes subjects in the enrolled population who were 
randomized, received a study vaccination, and have post-vaccination immunogenicity measurement(s). 
Analysis will be according to the treatment received by each subject, even if different from that to 
which the subject was randomized. The analysis based on this population will serve as supportive 
results for the immunogenicity objectives if warranted as defined in the SAP.  
The Per Protocol Immunogenicity Population (PP_IMM) includes all subjects in FIP who received all 
study vaccines and have post-dose immunogenicity measurement(s) with no major protocol violations 
that were determined to potentially interfere with immune response to the study vaccine. This 
population will serve as the primary analysis population for the immunogenicity primary and secondary 
objectives.  
The criteria for exclusion of subjects from the Full Immunogenicity Population will be established 
before breaking the blind and will be based on the blinded review of protocol violations. 
The Immunogenicity Persistence Population (IPP) is a subset of PP_IMM consisting of subjects in the 
booster cohort who provide evaluable data at Visit 7, excluding subjects with protocol violations that 
could affect this analysis (e.g. use of prohibited medication or treatment).  
12.2. Conduct of the Analyses 
Analysis of primary and secondary endpoints as well as supporting analysis (e.g. baseline, study 
disposition) will be conducted following initial study unblinding of the Sponsor, statistical personnel 
and medical monitor. Analysis of supplementary endpoints will be conducted following closure of the 
Visit 7 data. Data listings will be sorted by treatment group and subject identification number. All 
tabular summaries will be presented by treatment group. Categorical data will be summarized by the 
number and percentage of subjects falling within each category. Continuous variables will be 
summarized by descriptive statistics, including mean, standard deviation or error, median, minimum, 

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and maximum. Testing for superiority will be done at the two-sided 0.05 level. Details of endpoint 
analyses will be described in the SAP.  
No formal interim analyses are planned for this study. 
12.2.1. Handling of Dropouts or Missing Data 
Generally, no imputation will be made for missing values in safety and immunogenicity analyses, 
except that immunogenicity values below the limit of quantitation (BLQ) that are reported as < BLQ 
will be assigned a value of ½ the limit of quantification. Any additional imputation for missing values 
will be documented in the SAP. 
12.3. Statistical Methods 
12.3.1. Immunogenicity Analysis 
Comparisons for primary immunogenicity objectives will be based on the serotype-specific 
concentrations of IgG antibody 4 weeks after the primary vaccination series, measured by ELISA. 
Comparisons for secondary objectives will be based on the serotype-specific IgG concentration and 
OPA titer 4 weeks after the 3-dose primary series and 4 weeks after the booster dose. Comparisons 
for the supplemental objective will be based on the serotype-specific IgG concentration and OPA 
titer 1 year after the booster dose.  
Response to study vaccination is defined as concentration ≥ 0.35 µg/mL for IgG and titer ≥ 1:8 for 
OPA. 
For each of the 10 serotypes in PNEUMOSIL, the distributions of IgG concentration and OPA titer 
will be displayed in tabular form (eg, number of observations, number of responders, percentage 
responding, geometric mean and its 95% confidence interval (CI)) and graphically by reverse 
cumulative distribution (RCD) curves. These curves will allow visual comparison of percentiles (eg, 
median, 25th and 75th percentiles) for each serotype in PNEUMOSIL. Summaries will include 
percentage of responders, geometric mean concentration (GMC) or geometric mean titer (GMT), and 
ratio of GMCs or GMTs for PNEUMOSIL to those for Synflorix.  
Primary objective 1 is to show equivalence of 3 lots of PNEUMOSIL 4 weeks after the primary 
vaccination series. For each serotype in PNEUMOSIL and each pair of lots, the two-sided 95% 
confidence interval (CI) for the ratio of the geometric mean concentration (GMC) of IgG antibody in 
one lot to the GMC in the other lot will be calculated, assuming a normal distribution for log10 
(concentration). The 3 lots will be considered equivalent if, for each serotype, all 3 of the CIs for 
GMC ratio lie within the interval (0.5, 2). If equivalence of lots is shown, data for the three lots will 
be combined for all further immunogenicity analyses. 
Primary objective 2 is to show non-inferiority of the IgG antibody response after PNEUMOSIL 
vaccination to the response after Synflorix, for at least 7 of the 10 serotypes in PNEUMOSIL 4 weeks 
after the primary series. NI comparisons will be based on a CI for the difference in proportions 
(calculated by a likelihood score method) or a CI for a ratio of GMCs (calculated by exponentiating 
the limits of a CI for the difference in means of log10 (concentration), which will be calculated 
assuming a normal distribution for log10 (concentration)).38 NI will be established for each serotype 
separately based on evaluation of two NI criteria: for each serotype, NI will be shown if a two-sided 
97.5% CI for the absolute difference in proportions responding (proportion responding after Synflorix 
vaccination minus proportion responding after PNEUMOSIL) has upper limit < 0.10, or if a two-
sided 97.5% CI for the GMC ratio (Synflorix GMC divided by PNEUMOSIL GMC) has upper limit 

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< 2. For serotypes 6A and 19A, the response rate for Synflorix will be assumed to be the lowest 
observed rate among the 8 serotypes in common with PNEUMOSIL, and the GMC will be assumed 
to be the GMC of the serotype with the lowest response rate.  
Primary objective 3 is to show NI of responses, 4 weeks after the primary series, to pentavalent, 
polio and rotavirus vaccines when co-administered with PNEUMOSIL to responses when co-
administered with Synflorix. Except for pertussis, for each antigen in the pentavalent, polio or 
rotavirus vaccines NI will be shown if a two-sided 95% CI for the difference in response proportions 
(proportion with Synflorix co-administration minus proportion with PNEUMOSIL co-
administration) has upper limit < 0.10; for pertussis, NI will be demonstrated if the two-sided 95% 
CIs for the GMC ratios of the response to both pertussis toxoid and fimbriae (GMC with Synflorix 
co-administration to the GMC with PNEUMOSIL co-administration) has upper limit < 2. Response 
is defined for the various antigens as follows: anti-diphtheria toxoid ≥ 0.1 IU/mL; anti-tetanus toxoid 
≥ 0.1 IU/mL; anti-HBs concentration ≥ 10 mIU/mL; anti-PRP concentration ≥ 0.15 μg/mL; anti-polio 
types 1, 2 and 3 titer ≥ 1:8 anti-rotavirus concentration ≥ 20U/mL. 
Secondary objective 1 is to demonstrate that the immune responses to serotypes 6A and 19A in 
PNEUMOSIL recipients 4 weeks after the 3-dose primary series are superior to the responses to these 
serotypes induced by Synflorix, either for the proportion of IgG antibody concentrations ≥ 0.35 
µg/mL or for GMC. For each of the two serotypes, proportions with IgG concentration ≥ 0.35 µg/mL 
will be compared using a z-test for proportions and GMCs will be compared by a two-sample t-test 
on the difference between means of log10 (antibody). Both tests will be done at the two-sided 2.5% 
significance level to adjust for the two superiority tests. 
Secondary objective 2 is to evaluate, in a subset of subjects (250 PNEUMOSIL recipients and 250 
Synflorix recipients), the serotype-specific functional antibody responses, measured by OPA, to 
PNEUMOSIL in comparison with Synflorix for each of the 10 serotypes in PNEUMOSIL, when 
measured 4 weeks after a 3-dose primary series. The percentage of subjects with OPA ≥ 1:8 and OPA 
GMT will be reported.  
Secondary objective 3 is to evaluate, in a subset of subjects, serotype-specific booster responses 
(antibody concentrations and functional responses) to PNEUMOSIL in comparison to Synflorix, 
from 4 weeks after a 3-dose primary series to 4 weeks after a booster dose. The comparisons will be 
based on the ratio of IgG GMC post-booster to the IgG GMC post-primary series, and on a similar 
ratio of OPA GMT. The vaccines will be compared using the ratios of these ratios for the two vaccines 
(ie, the Synflorix ratio divided by the PNEUMOSIL ratio), and the corresponding 95% CIs. The 
number of subjects with evaluable data for this comparison is planned to be approximately 600 (400 
PNEUMOSIL recipients and 200 Synflorix recipients) for the analysis of IgG GMC ratios, and 200 
(100 PNEUMOSIL recipients and 100 Synflorix recipients) for the analysis of OPA GMT ratios. 
Secondary objective 4 is to demonstrate non-inferior immune responses to routine pediatric vaccines 
co-administered with the booster dose (measles, rubella, yellow fever). The analysis will consist of 
comparison by z-test at the two-sided 5% level of proportions responding, using a NI margin of 10%. 
It is planned to have data on approximately 600 subjects (400 PNEUMOSIL recipients and 200 
Synflorix recipients) for these comparisons.  
Supplemental objective 1 is to evaluate, in subsets of subjects, the persistence of serotype-specific 
immune responses (antibody concentrations and functional responses) to PNEUMOSIL in 
comparison to Synflorix for each of the 10 serotypes in PNEUMOSIL, when measured 1 year after a 
booster dose. To evaluate the persistence of serotype-specific antibody concentrations, treatment-
group-specific IgG GMCs and percentage of responders (IgG concentration ≥ 0.35 µg/mL) will be 

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reported. PNEUMOSIL will be compared to Synflorix by the ratio of IgG GMCs (and its 95% CI) 
and the difference in percentage of responders (and the 95% CI around the difference). The number 
of subjects with evaluable data for these analyses is planned to be approximately 600 (400 
PNEUMOSIL recipients and 200 Synflorix recipients). The same approach will be used to evaluate 
the persistence of serotype-specific functional responses based on treatment-group GMTs and 
percentage of responders (OPA titer ≥ 1:8). The number of subjects with evaluable data for these 
analyses is planned to be 100 (50 PNEUMOSIL recipients and 50 Synflorix recipients). Analyses 
will be supported by summary descriptive tables, by treatment group, RCD curves and graphs of 
GMCs and 95% confidence intervals across time.  
12.3.2. Safety Analysis 
Safety and tolerability of study vaccines will be evaluated using the following endpoints:  
 Number and severity of solicited local and systemic adverse events (reactogenicity events 
[REs]) through Day 6 after each vaccination 
 Number, severity and relatedness of all AEs and serious adverse events (SAEs) during the entire 
study period through 4 weeks post dose 4 
 Number, severity and relatedness of all serious adverse events (SAEs) from 4 weeks post dose 
4 through 12 months post dose 4 
 Number, severity and relatedness of all AEs and SAEs during the 2 week period post each 
vaccination 
Unsolicited AEs and SAEs will be summarized by SOC and PT using the MedDRA dictionary. 
Adverse events and SAEs will also be summarized by severity and relationship to vaccine.  
Generally, safety evaluations will be descriptive in nature, and observed differences will be evaluated 
for medical relevance. Tabular summaries of safety data will be provided for each treatment group.  
Occurrence of local and systemic reactions (REs) within 6 days after vaccination, as well as AEs 
during the entire study period through 4 weeks post dose 4 (Visit 6), will be reported for both 
PNEUMOSIL and Synflorix. Proportions of severe reactions and classes of AEs of particular interest 
will be compared. 
For RE’s, treatment groups will be compared on the distribution of highest reactogenicity grades 
(0,1,2,3,4) (a) post any vaccination and (b) post each vaccination using the Cochran-Mantel-Haenszel 
test stratifying on field site. The modified ridit method will implemented to take advantage of the 
ordinality of grades. To avoid sparse data, categories may be pooled (e.g. 0, 1, 2+) based on the 
statistician’s blinded review of distributions. The analysis will be supported by appropriate 
descriptive tables.   
12.3.3. Multiple Comparisons/Multiplicity 
No adjustment of significance levels (α) is planned for immunogenicity comparisons in this study, 
except in testing for NI when NI can be established either by a comparison of proportions of 
responders or by a GMC ratio, or in superiority testing when superiority can be established based on 
either a comparison of proportions or a GMC ratio. In that case the NI testing will be done with α = 
0.0125 (ie, using the upper limit of a two-sided 97.5% CI). 
For analysis of safety data, statistical comparisons will be done for solicited AEs as described above 
with no adjustment for multiple comparisons, since the primary purpose of these statistical 
comparisons is to screen out potential AEs that need further clinical evaluation, and we therefore 

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don’t want to miss an important association. It is acknowledged that the overall type I error rate for 
these comparisons will be greater than the nominal two-sided 0.05. 
12.4. Sample Size and Power Calculations  
The study is designed to have at least 90% power to meet all 3 primary objectives. The sample size was 
chosen in an iterative, trial-and-error fashion to give the desired power. We plan to enroll (i.e., assign 
a treatment by a randomization process) 2250 subjects: 1500 subjects to receive PNEUMOSIL (500 in 
each of 3 lots) and 750 to receive Synflorix. The sample size for the primary non-interference study 
will be lower: 675 total (450 recipients of PNEUMOSIL and 225 recipients of Synflorix). Power 
calculations were done using PASS 13 (Number Cruncher Statistical Systems, Kaysville, Utah). 
Primary objective 1: Lot-to-lot comparisons 
Assuming a 10% loss of data from withdrawals, loss to follow-up, etc., the numbers of subjects with 
analyzable data on immune response will be approximately 450 per lot of PNEUMOSIL and 675 for 
Synflorix. With these numbers, as shown below the power will be ~94% for showing equivalence of 
lots for all serotypes, under somewhat conservative assumptions about variability of antibody levels 
and differences between lots. The standard deviations (SDs) of log10 (antibody concentration) assumed 
for the power calculations were chosen by the following procedure. The observed SDs for 
PNEUMOSIL serotypes from study VAC-017 were arranged in descending order. For each of the 5 
pairs of ranked SDs, beginning with the largest SD, the SD for power calculations was assumed to be 
the higher of the 2 SDs in the pair. Thus for 5 of the serotypes, the assumed SD was the same as 
observed in VAC-017, and for the other 5 the assumed SD was higher than the observed SD in VAC-
017. We estimated the overall power by assuming the values for different serotypes were independent, 
so that the power to show equivalence for multiple serotypes is estimated by multiplying the powers 
for the individual serotypes. For each serotype there are 3 possible comparisons of two lots; for the two 
serotypes with the highest SDs, we assumed a true ratio of GMCs of 1.4 for 2 of the comparisons of 
lots, which implies a ratio of 1 for the 3rd comparison. (This is a slightly more conservative assumption 
– ie, gives a lower power – than assuming equal spacing on the multiplicative scale of the GMCs of the 
three lots). For the other serotypes, we assumed a ratio of 1.3 for 2 of the comparisons and 1 for the 3rd 
comparison. The assumed values of the SDs by serotype and the resulting power estimates are given in 
Table 6 below. 
 
 

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Table 6.  Power of lot-to-lot comparisons for 3 lots to show equivalence of IgG GMCs after the 
3-dose primary series, for sample sizes of 450 per lot and equivalence margins of 0.5 and 2 for 
the GMC ratio 
Serotype 
SD of log10 
(concentration), 
VAC-017 
Assumed SD for 
power 
calculations 
Assumed true 
GMC ratio* 
Power** 
6A 
0.56 
0.56 
1.4 
0.9856 
14 
0.55 
0.56 
1.4 
0.9856 
6B 
0.53 
0.53 
1.3 
0.9996 
19A 
0.45 
0.53 
1.3 
0.9996 
23F 
0.43 
0.43 
1.3 
1.0000 
19F 
0.38 
0.43 
1.3 
1.0000 
7F 
0.38 
0.38 
1.3 
1.0000 
9V 
0.37 
0.38 
1.3 
1.0000 
1 
0.36 
0.36 
1.3 
1.0000 
5 
0.34 
0.36 
1.3 
1.0000 
*Ratio for 2 of the 3 between-lot comparisons; ratio is 1 for the 3rd comparison. 
**Power for the 2 comparisons with the indicated ratio; power for the 3rd is 1.0000. 
 
The power to show equivalence of lots for all serotypes is approximately 94.2%, which is calculated 
by taking the product of the power estimates in the above table and then calculating the square of that 
product.  
Primary objective 2: Comparison of responses to PNEUMOSIL and Synflorix 
Assuming 1350 subjects who received PNEUMOSIL and 675 recipients of Synflorix are included in 
the analysis, the power will be approximately 99.8% to show NI of PNEUMOSIL to Synflorix for at 
least 7 of 10 serotypes in PNEUMOSIL, under the assumption that the true underlying proportions 
responding with IgG antibody ≥ 0.35 µg/mL after the 3-dose primary series are 0.02 lower after 
PNEUMOSIL vaccination than after receipt of Synflorix for each serotype. This assumption is made 
to introduce some conservativeness into the calculations. For each serotype, NI will be shown if either 
a two-sided 97.5% CI for the absolute difference in response proportions (proportion of responders 
with Synflorix minus proportion with PNEUMOSIL) has upper limit < 0.10, or a two-sided 97.5% CI 
for the GMC ratio (Synflorix GMC divided by PNEUMOSIL GMC) has upper limit < 2. For serotypes 
6A and 19A, the response rate with Synflorix will be assumed to be the lowest observed rate among 
the 8 serotypes in common with PNEUMOSIL, and the GMC will be assumed to be the GMC of the 
serotype with the lowest response rate. Table 7 shows the assumed proportions and resulting power for 
each serotype. 
 
 

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Table 7. 
Power of comparisons between PNEUMOSIL and Synflorix to show non-
inferiority of proportion of subjects with IgG antibody concentration ≥ 0.35 µg/mL after the 3-
dose primary series, for sample sizes of 1350 for PNEUMOSIL and 675 for Synflorix and NI 
inferiority margin of 0.10 for the difference between the proportion responding for 
PNEUMOSIL and the proportion responding for Synflorix 
Serotype 
Assumed true 
proportion 
responding after 
Synflorix* 
Assumed true 
proportion 
responding with 
PNEUMOSIL 
Power 
6A 
0.89 
0.87 
0.9993 
14 
0.98 
0.96 
1.0000 
6B 
0.89 
0.87 
0.9993 
19A 
0.89 
0.87 
0.9993 
23F 
0.91 
0.89 
0.9999 
19F 
0.92 
0.90 
1.0000 
7F 
0.97 
0.95 
1.0000 
9V 
0.94 
0.92 
1.0000 
1 
0.99 
0.97 
1.0000 
5 
0.999 
0.979 
1.0000 
*Assuming response proportions are as for PNEUMOSIL in VAC-017 for the 8 common serotypes and the lowest of 
these observed proportions for 6A and 19A. 
 
The approximate power for meeting primary objective 2, obtained by multiplying the 7 highest powers 
in Table 7, is 99.8%. 
Primary objective 3: Non-interference with responses to EPI vaccines 
For each EPI vaccine antibody tested (except antibodies to pertussis antigens), NI will be shown if a 
two-sided 95% CI for the absolute difference in response proportions (proportion of responders with 
Synflorix minus proportion with PNEUMOSIL) has upper limit < 0.10. For  pertussis, NI is defined as 
a two-sided 95% CI for the GMC ratio (GMC with Synflorix co-administration divided by GMC with  
PNEUMOSILco-administration) with upper limit < 2 for each of two separate antigens (pertussis 
toxoid and fimbriae). Based on prior studies, we assume response proportions of at least 96% for each 
antibody level tested (other than anti-pertussis antibodies) and a standard deviation of 0.82 for log10 
(anti-pertussis antibodies). We assume there is no interference, ie, the underlying response probabilities 
are equal for co-administration with PNEUMOSIL and with Synflorix. For 450 recipients of 
PNEUMOSIL and 225 recipients of Synflorix, each comparison will have > 99% power, and the power 
will also be > 93% to show non-interference of PNEUMOSIL with routine vaccinations for all the 
comparisons simultaneously, ie, to show NI of PNEUMOSIL to Synflorix for all responses to co-
administered pentavalent, polio and rotavirus vaccines that are tested.  
The overall power to show lot-to-lot consistency, NI of PNEUMOSIL to Synflorix for responses to 
antigens in PNEUMOSIL, and non-interference of PNEUMOSIL with responses to pentavalent, polio 

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and rotavirus vaccines, is obtained by multiplying the powers of the study to meet primary objectives 
1, 2, and 3 – approximately 93%. 
Secondary objective 1: Superiority of responses to 6A and 19A 
We assume the true GMCs and proportions of responders 4 weeks after the 3-dose primary series are 
as in VAC-017 for PNEUMOSIL and as in the COMPAS study for Synflorix cross-reactivity; in the 
COMPAS study the seroresponse rate was 64.4% for 6A and 61.1% for 19A, and the GMC was 0.32 
(95% CI 0.27-0.37) for 6A and 0.29 (95% CI 0.25-0.33) for 19A.27 For tests at the two-sided 0.025 
significance level on data from 1350 recipients of PNEUMOSIL and 675 recipients of Synflorix, the 
power of the study is virtually 100% to show that the GMC for PNEUMOSIL is significantly higher 
than the GMC for Synflorix for both serotype 6A and serotype 19A. The power is > 99% to show that 
the GMC ratio (GMC for PNEUMOSIL divided by GMC for Synflorix) is greater than 2 for both 
serotypes. The power is virtually 100% to show the response rates for both serotypes are significantly 
higher for PNEUMOSIL. For showing the response rate after PNEUMOSIL vaccination is higher by 
at least 0.10 than the response rate after Synflorix vaccination, the power is approximately 69% for 
serotype 6A and 100% for serotype 19A. 
Safety 
The sample size for evaluation of solicited AEs (local and systemic reactions to vaccine, i.e., REs) will 
be approximately 1125. For 750 recipients of PNEUMOSIL and 375 recipients of Synflorix, the power 
to find a significant increase in the rate of severe local or systemic reactions after PNEUMOSIL 
vaccination compared to Synflorix, using a z-test at the one-sided 2.5% significance level, will be about 
84% if the rate of severe reactions or adverse events is 5% after Synflorix vaccination and 10% after 
PNEUMOSIL vaccination. The power will be approximately 99% if the respective rates are 10% and 
20%. 
In a sample size of 1500 infants vaccinated with PNEUMOSIL, the probability of observing at least 
one occurrence of an unsolicited adverse event that occurs with frequency 1% will be virtually 100%. 
For an event that occurs with frequency 0.1%, the probability will be ~78%. If there are no events of a 
specific adverse event in 1500 PNEUMOSIL recipients, the upper limit of a two-sided 95% CI for the 
probability of the event’s occurrence will be 0.25%. 
13. STUDY MONITORING 
Sponsor monitoring responsibilities will be provided by the CRO. A site initiation visit will be 
conducted prior to beginning the study, and monitoring will be conducted at initiation, during, and at 
closeout of the study by the study monitor or designee. See Section 7.4 for a discussion of the roles of 
blinded and unblinded study monitors in this study. 
During the course of the study, the monitor will visit the site (including field sites) at intervals to verify 
compliance to the protocol; completeness, accuracy, and consistency of the data and study product 
accountability; adherence to protocol and regulatory obligations; and to ensure that conduct of the 
research follows GCP. The monitor should have access to subject medical records, study product 
accountability and other study-related records needed to verify the entries on the CRFs. 
The PI and the monitor will cooperate to ensure that any problems detected in the course of these 
monitoring visits, including EDC completion and query resolution, are resolved in a predefined time 
frame to be agreed in the Clinical Monitoring Plan. 
To ensure the quality of clinical data for all subjects, a clinical data management review will be 
performed on subject data received by the CRO. During this review, subject data will be checked for 

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consistency, omissions, and any apparent discrepancies. In addition, the data will be reviewed for 
adherence to the protocol and GCP. To resolve any questions arising from the clinical data management 
review process, data queries and/or site notifications will be sent to the site for resolution as soon as 
possible and within the time frame described in the Clinical Monitoring Plan; all queries must be 
resolved prior to database lock. 
Essential documents must be filed in the site study file on an ongoing basis and be available for review 
by the Sponsor’s contracted site monitor. Monitoring visits will be performed according to the Clinical 
Monitoring Plan. 
13.1. Independent Auditing 
PATH representatives may audit the study to ensure that study procedures and data collected comply 
with the protocol and applicable SOPs of the site and the CRO, and that data are correct and complete. 
The PI will permit auditors (employees of the Sponsor or an external company designated by the 
Sponsor) to verify source data validation of the regularly monitored clinical study. The auditors will 
compare the entries in the CRFs with the source data and evaluate the study site for its adherence to the 
clinical study protocol and GCP guidelines and applicable regulatory requirements. 
13.2. Regulatory Agency Auditing 
The PI must be aware that representatives from regulatory authorities may wish to inspect the CRFs 
and associated study records. The PI will notify the Sponsor within 24 hours following contact by a 
regulatory agency. The PI will make the relevant records available for inspection and will be available 
to respond to reasonable requests and audit queries made by authorized representatives of regulatory 
agencies. The PI will provide the Sponsor with copies of all correspondence that may affect the review 
of the current study or his qualification as PI in clinical studies conducted by the Sponsor. The Sponsor 
will provide any needed assistance in responding to regulatory audits or correspondence. 
14. OBLIGATIONS AND ROLES OF THE SPONSOR, PI AND STUDY PERSONNEL 
This study will be conducted according to GCP as well in accordance with Gambian regulations. The 
Sponsor will assure the trial is conducted in compliance with the protocol, GCP, and regulatory 
authority requirements. The Sponsor will provide the PI with the funding and information needed to 
conduct the trial properly, ensuring proper monitoring of trial activities, and that the trial is conducted 
in accordance with the general investigational plan and protocol contained in the submissions to the 
regulatory authorities. The Sponsor will ensure that the PI and regulatory authorities are immediately 
informed (within 24 hours of the Sponsor becoming aware) of significant new adverse effects or risks 
with respect to the study vaccine. The Sponsor will ensure that they will be immediately informed 
(within 24 hours of SIIPL becoming aware) of significant new adverse events in the Phase 3 trial in 
India or of any other safety concerns which could influence decisions regarding informed consent, 
enrollment and vaccination in this trial. 
The PI agrees to perform the research in strict accordance with this protocol, the ICH GCP (E6), as 
well as in conformity with applicable US or local regulations regarding the conduct of clinical studies 
(see Statement of Compliance). 
In addition, the PI will follow local and institutional requirements including, but not limited to, 
investigational vaccines, clinical research, informed consent and ethics regulations. The Sponsor will 
provide notification to the PI of protocol and amendment approvals by regulatory authorities when 
applicable. Any modifications to the research protocol, the ICF, and/or change in PI will be submitted 

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for review and approval to regulatory authorities per their guidelines. The PI may deviate from the 
protocol without prior approval only when the deviation is necessary to eliminate an apparent 
immediate hazard to the study subject. 
While the PI may delegate study duties to appropriate study personnel, the PI is ultimately responsible 
for the conduct of all aspects of the study. 
15. ETHICAL CONSIDERATIONS AND INFORMED CONSENT 
The study will be performed in accordance with SSPs and study plans generated and agreed between 
the Sponsor-designated CRO and the PI. The CRO has the responsibility for ensuring the site has the 
appropriate SSPs to perform the study. These SSPs have been developed in accordance with ICH 
Guidelines for GCP (1996), Directive 2001/20/EC, and GCPs for Clinical Research in The Gambia, 
which are consistent with the Ethical Guidelines outlined in the Declaration of Helsinki (2013), thus 
ensuring protection of the subjects. The study will commence only after receipt of a favorable opinion 
from the EC/IRB listed in this protocol and national authorities under Gambian law. 
15.1. Institutional Review Board/Ethics Review Committee 
The PI at the study site will be responsible for obtaining approval from the MRC Scientific 
Coordinating Committee (SCC) and The Gambia Government/MRC Joint EC for the conduct of the 
study. The PI will submit the final protocol, IB, proposed ICF, any proposed advertising material, and 
all other relevant study-related information in writing for The Gambia Government/MRC Joint EC 
review and written approval, according to guidelines. The Sponsor will ensure approval to undertake 
the study is obtained from WIRB. The PI will obtain import authorization and clinical trials 
authorization from the NMRA in The Gambia. Recruitment and enrollment of subjects will not take 
place until all approvals from regulatory authorities involved in this trial are received. The PI will notify 
the EC/IRB of SAEs, protocol amendments, and protocol violations and deviations according to the 
EC/IRB requirements. 
15.2. Informed Consent Process 
Prior to any study-related screening procedures being performed on the subject, written (or thumb-
printed) informed consent will be obtained from each subject’s parent. Only one parent (usually the 
mother) will provide written consent but in general both parents should agree to a subject’s 
participation. If either parent specifically states that they do not want their infant to participate, the 
infant will not be enrolled. Consent will only be obtained from birth parents. Consent will not be 
obtained from guardians in this study. Once informed consent has been obtained the subject will be 
considered to be enrolled. The method of explanation to the subject’s parent or impartial witness, and 
obtaining of parental consent will comply with the ICH GCP Guidelines and the ethical principles in 
the amended Declaration of Helsinki (2013), whichever represents the greater protection for the 
individual. The PI will obtain and document the informed consent process in accordance with the 
requirements for source documentation in PATH-sponsored clinical trials. See Section 6.1.2 for a 
detailed explanation of the informed consent process. Of note, as consent in many cases will be obtained 
through verbal translation of the ICF from English into the local language, the ICF will be concise, 
appropriate for use in this context, and consistent with the requirements of ICH-GCP. Individuals at 
The MRC Unit have longstanding expertise in this area. The local languages are not written therefore 
translation and back-translation has been proven to be unreliable/ineffective. The approach taken has 
been approved by The Gambia Government/MRC Joint Ethics Committee. 

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15.3. Research Involving Children 
Before undertaking research involving children, the PI must ensure that the research has the goal of 
bettering the health of children. PNEUMOSIL contains 10 pneumococcal serotypes chosen specifically 
because of their prevalence in low-resource countries such as The Gambia. This Phase 3 study aims to 
provide the data necessary for licensure and WHO prequalification of PNEUMOSIL, which is being 
developed as an affordable and effective alternative PCV for children in low- and middle-resource 
countries. Because of the early successful introduction of PCV into the national EPI program, and 
continued high coverage rates for Prevenar 13, rates of vaccine-type IPD are low in The Gambia. This 
fact, together with the substantial immune response to all 10 serotypes in PNEUMOSIL seen in infants 
in the Phase 1/2 trial (VAC-017), and the demonstrated efficacy and effectiveness of Synflorix against 
IPD and pneumonia in randomized controlled trials, provides assurance that it is safe for infants to be 
vaccinated with a 3-dose primary series of PNEUMOSIL or Synflorix instead of Prevenar 13 in this 
clinical trial. 
15.4. Insurance and Indemnity 
Subjects will be insured against injury caused by the study according to legal requirements. The parent 
will be informed about the insurance and the responsibilities on their part. In the event that a subject 
suffers injury or death directly attributable to participation in this study, appropriate treatment and/or 
compensation will be provided by and/or paid to the subject by the Sponsor in accordance with 
applicable national laws and/or guidelines. 
15.5. Risk/Benefit 
No benefits can be guaranteed to subjects for their participation in this research study.  
As with any vaccine, severe allergic reaction is a potential rare event. In the VAC-017 study, 
conducted in The Gambia, PNEUMOSIL was well-tolerated in all age cohorts, and no meaningful 
safety signals were identified in any cohort, including 100 infants who received a 3-dose primary 
series of PNEUMOSIL (at 6, 10, and 14 weeks of age) co-administered with EPI vaccines, including 
DTwP-HepB-Hib vaccine. When observed, reactogenicity was primarily mild or moderate and of 
short duration. There were no related SAEs or severe TEAEs reported during the study and no 
meaningful trends in SAEs, vaccine-related TEAEs, or overall TEAEs. As was the case in the VAC-
017 trial, additional risk mitigation in the planned Phase 3 trial will be provided by clinical monitoring 
and access to clinical evaluation and management. 
Potential health benefits include the clinical assessments and physical examinations by a study 
clinician outlined in the protocol which may identify illnesses or other medical issues, thus allowing 
for their prompt treatment. Medical issues will also be investigated and managed by the study team 
according to good clinical practice in The Gambia and within the limits of the regular practice of the 
MRC clinical services department and associated laboratory, radiology and pharmacy facilities. Certain 
issues beyond this (including in particular, but not limited to, any surgical issues) would instead be 
referred to the appropriate government health facility for management, in which case transport and 
other small costs would generally be covered by the study team (note that these limitations do not apply 
to study-related injury, which are covered by clinical trial insurance). 
 
Infants who participate in the booster phase (n = 675) will receive a booster dose of PNEUMOSIL, 
which is expected to provide additional protection against pneumococcal disease by boosting 
immunity. A booster dose of PCV is not currently offered by the Gambian EPI program. The overall 

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aim of the program is to license an affordable pneumococcal conjugate vaccine targeting those 
pneumococcal serotypes most prevalent in The Gambia and other low- and middle-income countries; 
parents (and in the future infants) may feel benefit from knowing that they have been a part of this 
endeavor.  
15.6. Subject Confidentiality 
Every effort will be made to protect subject privacy and confidentiality. Personal identifiers will not be 
included in any study reports. All study records will be kept confidential to the extent provided by 
national and local laws. Medical records containing identifying information will be made available for 
review when the study is monitored by the Sponsor or an authorized regulatory agency. Direct access 
may include examining, analyzing, verifying, and reproducing any records and reports that are 
important in the evaluation of the study. 
All study-related information will be stored securely at the study site. All subject information will be 
stored in locked file cabinets in areas with access limited to study staff. Data collection, process, and 
administrative forms, and other reports will be identified only by a unique trial-related subject 
identification code (screening/randomization ID) to maintain subject confidentiality. Laboratory 
reports may include the name and date of birth of the subject to minimize the risk of errors in the busy 
clinical laboratories. All local databases will be secured with password-protected access systems. 
Forms, lists, logbooks, appointment books, and any other listings that link subject ID numbers to other 
identifying information will be stored in a separate, locked file in an area with limited access. Subjects’ 
study information will not be released without their written permission, except as necessary for 
monitoring, or as required/permitted by law/regulatory authorities. 
15.7. Reimbursement 
Pending EC approval, parents of subjects will be compensated for travel to study visits. In addition, 
appropriate food during a visit and services to allow phone contact for follow-up purposes will be 
provided. The study ICF will explain this. Parents of study subjects will not be charged for vaccines, 
research clinic visits, research-related examinations, or research-related laboratory tests or health care 
in line with good practice in The Gambia while on follow-up in the study. 
15.8. Storage of Specimens 
15.8.1. Use of Specimens during the Study 
Each blood sample drawn for a subject will be uniquely labeled at the subject level to allow the site, 
the laboratories performing the assays, and the Sponsor to remain blinded to treatment assignment until 
the blind is broken during the primary and secondary analyses. After the blind is broken, the laboratories 
performing the assays will continue to be blinded for the supplemental analysis. Stored study research 
samples will be labeled by screening ID. All stored research samples will be logged into a secure 
database that tracks total samples collected and used. The transport of samples to any laboratory outside 
of the clinical site will be traceable and logged at the time of transit (at the package level) and receipt 
(at the sample level) and temperature monitored when appropriate to ensure sample integrity. Any 
deviations identified during transport that might affect the integrity of the sample analysis will be 
reported to the data management system for logging. Refer to the SSP for specifics on sample labeling, 
transport, tracking and logging. Samples may be stored at several different central laboratories in order 

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to complete the analyses required to meet study primary and secondary analyses. After the completion 
of immune testing, all remaining samples at the central laboratories ______________. 
15.8.2. Future Use of Stored Specimens 
Some blood samples will be retained at the ______________ in case testing needs to be repeated. When 
these samples are no longer needed for the purposes of the study, they will be kept or destroyed, 
depending on whether subjects’ parents consented to any remaining samples being used for other, 
ethically approved research ______________. Samples that will remain at the ______________will have 
the same label as was used in the current study. Their use will be governed by a repository plan that is 
mutually agreeable to PATH and MRC. The samples will be used in accordance with what is stated in 
the study consent form and with review by relevant ethics committees in accordance with laws of 
______________ policies. No genetic testing will be done on the samples. 
 

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16. APPENDICES 
16.1. Appendix 1:  Solicited Local and Systemic Reactions Toxicity Grading Table 
Local Reaction to 
Injectable Product 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Tendernessa 
Minor reaction to 
touch 
Cries / protests on 
touch 
Cries when limb 
is moved / 
spontaneously 
painful 
Hospitalization 
Erythema/Rednessb 
Erythema present 
but ≤ 2.5 cm 
diameter 
Erythema >2.5cm 
diameter but < 
50% surface area 
of the extremity 
segment (e.g., 
upper arm/thigh) 
Erythema 
involving ≥ 50% 
surface area of 
the extremity 
segment (e.g., 
upper arm/thigh) 
OR Ulceration 
OR Secondary 
infection OR 
Phlebitis OR 
Sterile abscess 
OR Drainage 
Necrosis 
(involving dermis 
and deeper) of 
tissue OR 
Hospitalization 
Induration/Swellingb
Induration OR 
Edema present 
but ≤ 2.5 cm 
diameter 
Induration OR 
Edema > 2.5 cm 
diameter but  
< 50% surface 
area of the 
extremity segment 
(e.g., upper 
arm/thigh) 
Induration OR 
Edema involving 
> 50% surface 
area of the 
extremity 
segment (e.g., 
upper arm/thigh) 
or Ulceration OR 
Secondary 
infection OR 
Phlebitis OR 
Sterile abscess 
OR Drainage 
Necrosis 
(involving dermis 
and deeper) of 
tissue OR 
Hospitalization 
Temperature 
(axillary) 
≥ 37.5C (99.5F) 
to ≤ 38.0C 
(100.4F) 
> 38.0C 
(100.4F) to  
≤ 39.0C 
(102.2F) 
> 39.0C 
(102.2F) to  
≤ 40.0C 
(104.0F) 
> 40.0C 
(104.0F) 
Irritabilitya 
Crying more than 
usual / no effect 
on normal activity
Crying more than 
usual / interferes 
with normal 
activity 
Crying that 
cannot be 
comforted / 
prevents normal 
activity 
Hospitalization 
Drowsiness 
Drowsiness easily 
tolerated  
Drowsiness that 
interferes with 
normal activity 
Drowsiness that 
prevents normal 
activity 
Hospitalization 

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Local Reaction to 
Injectable Product 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Decreased  
Appetitea 
Eating less than 
usual / no effect 
on normal activity
Eating less than 
usual / interferes 
with normal 
activity 
Not eating at all 
Hospitalization 
Cutaneous Rash 
Localized 
macular rash (not 
directly 
associated with 
the injection site 
– ie not a local 
reaction at the site 
of injection) 
Diffuse macular; 
maculopapular, or 
morbilliform rash 
OR Target lesions 
Diffuse macular, 
maculopapular, or 
morbilliform rash 
with vesicles or 
limited number of 
bullae OR 
Superficial 
ulcerations of 
mucous 
membrane limited 
to one site 
Extensive or 
generalized 
bullous lesions 
OR Stevens-
Johnson 
syndrome OR 
Ulceration of 
mucous 
membrane 
involving two or 
more distinct 
mucosal sites OR 
Toxic epidermal 
Necrolysis (TEN) 
Note: The preferred route for recording temperature in this study will be axillary. 
a Standard pediatric reactogenicity scales used in PCV studies. 
b Record redness and swelling at greatest surface diameter in millimeters using a ruler. 
NOTE: The above table is derived from Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events (Version 2.0, November 2014). 
 
 
 

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16.2. Appendix 2:  Vital Signs Toxicity Grading Table 
Vital Signsa 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Respiratory distressb 
Wheezing OR 
minimal 
increase in 
respiratory rate 
for age 
Nasal flaring 
OR Intercostal 
retractions OR 
Pulse oximetry 
90 – 95% 
Dyspnea at rest 
causing inability 
to perform usual 
social and 
functional 
activities OR 
Pulse oximetry 
< 90% 
Hospitalization 
Sinus bradycardiac 
Asymptomatic, 
intervention not 
indicated 
Symptomatic, 
non-urgent 
medical 
intervention 
indicated 
Severe, 
medically 
significant, 
medical 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Sinus tachycardiac 
Asymptomatic, 
intervention not 
indicated 
Symptomatic; 
non-urgent 
medical 
intervention 
indicated 
Severe, 
medically 
significant, 
medical 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
a Subject should be at rest for all vital sign measurements. 
b Derived from the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (Version 2.0, November 2014). 
c Derived from Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0, 
Published May 28, 2009 (v4.03: June 14, 2010). 
 
 

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16.3. Appendix 3:  References 
1 World Health Organization. Estimated Hib and pneumococcal deaths for children under 5 years of 
age; 
2008. 
March 
2012. 
http://www.who.int/immunization/monitoring_surveillance/burden/estimates/Pneumo_hib/en/ 
(accessed 8/26/16). 
2 Liu L, Oza S, Hogan D, et al. Global, regional, and national causes of child mortality in 2000–13, 
with projections to inform post-2015 priorities: an updated systematic analysis. Lancet 2014; 
385(9966):430–40. 
3 Levine OS, Cherian T. Pneumococcal vaccination for Indian children. Indian Pediatr. 2007 Jul; 
44(7):491-496 
4 O’Brien KL, Wolfson LJ, Watt JP, et al. Burden of disease caused by Streptococcus pneumoniae in 
children younger than 5 years: global estimates. Lancet 2009;374:893–902. 
5 Klugman KP. Contribution of vaccines to our understanding of pneumococcal disease. Philos Trans 
R Soc Lond B Biol Sci. 2011 Oct 12;366(1579):2790-8. 
6 O’Dempsey TJ, McArdle TF, Lloyd-Evans N, Baldeh I, Lawrence BE, Secka O, et al. Pneumococcal 
disease among children in a rural area of west Africa. Pediatr Infect Dis J. 1996;15: 431-37. 
7 Campbell JD, Kotloff KL, Sow SO, Tapia M, Keita MM, Diallos S, et al. Invasive pneumococcal 
infections among hospitalized children in Bamako, Mali. Pediatr Infect Dis J. 2004; 23: 642-49. 
8 Berkley JA, Lowe BS, Mwangi I, Williams T, Bauni E, et al. Bacteremia among children admitted to 
a rural hospital in Kenya. NEJM. 2005; 352: 39-47. 
9 Obaro SK. Prospects for pneumococcal vaccination in African children. Acta Trop. 2000; Mar 25; 
75(2):141-153. 
10 Cutts FT, Zaman SMA, Enwere G, Jaffar S, Levine OS, et al. Efficacy of nine-valent pneumococcal 
conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomized, 
double-blind, placebo-controlled trial. Lancet. 2005 Mar 26; 365: 1139-1146. 
11 Mackenzie GA, Hill PC, Jeffries DJ, Hossain I, Uchendu U, et al. Effect of the introduction of 
pneumococcal conjugate vaccination on invasive pneumococcal disease in The Gambia: a population-
based surveillance study. Lancet Infect Dis. 2016 Jun;16(6):703-11 
12 Johnson HL, Deloria-Knoll M, Levine OS, Stoszek SK, Freimanis Hance L, et al. Systematic 
evaluation of serotypes causing invasive pneumococcal disease among children under five: the 
pneumococcal global serotype project. PLoS Med. 2010 Oct 5;7(10). pii: e1000348. doi: 
10.1371/journal.pmed.1000348. 
13 Shapiro ED, Berg AT, Austrian R, et al. The protective efficacy of polyvalent pneumococcal 
polysaccharide vaccine. N Engl J Med. 1991; 325: 1453-1460. 
14 Temple K, Greenwood B, Inskip H, Hall A, Koskela M, Leinonen M. Antibody response to 
pneumococcal capsular polysaccharide vaccine in African children. Pediatr Infect Dis. 1991; 10: 386-
390. 
                                                 

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15 Pilishvili T, Lexau C, Farley MM, Hadler J, Harrison LH, et al. For the Active Bacterial Core 
Surveillance/Emerging Infections Program Network. Sustained reductions in invasive pneumococcal 
disease in the era of conjugate vaccine. JID. 2010; 201: 32-41. 
16 Gavi The Vaccine Alliance. The Gambia introduces vaccine against pneumococcal disease. Gavi 
The Vaccine Alliance website http://www.gavi.org/library/news/press-releases/2009/the-gambia-
introduces-vaccine-against-pneumococcal-disease/ (accessed 8/26/16). 
17 Gavi The Vaccine Alliance. Pneumococcal AMC. Gavi The Vaccine Alliance website 
http://www.gavi.org/funding/pneumococcal-amc/ (accessed 8/26/16). 
18 Vaccine Information Management System Report on Global Introduction (updated June 2016) 
http://www.jhsph.edu/research/centers-and-institutes/ivac/view-hub/IVAC-VIEW-hub-Report-2016-
06.pdf (accessed 8/26/16) 
19 United Nations. Transforming Our World: the 2030 Agenda for Sustainable Development, 2015. 
https://sustainabledevelopment.un.org/content/documents/21252030%20Agenda%20for%20Sustaina
ble%20Development%20web.pdf 
20 Drugs and Cosmetics (IInd Amendment) Rules, Ministry of Health and Family Welfare, New Delhi, 
the 20th January, 2005. 
21 ICH Harmonized Tripartite Guideline S6. Preclinical safety evaluation of biotechnology-derived 
pharmaceuticals, recommended for adoption by the ICH Steering Committee on 16 July 1997. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S6_R1/Step4/S6_R
1_Guideline.pdf 
22 WHO guidelines on nonclinical evaluation of vaccines. TRS 927, Annex 1, 2005. 
http://www.who.int/entity/biologicals/publications/trs/areas/vaccines/nonclinical_evaluation/ANNEX
%201Nonclinical.P31-63.pdf?ua=1 
23 WHO. Annex 3: Recommendations to assure the quality, safety and efficacy of pneumococcal 
conjugate vaccines. Replacement of WHO Technical Report Series, No. 927, Annex 2.  WHO 
Technical Report Series: World Health Organization; 2013 
24 WHO. Target Product Profile (TPP) for the Advance Market Commitment (AMC) for Pneumococcal 
Conjugate 
Vaccines. 
February 
22, 
2008. 
http://www.who.int/immunization/sage/target_product_profile.pdf 
25 State of PCV Use and Impact Evaluations.  A strategic gap analysis of the global evidence from 
published and ongoing impact studies evaluating routine PCV use. International Vaccine Access 
Center, 
Johns 
Hopkins 
Bloomberg 
School 
of 
Public 
Health 
March, 
2016. 
http://www.jhsph.edu/research/centers-and-
institutes/ivac/resources/PCVImpactGapAnalysis_MAR2016_FINAL_public.pdf 
26 Synflorix.  Annex I Summary of Product Characteristics. GlaxoSmithKline Biologicals s.a., 
Rixensart, Belgium, 2014. 
27 Palmu AA1, Jokinen J, Borys D, Nieminen H, Ruokokoski E, et al. Effectiveness of the ten-valent 
pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against invasive 
pneumococcal disease: a cluster randomised trial. Lancet. 2013 Jan 19;381(9862):214-22 

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28 Tregnaghi MW, Saez-Llorens X, Lopez P, Abate H, Smith E, et al. (2014) Efficacy of Pneumococcal 
Nontypable Haemophilus influenzae Protein D Conjugate Vaccine (PHiD-CV) in Young Latin 
American Children: A Double-Blind Randomized Controlled Trial. PLoS Med 11(6): e1001657. 
29 Vesikari T, Wysocki J, Chevallier B, Karvonen A, Czajka H, et al. Immunogenicity of the 10-valent 
pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) 
compared to the licensed 7vCRM vaccine. Pediatr Infect Dis J. 2009 Apr;28(4 Suppl):S66-76. 
30 Yeh SH, Gurtman A, Hurley DC, Block SL, Schwartz RH, et al. Immunogenicity and safety of 13-
valent pneumococcal conjugate vaccine in infants and toddlers. Pediatrics. 2010 Sep;126(3):e493-505. 
31 Jokinen J, Rinta-Kokko H, Siira L, Palmu AA, Virtanen MJ, et al. Impact of tenvalent pneumococcal 
conjugate vaccination on invasive pneumococcal disease in Finnish children–a population-based study. 
PLoS One 2015; 10(3):e0120290. 
32 Domingues CM, Verani JR, Montenegro Renoiner EI, de Cunto, et al. Effectiveness of ten-valent 
pneumococcal conjugate vaccine against invasive pneumococcal disease in Brazil: a matched 
casecontrol study. Lancet Respir Med 2014 June; 2(6):464-71. 
33 Deceuninck G, De Serres G, Boulianne N, Lefebvre B, De Wals P. Effectiveness of three 
pneumococcal conjugate vaccines to prevent invasive pneumococcal disease in Quebec, 
Canada.Vaccine 2015 May 28; 33(23):2684-9. 
34 WHO. Table 2: Summary of WHO Position Papers – Recommended Routine Immunizations for 
Children 
(updated 
31 
May 
2011). 
http://www.who.int/immunization/policy/Immunization_routine_table2.pdf 
35 Chevallier B, Vesikari T, Brzostek J, Knuf M, Bermal N, et al. Safety and Reactogenicity of the 10-
Valent Pneumococcal Non-typeable Haemophilus influezae Protein D Conjugate Vaccine (PHiD-CV) 
when Coadministered with Routine Childhood Vaccines. Pediatr Infect Dis J 2009;28: S109-S118 
36 
WHO. 
Best 
practices 
for 
injections 
and 
related 
procedures 
toolkit, 
2010. 
http://whqlibdoc.who.int/publications/2010/9789241599252_eng.pdf 
37 Guidance for Industry. E3 Structure and Content of Clinical Study Reports. U.S. Department of 
Health and Human Services, FDA, Center for Drug Evaluation and Research, CBER, January 2013. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM
336889.pdf 
38 Gart JJ, Nam J. 1990. Approximate interval estimation of the difference in binomial parameters: 
correction for skewness and extension to multiple tables. Biometrics 46, 637-643