A Phase 2, Multicenter, Randomized, Active-Controlled, Observer-Blind, Dose-Ranging Study to Evaluate the Safety, Tolerability, and Immunogenicity of a 25-Valent Pneumococcal Conjugate Vaccine in Healthy PCV-Naïve Adults
Phase: PHASE2
Conditions: Pneumococcal Vaccines
Sponsor: Inventprise Inc.

A Phase 2 Multicenter, Randomized, Active-Controlled, Observer-
Blind, Dose-Ranging Study to Evaluate the Safety, Tolerability, and 
Immunogenicity of a 25-Valent Pneumococcal Conjugate Vaccine in 
Healthy PCV-Naïve Adults 
 
CONFIDENTIAL 
 
March 6, 2024 
Sponsored by: 
Inventprise, Inc. 
18133 NE 68th St, D150 
Redmond, Washington 98052 
USA 
 
 
Version 4.0 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable Independent Ethics Committees or Institutional 
Review Boards. The contents of this document shall not be disclosed to others without written 
authorization from PATH (or others, as applicable), unless it is necessary to obtain informed consent 
from potential study participants or their legally authorized representatives. 
 
 

 
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LIST OF ABBREVIATIONS AND ACRONYMS ....................................................................................................... 4 
STATEMENT OF COMPLIANCE .............................................................................................................................. 6 
PROTOCOL SIGNATURE PAGE ............................................................................................................................... 7 
KEY ROLES AND CONTACT INFORMATION ...................................................................................................... 8 
PROTOCOL SUMMARY ............................................................................................................................................. 9 
BACKGROUND AND RATIONALE ..................................................................................................................... 17 
1.1 Burden of Disease ............................................................................................................................................ 17 
1.2 Pathogen and Clinical Disease ........................................................................................................................ 17 
1.3 Licensed Pneumococcal Conjugate Vaccines .................................................................................................. 17 
1.4 Rationale for IVT PCV-25 Development .......................................................................................................... 18 
1.5 Summary of safety profile of hydrazine and PEG in humans ........................................................................... 20 
1.6 Summary of Preclinical Studies ....................................................................................................................... 21 
1.7 Summary of First-in-Human Clinical Study (NCT05540028) ......................................................................... 26 
1.8 Study Rationale ................................................................................................................................................ 28 
2. HYPOTHESIS, OBJECTIVES, ENDPOINTS, ESTIMANDS ......................................................................... 30 
2.1 Study Hypothesis .............................................................................................................................................. 30 
2.2 Study Objectives, Endpoints, and Estimands ................................................................................................... 30 
3. STUDY DESIGN ................................................................................................................................................... 31 
4. STUDY POPULATION ....................................................................................................................................... 34 
4.1 Description of Study Population ...................................................................................................................... 34 
4.2 Inclusion Criteria ............................................................................................................................................. 34 
4.3 Exclusion Criteria ............................................................................................................................................ 35 
5. STUDY PRODUCTS ............................................................................................................................................ 36 
5.1 IVT PCV-25 ...................................................................................................................................................... 36 
5.1.1 Product Description ............................................................................................................................... 36 
5.1.2 Manufacturer ......................................................................................................................................... 36 
5.1.3 Presentation and Formulation ................................................................................................................ 36 
5.1.4 Storage ................................................................................................................................................... 37 
5.1.5 Potential Safety Risks ............................................................................................................................ 37 
5.2 Prevnar 20TM ................................................................................................................................................... 37 
5.2.1 Product Description ............................................................................................................................... 37 
5.2.2 Manufacturer ......................................................................................................................................... 37 
5.2.3 Presentation and Formulation ................................................................................................................ 37 
5.2.4 Storage ................................................................................................................................................... 37 
5.2.5 Potential Safety Risks ............................................................................................................................ 37 
5.3 Vaccine Storage, Transport, and Temperature Monitoring ............................................................................. 38 
5.4 Dose Preparation and Administration ............................................................................................................. 38 
5.5 Accountability and Disposal ............................................................................................................................ 39 
6. STUDY PROCEDURES ....................................................................................................................................... 40 
6.1 Recruitment ...................................................................................................................................................... 40 
6.1.1 Initial and Continuing Informed Consent .............................................................................................. 40 
6.2 Study Visits ....................................................................................................................................................... 40 
General information: ...................................................................................................................................... 40 
6.2.1 Screening ............................................................................................................................................... 41 
6.2.2 Randomization and Vaccination Visit General Information ................................................................. 41 
6.2.3 Visit 2 General Information ................................................................................................................... 42 
6.2.4 28-Day Post-Vaccination Visit (Visit 3) ................................................................................................ 42 

 
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6.2.5 Six Month Post-Last Vaccination Visits (Visit 4) ................................................................................. 42 
6.2.6 Interim Contacts and Visits .................................................................................................................... 43 
6.3 Participant Discontinuation Termination ........................................................................................................ 43 
6.4 Concomitant Medications and Treatments ....................................................................................................... 44 
6.5 Emergency Unblinding Procedure ................................................................................................................... 44 
6.6 Management of Pregnancy .............................................................................................................................. 45 
6.7 Clinical Procedures ......................................................................................................................................... 45 
6.7.1 Vital Signs ............................................................................................................................................. 45 
6.7.2 Height and Weight ................................................................................................................................. 45 
6.7.3 Complete Physical Examination ............................................................................................................ 45 
6.7.4 Injection Site Examination .................................................................................................................... 46 
7. LABORATORY EVALUATIONS ...................................................................................................................... 46 
7.1 Sample Collection, Distribution, and Storage .................................................................................................. 46 
7.2 Clinical Laboratory Assays .............................................................................................................................. 47 
7.3 Immunological Assays ...................................................................................................................................... 47 
7.4 Assay Qualification, Standardization, and Validation ..................................................................................... 47 
7.5 Biohazard Containment ................................................................................................................................... 48 
8. SAFETY ASSESSMENT AND REPORTING ................................................................................................... 48 
8.1 Collection of Safety Events ............................................................................................................................... 48 
8.2 Definitions ........................................................................................................................................................ 49 
8.2.1 Adverse Event........................................................................................................................................ 49 
8.2.2 Solicited AE ........................................................................................................................................... 49 
8.2.3 Unsolicited AE ...................................................................................................................................... 50 
8.2.4 Serious Adverse Event ........................................................................................................................... 50 
8.2.5 Severity (Intensity) of an AE ................................................................................................................. 51 
8.2.6 Causal Relationship of an AE ................................................................................................................ 51 
8.2.7 Assessment of Outcome of AE .............................................................................................................. 52 
8.3 AE Recording and Reporting ........................................................................................................................... 52 
8.4 SAE Reporting .................................................................................................................................................. 52 
8.4.1 Unanticipated Problems ......................................................................................................................... 53 
9. SAFETY MONITORING .................................................................................................................................... 53 
9.1 Data Safety Monitoring Board ......................................................................................................................... 53 
9.2 Pause Rules ...................................................................................................................................................... 54 
9.3 Protocol Deviation ........................................................................................................................................... 54 
10. DATA HANDLING AND RECORD KEEPING ........................................................................................................... 54 
10.1 Case Report Form Development and Completion ......................................................................................... 55 
10.2 Record Archival ............................................................................................................................................. 55 
10.2.1 Archiving Data at Study Site ............................................................................................................... 55 
10.2.2 Data Storage and Archival ................................................................................................................... 56 
10.3 Confidentiality ............................................................................................................................................... 56 
11. STATISTICAL CONSIDERATIONS .............................................................................................................. 56 
11.1 Overview and General Considerations .......................................................................................................... 56 
11.2 Randomization Procedures ............................................................................................................................ 57 
11.3 Sample Size and Power .................................................................................................................................. 57 
11.4 Definitions of Populations to be Analyzed ..................................................................................................... 59 
11.4.1 Enrolled Population ............................................................................................................................. 59 
11.4.2 Exposed Population ............................................................................................................................. 59 
11.4.3 Safety Analysis Population .................................................................................................................. 59 
11.4.4 Full Analysis Population ..................................................................................................................... 59 

 
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11.4.5 Per Protocol Population ....................................................................................................................... 59 
11.5 Estimands and Analytical Methodology ......................................................................................................... 60 
11.5.1 Estimands ............................................................................................................................................ 60 
11.5.2 Descriptive Methodology .................................................................................................................... 60 
11.5.3 Analysis Sequence ............................................................................................................................... 60 
11.5.4 Analysis of Demographic and Baseline Characteristics ...................................................................... 61 
11.5.5 Analysis of Primary Objective ............................................................................................................. 61 
11.5.6 Analysis of Secondary Objectives ....................................................................................................... 63 
11.6 Multiplicity ..................................................................................................................................................... 64 
11.7 Handling of Participant Discontinuations and Missing Data ........................................................................ 64 
12. QUALITY ASSURANCE AND QUALITY CONTROL ................................................................................. 64 
12.1 General Considerations ................................................................................................................................. 64 
12.2 External Monitoring ....................................................................................................................................... 65 
12.3 Independent Auditing ..................................................................................................................................... 65 
12.4 Regulatory Agency Auditing .......................................................................................................................... 65 
13. OBLIGATIONS AND ROLES OF THE SPONSOR, PI, AND STUDY PERSONNEL ................................ 66 
14. ETHICAL CONSIDERATIONS AND INFORMED CONSENT .................................................................. 66 
14.1 Ethical Review ............................................................................................................................................... 66 
14.2 Informed Consent Process ............................................................................................................................. 67 
14.3 Study-Related Injury ...................................................................................................................................... 67 
14.4 Risk/Benefit .................................................................................................................................................... 67 
14.5 Participant Confidentiality ............................................................................................................................ 68 
14.6 Reimbursement ............................................................................................................................................... 69 
14.7 Storage of Specimens ..................................................................................................................................... 69 
15. PUBLICATION POLICY .......................................................................................................................................... 69 
16. APPENDICES ..................................................................................................................................................... 71 
16.1 Appendix 1. Study Visits ................................................................................................................................. 71 
16.2 Appendix 2: Solicited Local and Systemic Reactions Toxicity Grading Tables: Adults ................................ 73 
16.3 Appendix 3: Vital Signs Toxicity Grading Table (Adults) ............................................................................. 75 
16.4 Appendix 4: Serum and Hematology Toxicity Grading Table ....................................................................... 76 
16.5 Appendix 5.  References ................................................................................................................................. 77 
16.6 Appendix 6 Protocol Signature Page for Additional Investigators ................................................................ 80 
 
 

 
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LIST OF ABBREVIATIONS AND ACRONYMS 
ABBREVIATION/ 
ACRONYM 
DEFINITION 
Ab 
antibody 
ADR 
adverse drug reaction 
AE 
adverse event 
alum 
aluminum as aluminum phosphate 
ALT 
alanine transaminase 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
bpm 
beats/breaths per minute 
CI 
Confidence interval 
CMO 
Chief Medical Officer 
CONSORT 
Consolidated Standards of Reporting Trials 
CRM197 
Cross Reactive Material 197 
CRO 
contract research organization 
DMP 
Data Management Plan 
DSMB 
Data and Safety Monitoring Board 
EC 
ethics committee 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
EPI 
Expanded Programme on Immunisation 
FA 
full analysis 
Gavi 
Gavi, The Vaccine Alliance 
GCP 
Good Clinical Practice 
GMC 
Geometric Mean Concentration 
GMFR 
Geometric Mean Fold Rise 
GMR 
Geometric Mean Ratio 
GMT 
geometric mean titer 
GSK 
GlaxoSmithKline 
HepB/HB 
Hepatitis B virus 
HBsAg 
Hepatitis B virus surface antigen 
HCV 
Hepatitis C virus 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
HZ 
hydrazide 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
ID 
identification 
IgG 
immunoglobulin G 
IPD 
invasive pneumococcal disease 
IRT 
IVT PCV-25 
Interactive response technology 
25-valent candidate pneumococcal conjugate vaccine manufactured by 

 
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Inventprise, Inc. 
IWRS 
Interactive Web Response System 
LLOQ 
lower limit of quantification  
LMIC 
low- and middle-income countries 
LSLV 
last participant last visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
MO 
Medical Officer 
MOPA 
multiplexed opsonophagocytic assay 
NML 
National Microbiology Laboratory 
NRA 
national regulatory authority 
NZW 
New Zealand White 
OPA 
opsonophagocytic assay 
ORA 
Office of Research Affairs 
PCV 
pneumococcal conjugate vaccine 
PE 
physical examination 
PEG 
polyethylene glycol 
PFS 
pre-filled syringe 
PI 
Principal Investigator (the term is used throughout to indicate PI or 
designee) 
Plts 
platelets 
PP 
per protocol 
PSRT 
Protocol Safety Review Team 
PQ 
prequalification 
PT 
Preferred Term 
RCD 
reverse cumulative distribution 
REB 
Research Ethics Board 
SAE 
serious adverse event 
SD 
standard deviation 
SOC 
System Organ Class 
SOP 
standard operating procedure 
SSP 
study specific procedure 
T bili 
total bilirubin 
TEN 
Toxic epidermal necrolysis 
TMF 
Trial Master File 
TRS 
Technical Report Series 
UK 
United Kingdom 
ULOQ 
upper limit of quantification 
USA 
United States of America 
WBC 
white blood cell 
WHO 
World Health Organization 
WCG IRB 
Western Institutional Review Board 
WOCBP 
women of childbearing potential 
2-PE 
2-phenoxyethanol 
 
 
 

 
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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: 
 
• 
Canada Food and Drug Regulations applicable to clinical studies (Part C, Division 5) 
• 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use (ICH) Guidance for Good Clinical Practice (GCP) E6 
• 
World Medical Association Declaration of Helsinki – Ethical Principles for Research Involving 
Human Participants (Oct 2013 or subsequent amendments) 
 
 
 

 
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PROTOCOL SIGNATURE PAGE 
The signatures below constitute the approval of this protocol and the attachments and provide 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.’ 
 
 
 
 
 
 
 
 
 
 
 
Sponsor 
 
 
 
 
 
 
Date 
 
Name: Sybil Tasker, M.D. MPH 
Title: Chief Medical Officer 
Organization: Inventprise, Inc. 
 
 
 

 
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BACKGROUND AND RATIONALE 
1.1 Burden of Disease 
According to the Global Burden of Disease Study 2016 [1] the bacterium Streptococcus pneumoniae 
kills approximately 300,000 children before their fifth birthday annually, mostly in low-resource 
areas of the world. The most common cause of childhood morbidity and mortality due to the 
bacterium is pneumonia, which in 2019 was estimated to be the cause of roughly 740,000 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 diseases, including sepsis and meningitis, and mucosal diseases, such as otitis media, which 
collectively result in tremendous morbidity and mortality. The highest incidence of invasive 
pneumococcal disease (IPD) is seen at the extremes of age, in adults ≥ 65 years and children < 5 
years of age [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 organism that is commonly carried as a commensal 
in the human nasopharynx. More than 100 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. Children commonly 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 [6]. 
 
 
1.3  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 [7], it is poorly immunogenic in children less 
than 2 years old [8]. 
 
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 conjugate vaccine, which elicits an 
enhanced immune response when the polysaccharide is conjugated to a carrier protein. Prevnar®, a 
7-valent pneumococcal conjugate vaccine (PCV), 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), Prevnar was first approved 

 
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and introduced in the US and Canada for use in infants and young children in the year 2000. Within 
eight years, overall and serotype-specific IPD in Canada were reduced by 48% and 87.5%, 
respectively [9]. 
 
However, given the limited coverage offered by Prevnar, and the increasing burden of disease caused 
by newly emergent non-vaccine (‘replacement’) serotypes after Prevnar introduction, two second-
generation PCVs, Synflorix® (GlaxoSmithKline [GSK] Biologicals) and Prevnar 13® (Wyeth, now 
Pfizer) were subsequently developed and approved for infants and young children, both expanding 
on Prevnar’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 
Prevnar 13®, the second-generation PCVs offered additional protection against common disease-
causing serotypes in Canada and worldwide. However, not only have these vaccines been less 
effective than the 7-valent PCV in addressing vaccine-type disease – with roughly 30% of cases of 
IPD in Canada still due to Prevnar 13® serotypes based on the most recent (2019) National 
Microbiology Laboratory (NML) data [10], there has been a significant increase in non-vaccine-type 
IPD since their introduction due to additional replacement serotypes. In Canada, rising incidence of 
IPD due to serotype 3 (contained in Prevnar 13®) and serotype 22F (a replacement serotype) are of 
particular concern [11]. 
 
In addition to the issues concerning their overall efficacy, the second-generation PCVs, like their 
predecessor, are relatively complicated and expensive to produce, making them difficult for low-
income countries to afford without considerable external financial assistance. Low- and middle-
income countries (LMICs) that do not qualify for financial support via Gavi, The Vaccine Alliance 
(Gavi) can rarely afford these vaccines within their health budgets. An exception is PNEUMOSIL® 
[12,13], a 10-valent PCV manufactured by the Serum Institute of India, Pvt., Ltd., which achieved 
World Health Organization (WHO) prequalification (PQ) in December 2019. However, the 
effectiveness of PNEUMOSIL will also be limited by the increasing burden of disease caused by 
non-vaccine serotypes. Prevnar 20™ [14], a 20-valent PCV manufactured by Pfizer, and 
VAXNEUVANCE™ [15], a 15-valent PCV manufactured by Merck, achieved US marketing 
authorization for adults 18 years of age and older in June 2021 and July 2021, respectively. Prevnar 
20TM has been approved for use in adults by Health Canada in May 2022. 
 
1.4  Rationale for IVT PCV-25 Development 
To address the above-mentioned issues, Inventprise Inc has partnered with PATH (a global health 
organization based in Seattle, Washington) to develop a safe, effective and low-cost third-generation 
PCV vaccine that will prevent IPD, pneumonia, and otitis media due to the remaining predominant 
serotypes causing disease in children, particularly those residing in Africa and other low- and 
middle-income regions of the world. The resulting candidate vaccine (IVT PCV-25) contains 
capsular polysaccharides from 25 pneumococcal serotypes: 1, 2, 3, 4, 5, 6B, 6C, 7F, 8, 9N, 9V, 10A, 
12F, 14, 15A, 15B, 16F, 18C, 19A, 19F, 22F, 23F, 24F, 33F, and 35B. Table 3 provides a comparison 
of the vaccine serotypes included in IVT PCV-25 to those included in currently licensed PCVs. 

 
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There have been numerous reports of immediate hypersensitivity reactions in humans exposed to 
drugs, biologicals, and vaccines containing PEG added either as an excipient to the product or as a 
conjugate to the active drug moiety [30-34]. Although considered rare, such hypersensitivity 
reactions can require prompt medical intervention and in some cases hospitalization. These rare 
adverse events (AEs) rare have been associated with IgM, IgG, and IgE antibodies to PEG although 
the presence of anti-PEG antibodies are not predictive of the probability of developing immediate-
type hypersensitivity-type reactions.  
 
In a retrospective study of the long-term safety of PEG-containing therapies in the pediatric 
population, children weighing 10 kg who were exposed to as much as 2.7 grams of PEG per year (in 
pegylated Factor VIII), and children weighing 50 kg exposed to as much as 21.8 gr per year were 
not found to be adversely affected [34]. These quantities of annual PEG exposure are substantially 
higher than the microgram levels of PEG that will be given in IVT PCV-25. 
 
1.6  Summary of Preclinical Studies 
A series of preclinical studies have been conducted to evaluate the immunogenicity and safety of 
IVT PCV-25, and to support the formulation of IVT PCV-25 vaccine candidate evaluated in this 
Phase 1/2 clinical study. A brief overview of these studies is provided in Table 5 below. Refer to the 
Investigator’s Brochure for additional details. 
 
Table 5. Preclinical studies conducted to evaluate IVT PCV-25 

 
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A total of 49 unsolicited AEs were reported through Day 29, of which 3 AEs were classified as 
related to investigational product. The three most frequently reported AEs were Headache, n=7 
(11.7%), Nasopharyngitis, n=5 (8.3%), and COVID-19, n=4 (6.7%). Up through Day 29, there were 
no serious adverse events (SAEs) reported. Additional safety information can be found in the 
Investigator Brochure.  
 
The Sponsor, consultants, and PATH reviewed the unblinded serotype-specific IgG antibody 
concentrations at baseline and 28 days after vaccination from the adult participants after the first 26 
participants completed Visit 3, and also from the entire 60-person cohort. The immunogenicity as 
represented by the geometric mean ratio (GMR) of the IgG concentrations at  28 days post 
vaccination in participants vaccinated with IVT PCV-25 compared to participants vaccinated with 
Prevnar 20TM are shown in Table 7. The blue-shaded serotypes are shared between IVT PCV-25 and 
Prevnar 20TM. The green-shaded serotypes are those unique to IVT-PCV-25. The red-shaded 
serotype 6A is unique to Prevnar 20TM. There was decreased GMRs in 14 of the 18 commonly shared 
serotypes between IVT PCV-25 and Prevnar 20TM although the sample size was too small to make 
any statistical significance with precision due to the descriptive study design. 
 
Table 7. Geometric mean ratio of GMCs 28 days after vaccination. 
 

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1.8 Study Rationale 
Inventprise Inc. now (subject of this protocol) intends to conduct an adult only study with various 
dose-ranging formulations to obtain safety and reactogenicity and also supportive immunogenicity 
data to enable age de-escalation of one or more of these formulations directly to a phase 2 infant 
study without prior age de-escalation to toddlers. Inventprise, Inc. has manufactured a new lot of 
IVT PCV-25 and reformulated the product into three different antigen and adjuvant combinations to 
be tested in the Phase 2 trial.  Inventprise Inc. is evaluating the new formulations in a toxicology 
study and will be included in an updated Investigator Brochure before advancement to infants.  
 
It is important to note that the magnitude of the type of protective immune responses elicited in 
adults (serotype-specific OPA antibodies) versus infants are not necessarily predictive of the 
protective immune responses elicited in infants (serotype-specific IgG concentrations), and that the 
regulatory criteria for approval of a PCV indication differ between adults and infants. Therefore 
dose-ranging in both adults and infants are necessary to optimize final dose selection for pivotal 
Phase 3 studies in infants and in adults. Furthermore, antigenic competition due to the large number 

 
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*Blood draw for clinical laboratory tests 
An independent DSMB will review unblinded safety data after the last participant completes the 
28-day follow-up visit (V3) in order to plan for advancement to the infant study.  
 
The sample sizes for each group were selected and weighted toward the higher antigen and adjuvant 
dose combinations to ensure that the safety assessment in each group at the interim analysis was 
adequate to advance to an infant Phase 2 trial and would reflect the probability for similar dose 
ranges to be included in a study in infants.  
 
The first study (interim) report will include the safety data up through Day 29 from the complete 
220 adult cohort (DSMB review) and the interim serotype-specific IgG results of IVT PCV-25 
from approximately 50% or more of the participants in study. The Sponsor plans to submit the 
report for a follow-on dose-ranging Phase 2 trial in infants, aged 8-11 weeks at first dose. A second 
analysis will include the OPA results through Day 29 from the complete 220 adult cohort as they 
become available.   
 
The Sponsor and its consultants, PATH, representatives from the Bill & Melinda Gates Foundation, 
and the site Investigators will review the group-level, unblinded interim safety report in order to 
prepare for a dose-ranging Phase 2 trial in infants. 
 
The Sponsor and its consultants, PATH,  and representatives from the Bill & Melinda Gates 
Foundation will review the unblinded group-level and individual level (with participant ID masked) 
serotype-specific IgG antibody responses from the first analysis and the unblinded group-level and 
individual level (with participant ID masked) serotype-specific OPA results  at baseline and Day 
29 from the second  analysis as they become available to ensure that the immune responses to 
IVT PCV-25 are sufficient to proceed to a dose-ranging Phase 2 trial in infants. The site 
investigators will be provided the group-level immunogenicity results but will remain blinded to 
the individual serotype-specific IgG and OPA results until study end. 
 
The third and final study report will include the complete safety data up through Day 169 from all 
participants with the complete IgG and OPA immunogenicity results from all the participants.  
 
After informed consent is obtained, participants will be screened to determine eligibility. 
Randomization will take place only after a participant has satisfied all eligibility criteria, including 
confirmation of having no acute illness or abnormal vital sign that precludes vaccination.  
 
Each participant will undergo a total of 4 clinic visits (V), including at least one screening visit (V0) 
not more than 28 days prior to Day 1 (V1), a vaccination visit on Day 1 (V1), and follow-up clinic 
visits at 7 (+3) and 28 (+7) days post-vaccination (V2 and V3, respectively). Re-screening is 
permissible if the window period exceeds 28 days.  
 
Blood will be collected for hematological and biochemical laboratory tests at screening (V0) and 
Day 8 (V2). Blood will be collected at baseline (V1) and 28 days post-vaccination (V3) to assess 

 
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serotype-specific IgG antibody responses and to assess serotype-specific functional responses as 
measured by OPA. There will be a final follow-up call at Day 169 (V4) to obtain any safety 
information (SAEs) that may have occurred since Visit 3. The study schema for the adult cohort is 
presented in Table 9. 
 
The DSMB will review unblinded safety and reactogenicity data from all adult participants after the 
last participant in the adult cohort completes the 28-day follow-up visit (V3).  
 
4. STUDY POPULATION 
4.1 Description of Study Population 
The study population will consist of healthy male and female pneumococcal vaccine-naive adults 
from 18 through 49 years of age, recruited and screened by the site staff at the participating study 
sites in Canada. Participants will by recruited to participate in the study from within the Canadian 
Immunization Research Network and possibly other clinical trial sites in Canada. In order to be 
eligible for randomization and vaccination, prospective participants must meet all of the inclusion 
criteria and none of the exclusion criteria. 
 
4.2 Inclusion Criteria 
Participants will be eligible for randomization if all of the following inclusion criteria apply at the 
time of screening: 
1. Healthy adults who are 18 through 49 years old on the day of randomization (Day 1).  
Note: ‘Healthy’ status is to be determined by medical history, physical examination, and 
clinical judgment.  
2. Participant must provide voluntary written informed consent to participate in the study. 
3. Participant must be able to comprehend and comply with study requirements and 
procedures and be willing and able to return for all scheduled follow-up visits. 
4. Adult female participants who are not surgically sterile must have a negative pregnancy 
test at screening and negative pregnancy test prior to vaccination. They will be advised 
through the informed consent process to avoid becoming pregnant through Day 57 of the 
study and must agree to employ a highly effective form of birth control through Day 57 
of the study.  
Note: Highly effective forms of birth control are the following: credible history of 
continuous abstinence from heterosexual activity, hormonal contraceptives (oral, 
injectable, implant, patch, and ring), double barrier contraceptives (condom and cervical 
cap or diaphragm, either with spermicide) and intrauterine device. When using 
contraceptives, participants must have been using their current contraceptive for the past 
2 months to be eligible. Adult female participants with documented sterilization via tubal 
ligation or hysterectomy may be enrolled and not be participant to pregnancy testing. 
 

 
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4.3 Exclusion Criteria 
An adult who meets any of the following exclusion criteria at screening will not be eligible for 
randomization in the study: 
1. Use of any investigational medicinal product within 90 days prior to randomization or planned 
use of such a product during the period of study participation. 
2. Adults who have previously been vaccinated against S. pneumoniae. 
3. History of microbiologically confirmed invasive disease caused by S. pneumoniae. 
4. History of allergic disease (including angioedema) or history of a serious reaction to any prior 
vaccination or known hypersensitivity to any component of the study vaccines, including 
PEG. 
5. Any abnormal vital sign deemed clinically relevant by the PI. 
6. Acute illness at time of randomization (moderate or severe) and/or fever (body temperature 
of ≥ 38.0°C) see note below. 
a. Note: A minimum of 48 hours following a documented fever must pass before the 
participant can be vaccinated.  
7. History of any non-study vaccine administration within 14 days of study vaccine 
administration. 
8. No planned vaccines until after Day 29 (Visit 3). 
9. Chronic administration (defined as more than 14 consecutive days) of immunosuppressant or 
other immune modifying drugs prior to the administration of the study vaccine (and within 
the 6 months prior to administration of the study vaccine), including the use of 
glucocorticoids. The use of topical and inhaled glucocorticoids will be permitted. 
10. Administration of immunoglobulins and/or any blood products within the 6 months prior to 
administration of the study vaccine or anticipation of such administration during the study 
period. 
11. Any medical or social condition that in the opinion of the PI*, may interfere with the study 
objectives, pose a risk to the participant, or prevent the participant from completing the study 
follow-up.  
12. Any screening laboratory test result outside the normal range and with toxicity score ≥ 2, 
unless allowed by the PI, IVT Chief Medical Officer (CMO), and PATH Medical Officer 
(MO).  A participant may repeat each laboratory assessment once during the screening period, 
with the most recent laboratory value being used for evaluation of exclusion criteria. 
13. A positive serologic test for human immunodeficiency virus (HIV)-1 or HIV-2 (HIV 1/2 Ab), 
hepatitis B (HBsAg) or hepatitis C (HCV Ab). 
 
* The term “PI” is used throughout this protocol to refer to either the PI or designee.  

 
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condition, a cautionary statement (“For Human Clinical Trial Use Only”), and the Sponsor’s name 
and address. 
 
5.1.4 Storage 
IVT PCV-25 should be stored 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, CRM197, and PEG) is a contraindication to 
vaccination. 
 
5.2 Prevnar 20TM 
5.2.1 Product Description 
Prevnar 20TM is approved for use in adults in Canada. A single 0.5 mL dose of Prevnar 20™  
contains approximately 2.2 μg of each of S. pneumoniae serotypes 1, 3, 4, 5, 6A, 7F, 8, 9V, 10A, 
11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, 33F saccharides, 4.4 μg of 6B saccharides, all 
conjugated to CRM197 and adsorbed onto aluminum phosphate (0.125 mg aluminum). The 
vaccine is a turbid white suspension. 
 
5.2.2 Manufacturer 
Prevnar 20™ is manufactured by Wyeth Pharmaceuticals, a subsidiary of Pfizer. 
 
5.2.3 Presentation and Formulation 
Prevnar 20™ is supplied in a single dose 0.5 mL glass pre-filled syringe (PFS) with a plunger stopper 
and protective tip cap. It will be labeled with the following minimum information: name of the 
medicinal product, route of administration, expiry date, lot number, and dose volume. 
 
5.2.4 Storage 
Prevnar 20™ should be stored between 2°C and 8°C. It must not be frozen. 
 
5.2.5 Potential Safety Risks 
Hypersensitivity to any component of the vaccine (including diphtheria toxoid and CRM197) is a 
contraindication. For Prevnar 20™, in adults 18 years of age and older, the most commonly reported 
solicited adverse reactions (>10%) were pain at the injection site, muscle pain, fatigue, headache, 
and arthralgia. Additionally, injection site swelling was also reported (>10%) in adults 18 through 
59 years of age. 
 

 
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5.3 Vaccine Storage, Transport, and Temperature Monitoring 
The temperature of study vaccines will be monitored during shipment and storage at the 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 the site, all vaccines will be stored at 2°C to 8°C in dedicated refrigerators that are 
locked, and not accessible to unauthorized personnel.  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.  
 
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 PATH and 
IVT, Inc. who will advise the unblinded study staff of the action to be taken based on the magnitude 
and duration of the temperature deviation. All vaccine accountability procedures, including cold 
chain monitoring will be documented and are the responsibility of the unblinded study personnel. 
 
5.4 Dose Preparation and Administration 
Appropriately trained, unblinded study personnel will be responsible for preparing study vaccine 
doses in accordance with the randomly determined assignment, administering the study vaccines, 
and handling all vaccine accountability procedures. Unblinded personnel will not participate in the 
other aspects of the clinical trial after vaccine administration, to help ensure the integrity of the blind 
at the site. The unblinded personnel will not reveal participants’ randomization assignments to the 
participants, or staff associated with the Sponsor, PATH, CRO, or site. Unblinded personnel will 
retrieve a participant’s randomization assignment after being informed by the PI that a participant is 
eligible for randomization. They will prepare the study vaccine based on the participant’s 
randomization assignment in a setting distinct from the study staff, and then the unblinded study 
nurse will administer study vaccine to a participant.  All study personnel will be trained in immediate 
management of AEs following immunization including anaphylaxis. Vaccination will take place in 
a clinical setting in which there is immediate access to the medical personnel, equipment, and 
medications required for emergency resuscitation. 
 
Since IVT PCV-25 and Prevnar 20TM 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 
Pharmacy Manual and Lab Manual for documentation and disposal will be followed. One separate 

 
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multi-dose single vial will be used for each participant randomized to be vaccinated with IVT PCV-
25.  
 
A detailed account of procedures related to preparation and administration of study vaccine will be 
included in the Pharmacy Manual . 
 
• IVT PCV-25 or Prevnar 20TM will be administered to adults as an intramuscular injection into 
the mid-deltoid muscle of the participant’s non-dominant arm.  
Injectable vaccines may be given at other sites if there is a good reason to do so (e.g., local infection, 
or pre-existing swelling).  
 
5.5 Accountability and Disposal 
Following vaccination, the single multi-dose vaccine vial/PFS will be labeled with the participant ID 
of the participant to whom 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 vaccine accountability log on the day of vaccination. All used 
vials/PFS without the needle 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 participants, 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 unblinded 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 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 vaccine 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.  
 

 
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6. STUDY PROCEDURES 
6.1 Recruitment  
Prospective participants will be recruited by study sites by means of 1) print and/or electronic media 
prompting calls by interested individuals to the site, 2) contacting individuals who have previously 
given permission to be contacted about future research studies, and 3) word of mouth. All 
recruitment materials will be approved by the center’s Ethics Committee (EC) /Research Ethics 
Board (REB) prior to use. During recruitment telephone calls, prospective participants will be given 
information (e.g., some elements of inclusion and exclusion criteria) to help them decide whether to 
make an appointment to learn more about the study, and, if interested to take part in the informed 
consent process. 
 
6.1.1 Initial and Continuing Informed Consent 
Informed consent is the process of ensuring that study participants fully understand the purpose of 
the study, procedures, and benefits and risks. The informed consent process continues throughout 
the study. Key study concepts will be reviewed with the participant 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 the Sponsor and/or the PI may affect participants’ decision to 
continue in the trial, such information will be shared, and may be the basis for requiring a new 
consent form to be signed. 
  
The Standard Operating Procedure (SOP) for informed consent will be followed at each study site. 
The participant will review the consent form and have adequate opportunity to discuss the study 
with an investigator or a qualified designee. The consent process will be documented in the 
participant’s source documents and must comply with the International Conference on 
Harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH) 
Good Clinical Practice (GCP) guidelines and any local regulatory requirements. 
 
The consent form will be signed and dated by the person conducting the consent process, the 
participant, and investigator (if applicable per local requirements). A copy of the signed ICF will be 
provided to the participant and the original ICF will be filed with other participant records by the 
study staff. 
 
The ICF will only be completed once at the time of enrollment and prior to screening (unless new 
information necessitating repeat consent is required). 
 
Regardless of duration on study, ongoing willingness of participation will be documented in the 
source documents at each visit. 
 
6.2 Study Visits 
General information:  
• Study-specific procedures for participants are indicated in Appendix 1.  

 
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• Blood sample volumes at designated visits are detailed in Section 7. 
• Participants will be reminded at each visit to contact the study staff to report any SAE 
occurring at any time during the study.  
• Participant ID will be confirmed on day of each visit 
• Scheduling of subsequent visits will occur at each visit. 
6.2.1 Screening  
Once informed consent has been documented, the participant will be considered to be enrolled in the 
trial and may be screened to determine study eligibility. 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, screening procedures will be performed.  
 
The PI will use good clinical judgment in considering a prospective participant’s overall eligibility. 
Individuals who are not deemed eligible will be recorded as screen failures, along with the basis for 
this determination, on the appropriate CRF. Individuals who screen fail may not be rescreened.  
 
At screening, screening positive serum or urine pregnancy tests and laboratory test results outside 
the normal range and with toxicity score ≥ 2 are exclusionary unless allowed by the PI, IVT Chief 
Medical Officer (CMO), and PATH Medical Officer (MO) (see Appendix 4). During the defined 
screening period for adults, prospective participants may return once for repeat assessments to be 
reassessed for eligibility. The last measurement will be taken as the baseline for purposes of analysis.  
 
Unscheduled clinical laboratory measurements may be obtained at any time during the study to 
assess any perceived safety issues. 
 
6.2.2 Randomization and Vaccination Visit General Information  
1. Eligibility for vaccination will be confirmed based on review of inclusion/exclusion 
criteria. Any participant who cannot be vaccinated due to an acute abnormality (e.g., ≥ 
Grade 2 acute illness, or abnormal vital sign deemed clinically relevant by the PI) may 
return once the acute issue has resolved, if deemed appropriate by the PI. A minimum of 48 
hours must have passed after a documented fever (body temperature of ≥ 38°C) before a 
participant can be vaccinated.  
 
2. Pregnancy testing (urine) will be collected from all women of childbearing potential 
(WOCBP). 
 
3. At Visit 1, all participants will be randomized to a vaccine group if eligibility is confirmed 
by the investigator(s). The randomization ID will be recorded by unblinded study staff, who 
will maintain a list documenting the study vaccine assigned and administered to given 
randomization IDs in a secure location that is not accessible to blinded study staff. The 
participant will be referred to by a participant ID for the remainder of the study.  

 
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4. Approximately 50 mL of blood will be obtained by venipuncture for immunogenicity 
testing prior to the administration of the study product. 
5. After the study product is administered, the participant will be observed by blinded study 
staff for at least 30 minutes post-vaccination. 
6. Vital signs and any solicited AEs will be recorded at 30 (+10) minutes post-vaccination. 
See Appendices 2 and 3 for relevant severity grading scales. 
7. During the observation period, the participant will be provided with a ruler, thermometer, 
and memory aid, and given instructions on how to complete the memory aid. The 
participant will be instructed to collect solicited AEs daily for seven days (the day of Visit 
1 and the following six days) by recording them in the memory aid, preferably at 
approximately the same time each day. The participant will also be instructed to record 
unsolicited AEs and concomitant medications on the memory aid.  
8. The participant will be instructed to call the study staff in the event of any severe (Grade 3) 
symptoms, if there is ongoing local or systemic reactogenicity on Day 8, or for any other 
health issues that require medical attention. The PI will assess the need to evaluate such 
events/issues at an unscheduled visit. 
 
6.2.3 Visit 2 General Information 
1. Unsolicited AEs will be recorded, including assessment of relatedness to vaccination, 
severity, and outcome. Ongoing unsolicited AEs will be reviewed. 
2. The completed memory aid will be reviewed with the participant for completeness and 
accuracy. Possible inaccuracies will be clearly documented. 
3. Blood sample obtained for safety labs. 
 
6.2.4 28-Day Post-Vaccination Visit (Visit 3) 
1. Unsolicited AEs will be recorded, including assessment of relatedness to vaccination, 
severity, and outcome. Ongoing unsolicited AEs will be reviewed. 
2. The completed memory aid will be reviewed for completeness and accuracy. Possible 
inaccuracies will be clearly documented. 
3. Approximately 50 mL of blood will be obtained by venipuncture for immunogenicity 
testing. 
4. Pregnancy testing (urine) will be collected from all women of childbearing potential 
(WOCBP). 
 
6.2.5 Six Month Post-Last Vaccination Visits (Visit 4) 
1. Participant will be contacted by telephone 

 
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2. Participant ID will be confirmed. 
3. SAEs since the last visit will be recorded, including any concomitant medications taken for 
the AE. Any ongoing unsolicited AEs will be reviewed. 
4. Participants will exit the study after completion of the Study Exit CRF. 
 
6.2.6 Interim Contacts and Visits 
Interim unscheduled contacts and visits (e.g., unscheduled visits) in between regularly scheduled 
follow-up visits may occur at any time at the request of the participant or as deemed necessary by 
the PI. All unscheduled interim contacts and visits will be captured in the participant’s study records 
and on applicable CRFs. 
 
6.3 Participant Discontinuation Termination 
Participant discontinuation from study procedures prior to completion of the last study visit may 
occur for any of the following reasons: 
• Withdrawal (defined as discontinuation initiated by a participant): Participation in the study 
is strictly voluntary. Participants have the right to withdraw their consent from study 
participation at any time and for any reason, without penalty. The participant may also 
withdraw due to an AE. Non-coercive attempts (e.g., phone calls) will be made to obtain AE 
data according to the schedule of events if the participant is willing to provide. 
• PI-initiated: The PI may, at their discretion, discontinue a participant from the study if it is 
considered to be in the participant’s best interest to do so (e.g., for safety concerns), or if the 
participant does not comply with the study requirements.  
• Lost to follow-up: For participants who fail to attend scheduled visits, study staff are to make 
at least three attempts to contact the participant prior to considering the participant as lost to 
follow-up. These attempts should be recorded in the source documents. 
• Sponsor-initiated: For example, if the Sponsor is obliged to end the study for administrative 
or any other reason, such as a recommendation by the DSMB based upon safety review. 
Participants who discontinue prior to first administration of study vaccine will be replaced, whereas 
those withdrawn after first administration of study vaccine will not be replaced. 
 
The reason for and date of participant discontinuation will be recorded in the relevant CRF. Before 
concluding the reason for the participant’s discontinuation from the study, the PI should make every 
effort to investigate whether an AE may have been related to the participant’s discontinuation from 
the study. For participants considered lost to follow-up, the discontinuation date for the participant 
to be captured on the Study Exit CRF page is the date of the participant’s last completed study visit. 
 
In the event of participant discontinuation from the study, reasonable efforts should be made to 
conduct the following procedures (unless participant consent to do so has been withdrawn): 
• Update participant contact information. 

 
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• Review the memory aid if still in use prior to discontinuation. 
• Update any AEs that remained ongoing at the time of the participant’s last visit prior to 
discontinuation. 
• Collect any new reportable AEs and concomitant medications since the participant’s last visit, 
based on the protocol-defined reporting period at the time of discontinuation.  
• Perform a targeted PE to evaluate any newly reported AEs since the participant’s last visit.  
 
6.4 Concomitant Medications and Treatments 
Concomitant medications will be recorded for any AE with onset ≤ 28 days post-vaccination and for 
any SAEs that occurs throughout the study. Details on concomitant medications to be recorded 
include the generic and/or trade name, over-the-counter or herbal, indication, dosage, regimen, route 
of administration, and start and end dates of the medication.  
 
The following concomitant medications are prohibited during the study; however, they must not be 
withheld by the treating physician if clinically indicated: 
• Any investigational drug/vaccine other than the study vaccines  
• Pneumococcal vaccine other than the blinded study vaccine 
• Planned vaccines (e.g., influenza, etc.) 
• Chronic administration (defined as more than 14 days) of immunosuppressant or other 
immune modifying agents. 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 
Use of any prohibited medication must be recorded in the CRF. Whether a participant who uses a 
prohibited medication will be included in the per protocol (PP) population will be evaluated on a 
case-by-case basis. 
 
6.5 Emergency Unblinding Procedure 
In the event of a medical emergency, the PI and/or site investigator may require that the blind be 
broken for the participant experiencing the emergency when knowledge of the participant’s 
treatment assignment may influence the participant’s clinical care. Every effort will be made not to 
unblind the participant unless it is considered absolutely necessary for the welfare of the participant. 
Prior to unblinding, the investigator is encouraged (to the extent possible, without jeopardizing the 
participant’s health) to contact the Sponsor (or designee) to discuss the decision to break the blind. 
 
The PI and/or site investigator will be expected to provide a rationale for the necessity of unblinding, 
based on the expectation that knowledge of the participant’s treatment assignment will have a 
meaningful impact on the participant’s medical care in the short term. If a participant’s treatment 
assignment is unblinded, the participant will remain in the study and continue with protocol-defined 

 
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study visits and procedures, unless there is another reason for participant discontinuation. The 
decision to unblind will be communicated to all regulatory bodies as required. At the end of the 
study, documentation of all unblinded participants (and the rationale for unblinding) will be 
incorporated into the trial master file. 
 
6.6 Management of Pregnancy 
All WOCBP will be monitored for the use of adequate contraception until completion of Visit 3. At 
Visit 3, WOCBP will have a pregnancy test and will be monitored for pregnancy until end of study 
Visit 4.  
 
Any WOCPB who become pregnant during the study will be followed to term, and the following 
information will be gathered in regard to the pregnancy outcome: date of delivery and health status 
of the mother and child, including the child’s gender, height, and weight. Complications and/or 
abnormalities must be reported, including any premature terminations. A pregnancy is reported as 
an AE or SAE only when there is suspicion that the investigational product may have interfered with 
the effectiveness of contraception or there was a serious complication in the pregnancy, including a 
spontaneous abortion or an elective termination for medical reasons. Pregnancies that occur up to 
Visit 3 (Day 29) will be included in the interim analysis (primary analysis) and the CSR, and any 
pregnancies that occur after Day 29 through Visit 4 and the outcome of pregnancies will be reported 
to the Sponsor as part of the safety management plan. 
 
The PI is required to notify the Sponsor (or designee) within 24 hours of knowledge of a pregnancy. 
 
6.7 Clinical Procedures 
6.7.1 Vital Signs 
• Body temperature will be measured in degrees Celsius (recorded to the nearest 0.1 degree) by 
oral (sublingual) thermometer following at least 20 minutes of avoidance of food and drink.  
• Respiratory rate will be measured in breaths per minute. 
• Heart rate will be measured in beats per minute by automated device or manually, and not on 
the arm used for study vaccination in adults if an arm cuff is used. 
• Blood pressure will be measured in millimeters (mm) of mercury by automated device or 
manually. 
• Vital signs will be graded according to the toxicity grading scale in Appendix 3. 
6.7.2 Height and Weight 
• Height will be measured in centimeters (cm) and recorded to the nearest 1 cm. 
• Weight will be measured in kilograms (kg) and recorded to the nearest 0.1 kg. 
6.7.3 Complete Physical Examination 
• A complete physical examination will include head, eyes, ears, nose, oropharynx, neck, chest 

 
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8.2 Definitions 
8.2.1 Adverse Event  
An AE, as defined in this protocol, is any untoward medical occurrence in a participant administered 
an investigational vaccine and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an investigational 
product. An AE will be documented as to whether or not it is considered to be related to study 
vaccine. An AE includes, but is not limited to, the following: 
• An intercurrent illness or injury during the course of the study after receipt of an 
investigational product 
• Any clinically significant worsening of a preexisting condition after receipt of an 
investigational product 
A medical condition, in the form of signs, symptoms, disease, or laboratory or 
psychological/physiologic observations, occurring in a participant from whom consent has been 
obtained but prior to having received a study vaccine is not classified as an AE but will be captured 
and recorded on the medical history form. 
 
8.2.2 Solicited AE  
Solicited AEs are pre-specified local (injection-site specific) and systemic AEs that occur relatively 
more frequently, or are known to be associated with vaccination, and which are monitored actively 
as potential indicators of vaccine reactogenicity. Investigators will not be required to assess causality 
of solicited AEs if the onset is during the solicitation period. 
The following specific solicited AEs will be monitored: 
 
Local solicited AEs: 
• Pain and/or tenderness 
• Swelling  
• Redness 
 
Systemic solicited AEs: 
• Fever (defined as body temperature ≥ 38°C) 
• Headache 
• Fatigue  
• Myalgia 
• Arthralgia 
• Rash 

 
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8.2.3 Unsolicited AE 
An unsolicited adverse event is any AE reported spontaneously by the participant, observed by the 
study staff during study visits, or those identified during review of medical records or source 
documents. Solicited AEs with an onset after the 7-day solicitation period will be considered 
unsolicited AEs. In the absence of a diagnosis, abnormal physical examination findings, or abnormal 
clinical safety laboratory test results that are assessed by the investigator to be clinically significant 
will be recorded as an AE. 
 
8.2.4 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 in the situation where there is an AE. A period 
of observation at a clinical trial site 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 a 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. 
• 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 that may not be immediately life-

 
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Note: solicited reactogenicity events will not be judged for relatedness. 
  
8.2.7  Assessment of Outcome of AE 
The outcome of the AE will be assessed and recorded as per the following categories: 
• Ongoing. 
• Recovered/resolved. 
• Recovered/resolved with sequelae. 
• Fatal. 
• Unknown. 
 
8.3  AE Recording and Reporting 
All AEs will be recorded and reported after receipt of each study vaccine through 28 days post-
vaccination (Visit 3). SAEs will be recorded throughout the entire study period.  
 
The study staff must completely and promptly record each AE in the source documentation and on 
the relevant CRF, regardless of relationship to the vaccine administered or 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. AEs will be classified by the Medical Dictionary for Regulatory 
Activities (MedDRA) term and by severity, relatedness, and outcome. 
 
 
Reporting of AEs will follow the regulatory guidelines of Health Canada, the local ethics committees 
(ECs), WCG IRB, and the PATH Office of Research Affairs (ORA) in regard to requirements, 
processes, and forms. 
 
8.4 SAE Reporting 
If an AE is classified as serious, 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 (or designee) to initiate any DSMB evaluation, and any 
additional reporting requirements. The SAE submission will follow the regulatory guidelines of 
Health Canada, the local ECs, WCG IRB, and PATH ORA in regard to requirements, processes and 
forms. SAEs deemed related to study vaccine that are ongoing at the time of last participant last visit 
(LSLV) will continue to be followed until 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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8.4.1 Unanticipated Problems 
Unanticipated problems will be submitted to Health Canada, the local ECs, WCG IRB, and PATH 
ORA 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 (or designee). Follow-up reports will be submitted as soon as 
additional information becomes available. 
 
9. SAFETY MONITORING 
The PI will be responsible for continuous monitoring of all study participants’ safety. In case of 
urgent need, participants will have the means to get in contact with study staff at any time (24 hours 
per day). The PI will also be available by cell phone 24-hours per day for medical emergencies. 
Weekly notifications of group-blinded Grade 3 or greater AEs will be sent to the PI, site 
investigators, CRO Medical Monitor, PATH Medical Officer (MO), and Inventprise’s Chief Medical 
Officer (CMO) for situational awareness and ongoing safety assessment.  
 
9.1  Data Safety Monitoring Board 
A DSMB, composed of at least three independent members with expertise in vaccine clinical trials, 
will be convened to provide safety oversight. The DSMB will review unblinded safety and 
tolerability data after the last participant completes the 28-day follow-up visit (V3).  
 
The DSMB will also meet on an ad hoc basis if a study pause rule is met (Section 9.2.) or upon the 
recommendation from the PI, PATH MO and Inventprise Inc.. In the event of a study pause, events 
will be unblinded, and no further enrollment will occur, and no study product will be administered 
until the DSMB approves lifting the pause.   
 
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 CMO (or designee), PATH, 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 situations, the Sponsor will inform Health Canada and 
local ECs of the Sponsor’s perspective, and any changes to the trial.  
 
The PI, PATH MO may also seek additional guidance from the DSMB as dictated by the occurrence 
of certain events that do not warrant a study pause.  
 
The composition, responsibilities, and procedures of the DSMB will be detailed in the DSMB 
Charter. 
 

 
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9.2  Pause Rules 
The DSMB will be convened if it is established that any of the following study pause rules has been 
met during the conduct of the trial:  
 
• Rule 1: 1 or more participant experiences any vaccine-related Grade 4 AE or any vaccine-
related SAE.  
• Rule 2: 1 or more participant experiences Grade 3 or greater local reaction classified as related 
to vaccination by the PI: ulceration, necrosis, or sterile abscess at the injection site requiring 
drainage or surgical intervention.  
Rule 3: > 5 participants in the same group inclusive of participants from Groups A, B, C, and 
D that experience the same Grade 3 (or greater) AE or laboratory abnormality attributed 
(related) to study vaccine. In the case of fever and pain at the injection site, the episode must 
last longer than 48 hours, and, in the case of fever, be confirmed by the PI without evidence 
of other medical causes. 
9.3  Protocol Deviation 
A protocol deviation is any nonconformity with the clinical trial protocol, GCP, SSP and site SOP 
requirements, or departure from planned study procedures or applicable regulatory requirements. 
Protocol deviations  may be either on the part of the participant or the site staff/PI. 
 
Protocol deviations are considered critical quality events if they significantly impact the 
completeness, accuracy, and/or reliability of the study data, or if they may significantly affect a 
participant's rights, safety, or well-being. Critical quality events must be reported to PATH within 
24 hours of awareness. Examples of critical quality events may include failure to obtain informed 
consent, failure to report SAEs, enrolling participants in violation of key eligibility criteria designed 
to ensure a specific participant population or failing to collect data necessary to interpret primary 
endpoints, as this may compromise the scientific value of the trial. 
 
When appropriate, corrective actions and preventive actions will be developed by the site to address 
critical quality events or deviations. These practices will be consistent with ICH E6 Guidelines. 
 
10. DATA HANDLING AND RECORD KEEPING 
The study monitors will visit the site at regular intervals, as per the Monitoring Plan, and perform 
pre-agreed source data verification of the data recorded in the 21 Code of Federal Regulations Part 
11-compliant electronic data capture (EDC) system against the source documents available at the 
site. In addition, missing data forms and fields will be queried by electronic edit checks or through 
manual review of the data by the data management team. It is the PI’s responsibility to ensure the 
accuracy, completeness, and timeliness of the data reported in the participant’s EDC records and any 
supporting documentation. Study monitors will closely evaluate informed consents, 
inclusion/exclusion criteria, data entry timeliness, and visit dates and windows to ensure integrity of 
the study is maintained. 

 
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Any data discrepancies generated by the review will be flagged for the site staff to provide a 
satisfactory resolution. The data management team will review all the data discrepancy responses 
by the site to ensure the correctness of data. The medical history events and the AEs will be coded 
using MedDRA dictionary Version 24 or later and the concomitant medications will be coded using 
the WHO Drug Dictionary Version 2021 Sep 1 or later. After participants have completed all follow-
up visits, and data coding and resolution of all the queries has been completed in the database, the 
database will be declared to be complete and accurate and will be locked for final statistical analysis 
of primary and secondary endpoints. 
 
10.1 Case Report Form Development and Completion 
Based on the final protocol of the study, a comprehensive set of CRFs will be prepared to capture 
all the relevant data required for analysis and reporting. This study will utilize a 21 CRF Part 11-
compliant EDC system such that the entire study data can be maintained in a secure electronic 
system. 
 
All study data will be collected by the clinical study staff using designated source documents and 
will be entered in the EDC system in an anonymized form. The study database will identify study 
participants by a unique study identification number(participant ID) and will not contain any 
identifying information such as name, address, or personal contact information, or any other 
regional/provincial/national identification number. CRFs will be reviewed by the clinical team who 
are responsible for ensuring that they are accurate and complete.  
 
A thorough Data Management Plan (DMP) and corresponding database compliant with ICH 
requirements will be developed by the CRO. The appropriately trained site personnel will ensure 
that the study data recorded in the EDC system is verifiable with the source documents available at 
the site. To ensure that data are entered in a timely fashion so as to monitor safety of the study, it is 
expected that sites will maintain data entry within the timeframe specified in the study DMP.  
 
The study sites will maintain the source documents for each study participant. 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. 
 
10.2 Record Archival 
10.2.1 Archiving Data at Study Site 
Study sites 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 participants. Sites 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. 
After completion of data coding and resolution of all the queries in the database, the database will 

 
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be declared to be complete and accurate and will be locked for final statistical analysis and made 
available to the Sponsor for long-term storage in a master file. 
 
10.2.2 Data Storage and Archival 
The sites will maintain an Investigator Site File, which will be used to file the IB, protocol, drug 
accountability records, correspondence with the EC, Sponsor (or designee), 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 two 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 two years have elapsed since the 
formal discontinuation of clinical development of the study product. These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements or by an 
agreement with the Sponsor. The documents will be archived either at sites 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. Participants’ medical 
records and other original data will be archived in accordance with the local regulations of the 
investigational sites. 
 
10.3  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 the Sponsor and all data and information generated by the sites as part 
of the study (other than a participant’s medical records) will be kept confidential by the PI and other 
study staff. This information and data will not be used by the PI or other study personnel for any 
purpose other than conducting the study. 
 
11. STATISTICAL CONSIDERATIONS 
11.1 Overview and General Considerations 
This is a multicenter, randomized, active-controlled, observer-blind, Phase 2 trial in healthy 
pneumococcal vaccine-naïve male and non-pregnant female adult participants of age 18-49 years 
old.  
 
No statistical hypothesis tests between treatment groups are planned in this study. All analyses for 
safety and immunogenicity data will be descriptive. All statistical analyses will be performed using 
SAS® software Version 9.2 or later. 
 

 
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11.4 Definitions of Populations to be Analyzed 
11.4.1 Enrolled Population 
All participants who provide written informed consent, regardless of the participant’s screening, 
randomization, and treatment status in the study. 
 
11.4.2  Exposed Population 
All participants in the enrolled population who were randomized and received one vaccination dose 
(i.e., were accrued). 
 
11.4.3  Safety Analysis Population 
All participants in the exposed population for whom any safety data is available. All safety analyses 
will be performed using this population. The denominators for different safety endpoints may vary 
according to the number of participants with available data for the specific endpoint. For instance, 
the solicited local and systemic AE endpoint will be based only on those who have the corresponding 
CRF data regardless of other safety data. Treatment groups for safety analysis will be assigned 
according to the actual treatment received. 
 
11.4.4 Full Analysis Population 
All participants in the exposed population for whom any post-study vaccine administration 
immunogenicity results are available. An immunogenicity analysis will also be performed using this 
population. The analysis based on this population will serve as supportive results for all secondary 
immunogenicity objectives. Participants in the full analysis (FA) population will be analyzed as 
randomized, i.e., according to the treatment group to which participants were assigned. 
 
11.4.5  Per Protocol Population 
All participants in the FA population who were correctly vaccinated per randomization and have no 
protocol deviations that are determined to potentially interfere with the immunogenicity assessment 
of study vaccine. 
 
The PP population will serve as the primary analysis population for the (secondary) immunogenicity 
analysis. The population will be adapted by assay; that is, a participant may be included in the PP 
population for IgG concentrations but not for OPA. The criteria (e.g., intake of prohibited medication 
expected to influence the immune response) for exclusion of participants from the PP population 
will be established before database lock for the final analysis and will be based on a blinded review 
of the data. 
 

 
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11.5 Estimands and Analytical Methodology 
11.5.1 Estimands 
The estimand corresponding to each primary and secondary objective is described in the table in 
Section 2. 
 
For the primary safety estimand, receipt of concomitant medications will be handled with treatment 
policy strategy, which means that participants who take concomitant medications will be included 
in the safety analysis.  The estimates will be calculated based on the safety analysis population. 
 
For the estimand to evaluate the immunogenicity objective, receipt of immune-modifying 
medications/vaccines/treatments will be handled according to principal stratum strategy, which 
means participants who receive immune-modifying medications/vaccines/treatments will not be 
included in the primary immunogenicity analysis. The corresponding estimates will be computed 
based on both PP and Full Analysis populations, to examine robustness of the estimates.  will be 
based on both PP and Full Analysis populations, to examine robustness of the estimates. 
Immunogenicity results that are below lower limit of quantification (LLOQ) will be set to half of 
LLOQ (LLOQ/2) in the analysis. Immunogenicity results above upper limit of quantification 
(ULOQ) will be set to ULOQ in the analysis. 
11.5.2 Descriptive Methodology 
When appropriate, continuous data will be summarized using descriptive statistics such as number 
of participants with non-missing values, mean, standard deviation (SD), median, minimum, and 
maximum. Categorical data will be presented using the percentage of participants in each category. 
A two-sided 95% CI will be provided for estimates, as appropriate. Individual participant data will 
be provided in listings. 
 
11.5.3 Analysis Sequence 
Upon completion of the Day 29 Visit 3 from all 220 participants, the CRO will prepare an unblinded 
safety report for review and approval by the DSMB to continue the study as planned.  
 
The first analysis (interim) includes the dataset of the safety from all participants having completed 
the Day 29 visit, and the serotype-specific IgG responses from approximately 50% or more of the 
participants having completed the day 29 visit, in order to provide the Sponsor an initial indication 
of the comparative immunogenicity among the three different IVT PCV-25 formulations and to 
compare to the immune responses elicited in participants vaccinated with Prevnar 20TM.  
 
The second analysis includes the serotype-specific OPA results (individual participant ID-masked) 
and unblinded group-level results at baseline and Day 29 visit from all participants after OPA data 
become available.  
 
For the first and second analyses, an independent CRO statistician and programmer team (whose 
responsibilities are otherwise limited to supporting the DSMB) will be unblinded to conduct the 

 
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analyses. Study unblinding will be conducted and documented in accordance with relevant CRO 
SOPs. The independent CRO statistician and programmer team will provide the unblinded group-
level safety and immunogenicity report directly to the Sponsor, its consultants, PATH, the Bill & 
Melinda Gates Foundation, and the site investigators.   
 
The independent CRO statistician and programmer team will provide the individual-level 
(participant ID masked) serotype-specific IgG and OPA responses to the Sponsor, its consultants, 
PATH, and the Bill & Melinda Gates Foundation. All other study personnel at the sites will remain 
blinded to individual treatment assignments until all participants complete Visit 4 and the database 
is locked.  
 
When all safety data through Visit 4 from all 220 participants have been collected following the 
adult LSLV (Visit 4), the database will be cleaned and locked, and a final analysis including all late 
safety events and the complete IgG and OPA immunogenicity results from all participants will be 
performed. Detailed statistical analyses including tables, listings, and figures shells will be provided 
in a separate statistical analysis plan (SAP) which will be finalized prior to the interim analysis.  
 
11.5.4 Analysis of Demographic and Baseline Characteristics 
Demographics and baseline characteristics, including age, height, weight, sex, race, and ethnicity 
will be summarized for both the exposed and per protocol populations by treatment group. 
 
For the exposed population, the number and percentage of participants with medical history will be 
tabulated by MedDRA System Organ Class (SOC), Preferred Term (PT) and treatment group. Using 
the WHO DD, the number and percentage of participants with concomitant medications will be 
tabulated by anatomical therapeutic chemical (ATC) classification, preferred drug name and 
treatment group.  
 
Summaries of participant disposition will be prepared for all participants, including the number and 
percent enrolled, screened, randomized, and administered study vaccine, as well as a Consolidated 
Standards of Reporting Trials (CONSORT) diagram describing study participation and 
discontinuation. The reasons for screen failures and discontinuations will be summarized and listed. 
 
A summary and listing of visit attendance will be prepared, in addition to a summary and listing of 
study vaccine administration and sample collection/availability for each sample. 
 
11.5.5 Analysis of Primary Objective 
All safety analyses will be conducted in the safety analysis population, according to the treatment 
received. Frequencies and percentages of participants with any solicited AE, solicited local AE, 
solicited systemic AE, unsolicited AE, clinical safety laboratory abnormality,  SAE will be tabulated 
along with an exact two-sided 95% CI computed via the Clopper-Pearson method. The denominators 
for percentages will be the number of participants with the data available for analysis for the given 
endpoint. Participant-level data listing will be provided. 

 
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Solicited local and systemic AEs: All solicited AEs reported during 7 days post vaccination will be 
summarized according to defined severity grading scales. Frequencies and percentages of participants 
experiencing each solicited AE will be presented by treatment group and severity.  
 
Hematological and biochemical measurements: For clinical safety laboratory data collected at 
screening and 7 days post-vaccination, individual Hgb, WBC count, Plts, AST, ALT, and creatinine 
values will be presented as number and percentage of participants out of range (above and below 
normal range as appropriate) and tabulated by toxicity grading and study group. In addition, 
summaries of changes from baseline will be presented. Clinically significant laboratory abnormalities 
will be considered an AE and relatedness will be reported. 
 
Unsolicited AEs: All unsolicited AEs with onset occurring during the first 28 days post vaccination 
will be assessed for severity and relatedness to study product by the PI. Frequencies and percentages 
of participants with unsolicited AEs will be summarized by the SOC, PT, and treatment group. 
Similar summaries will be provided for severity and relatedness of the unsolicited AEs. 
 
SAEs: All SAEs through Visit 4 (Day 169) will be recorded and summarized. Frequencies and 
percentages of participants with SAEs and relatedness to study vaccine of the events will be 
summarized by SOC, PT, and treatment group.  
 
When an AE occurs more than once for a participant, the participant will be only counted once for 
the corresponding PT according to the maximum severity of the events. A summary table will be 
prepared for unsolicited AEs comprised of the following categories: 
• Unsolicited AEs 
• Related unsolicited AEs 
• SAEs 
• Related SAEs 
• SAEs leading to death 
• Unsolicited AEs leading to participant discontinuation 
 
All reported AEs that start after vaccination will be tabulated. If a given disease/condition is already 
reported as ongoing at the first visit on the medical history form, it will be counted and tabulated as 
an AE only if it worsens after vaccination with the study vaccines.  
Onset day, duration, and outcome of unsolicited AEs will be summarized by treatment group. For 
SAEs, seriousness criteria will be summarized as well. 
 

 
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11.5.6 Analysis of Secondary Objectives 
The analysis of immunogenicity will be performed on the PP population as the primary analysis and 
the full analysis population as a secondary analysis. 
 
Immunogenicity data will be descriptively analyzed. Serotype-specific IgG antibody responses will 
be measured at baseline (V1), and 28 days after study vaccination (V3).  
 
• GMC with two-sided 95% CIs  
• GMFR from baseline with two-sided 95% CI  
Serotype-specific functional antibody responses will be measured by OPA and summarized at 
baseline (V1) and 28 days after study vaccination (V3),  
• 
GMTs with two-sided 95% CIs, 
• GMFR from baseline with 95% CI 
 
GMCs and GMTs will be calculated for each treatment group along with their two-sided 95% CI, by 
exponentiating the corresponding log-transformed mean and their two-sided 95% confidence limits.  
 
The ratio of the GMC/GMT between IVT PCV-25 formulations
 to 
Prevnar 20TM and corresponding two-sided 95% CI will be provided. The log-transformed antibody 
responses will be used to construct a mean difference between the treatment groups and the 
comparator vaccine, Prevnar 20TM and its two-sided 95% CI using the two-sample t-test method. The 
mean difference and corresponding 95% CI will be back-transformed to obtain the GMC/GMT ratio 
between the two groups and corresponding 95% CI. An adjusted GMC/GMT ratio between the 
treatment groups will be also provided along with its two-sided 95% CI. The log-transformed 
antibody responses will be used to compute a mean difference between the two groups and 
corresponding two-sided 95% CI using analysis of covariance (ANCOVA) with log-transformed 
baseline antibody responses as a covariate. Other variables, such as age and sex, will be evaluated for 
inclusion in the ANCOVA model as well. The mean difference and its 95% CI will be exponentiated 
to obtain the adjusted GMC/GMT ratio between the two groups and corresponding 95% CI.  
 
GMFRs and corresponding two-sided 95% CIs will be computed for each treatment group. The mean 
difference in the log-transformed antibody responses between 28 days post vaccination and baseline 
and corresponding two-sided 95% CI will be calculated using the paired t-test method and then back-
transformed to obtain GMFR and its 95% CI. The two-sample t-test method will be used to obtain 
the two-sided 95% CI of the ratio of GMFRs between the study groups. Additionally, the distribution 
of the titers will be summarized using reverse cumulative distribution curves. 
 
A secondary ad hoc analysis that combines the immunogenicity responses (IgG) from the Prevnar 
20TM comparator vaccine participants in the Phase 1 (NCT05540028) trial ( n = 30 participants) will 
be added to the first 50% of participants (n = 20) in this trial and expressed as the ratio of the GMC 

 
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between of IVT PCV-25 formulations
 and Prevnar 20TM in order to 
increase the precision in detecting relative serotype-specific differences between IVT PCV-25 and 
the comparator vaccine. The ad hoc analysis will occur at the time of the interim analysis. 
 
11.6 Multiplicity 
Due to the descriptive and exploratory nature of the analyses, no adjustment for multiplicity will be 
performed. 
 
11.7 Handling of Participant Discontinuations and Missing Data 
Missing immunogenicity data will not be imputed and will be analyzed as if they were missing 
randomly. Missing reactogenicity data will not be imputed. Missing AE dates will be imputed, and 
corresponding rules will be specified in the SAP. No other missing safety information will be 
imputed. Over the study period, the frequency and percentage of participants who discontinue from 
the study will be provided by treatment group. All participants who discontinue post-randomization 
will be further described regarding their time to and their reasons for discontinuation. For 
participants who discontinue from the study, their data collected before discontinuation will be 
analyzed under the analysis populations as applicable. If missing data rate for immunogenicity 
measures is higher than 20% or any patterns are spotted in the missing data, a sensitivity analysis 
will be outlined in the SAP to evaluate the robustness of the analysis results. 
 
12. QUALITY ASSURANCE AND QUALITY CONTROL 
12.1  General Considerations 
The study will be conducted in full compliance with the protocol and ICH GCP to provide public 
assurance that the rights, safety, and well-being of study participants are protected, and that the 
clinical study data are credible. To ensure quality and standardization, SSPs will be developed for 
key protocol procedures . 
 
All clinical testing sites in Canada will conduct the study guided by the protocol, SSPs, applicable 
site SOPs, and other written guidelines. Routine operational checks to verify that critical protocol 
requirements and procedures are executed correctly at the time the work is being performed will be 
conducted.  
 
Prior to study initiation, the Sponsor and the designated CRO will conduct training on the protocol 
and applicable SOPs for the study staff. 
 
The investigational sites will provide direct access to all study-related documents, source 
data/documents, and reports for monitoring and auditing by the Sponsor, and inspection by 
regulatory authorities. 
 

 
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12.2  External 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. As appropriate and informed by risk 
assessment, remote monitoring activities may be considered in place of or to supplement onsite 
monitoring.  
 
During the course of the study, the monitor will assess site activities 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 participant study 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 described in the Clinical Monitoring Plan. 
 
To ensure the quality of clinical data for all participants, a clinical data management review will be 
performed on participant data received by the CRO. During this review, participant data will be 
checked for consistency, omissions, and any apparent discrepancies. In addition, the data will be 
reviewed for adherence to the protocol and GCP. These reviews may include analysis of data quality 
(e.g., missing or inconsistent data, outlier data), identify data trend not easily detected by onsite 
monitoring, and performance metrics (e.g., screening or withdrawal rates, eligibility deviations, 
timeliness and accuracy of data submission). To resolve any questions arising from the clinical data 
management review process, data queries and/or site notifications will be sent to sites for resolution 
as soon as possible and within the time frame described in the DMP; all queries must be resolved 
prior to database lock. 
 
12.3  Independent Auditing 
Sponsor 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 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 
study sites for their adherence to the clinical study protocol and GCP guidelines and applicable 
regulatory requirements. 
 
12.4  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 (or designee) 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 

 
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correspondence that may affect the review of the current study or their qualification as PI in clinical 
studies conducted by the Sponsor. The Sponsor will provide any needed assistance in responding to 
regulatory audits or correspondence. 
 
13. OBLIGATIONS AND ROLES OF THE SPONSOR, PI, AND STUDY PERSONNEL 
This study will be conducted according to GCP as well as in accordance with Health Canada 
regulations. The Sponsor will ensure the trial is conducted in compliance with the protocol, GCP, 
and regulatory authority requirements. The Sponsor (or designee) 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 awareness) of any other safety 
concerns which could influence decisions regarding informed consent, enrollment and vaccination 
in this trial. 
 
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 (or 
designee) 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 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 participant. 
 
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. 
 
14. ETHICAL CONSIDERATIONS AND INFORMED CONSENT 
The study will be performed in accordance with ICH Guidelines for GCP E6 R2 (2018), Directive 
2001/20/EC, which are consistent with the Ethical Guidelines outlined in the Declaration of Helsinki 
(2013), thus ensuring protection of the participants. The study will commence only after receipt of 
a favorable opinion from the ECs listed in this protocol and Health Canada. 
 
14.1  Ethical Review 
Ethical review of this study for the clinical site will be conducted by the local site ECs and WCG 
IRB. The PI is responsible for obtaining approval from the local site ECs, which will review and 
approve the protocol, the informed consent form, and any recruitment materials (advertising or 
informational material). PATH is responsible for obtaining approval from WCG IRB. This includes 
any modifications to these documents prior to, or during the study. Any change to the protocol or 
informed consent form must be reviewed and approved prior to implementation, except when 

 
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necessary to eliminate apparent immediate hazard to study participants. In such a case, the change 
must be later documented in an amendment and reported to the ECs as soon as possible. When a 
change involves only logistical or administrative aspects of the study, formal EC approval may not 
be required, but such amendments shall still be submitted to the ECs for information purposes, and 
the PI must provide the Sponsor with written confirmation that such logistical or administrative 
amendments have been submitted to the local ECs. The PI is also responsible for obtaining 
continuing review throughout the duration of the study in accordance with existing regulations. 
 
14.2 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the 
study and continues throughout the participant’s participation in the study. Before any study-related 
activities, the delegated study staff must ensure that the potential participant is fully informed about 
the objectives, procedures, potential risks, and potential benefits of study participation. 
 
Potential subjects will be provided with the EC-approved ICF, allowed ample time to read the 
consent form, encouraged to ask questions about the study, have their questions answered and then 
be given time to decide about participation in the study. It will be emphasized that participation is 
voluntary and that they have the right to decline or discontinue at any time without giving any reason 
and without compromising rights in any way. 
 
The delegated study staff must obtain the participant’s voluntary, signed and dated ICF before any 
study-related procedures are performed. Study staff must document the informed consent process. 
The original, signed ICF must be kept in the site study file. A copy of the informed consent document 
will be given to the participant for their records. 
 
14.3  Study-Related Injury 
Participants will be informed that if they experience any severe illness, they should contact study 
staff as soon as possible, and they may be required to be evaluated at the study site depending on the 
AE. If participants seek medical care outside the study, they should inform the health care provider 
of their participation in this study. The Sponsor will cover all costs of care for study-related injury. 
 
The Sponsor and implementing partner will both obtain and maintain appropriate and commercially 
reasonable amounts of insurance, including commercial general liability insurance, and product and 
completed operations liability insurance, including coverage for the clinical trial. 
14.4  Risk/Benefit 
It is expected that IVT PCV-25 will be well-tolerated based on the tolerability profile of the licensed 
PCVs and safety data from the Phase 1 CVIA 096 study. There are certain symptoms and signs, 
systemic or injection site, which have historically been associated with immunization generally, and 
if they do occur, usually are of mild or moderate intensity and transient in nature. Consequently, in 
early clinical trials of investigational vaccines, these symptoms and signs are typically considered 

 
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as risks and are solicited as potential AEs in the first week following immunization. In this trial, the 
solicited injection site AEs include pain (or tenderness), swelling, and erythema.  
 
The solicited systemic AEs for the adult cohort are fever, headache, fatigue, myalgia, arthralgia,  and 
rash.  
 
It is expected that IVT PCV-25 will have an adequate safety profile based on the safety profile of 
the licensed PCVs. Since there may be unknown risks associated with the IVT PCV-25 vaccine, all 
participants will be monitored for any unsolicited AEs for 28 days following study vaccination and 
for any SAEs for the entire study period.  
 
Hypersensitivity reactions may occur following the administration of any vaccine, including licensed 
vaccines, which in rare circumstances may be life-threatening. All participants will be informed in 
the ICF of this possibility following study vaccine administration and will be observed for a 
minimum of 30 minutes following study vaccine administration. Appropriate emergency medical 
treatment will be available in case of severe immediate reactions, such as anaphylaxis. Participants 
with a known hypersensitivity to any component of the study vaccine, or a history of hypersensitivity 
to any vaccine, will be excluded from the study. 
 
Blood drawing- and venipuncture-associated risks may include minor bleeding or bruising at the 
venous access site, mild discomfort, upset stomach, dizziness, light-headedness, syncope, or very 
rarely infection. Blood samples will only be drawn by trained staff members, and medical assistance 
will be available in case of any complications. Subjects will be informed of these risks in the ICF, 
and participants will be in a seated or supine position during blood draws. 
 
No benefits can be guaranteed to participants for their participation in this research study. 
Participants who participate in this study may benefit by being protected against pneumococcal 
disease caused by the additional serotypes contained in IVT PCV-25 that are not contained in 
Prevnar 20TM.  
 
Participants who participate in this study may benefit from the clinical assessments (e.g., medical 
history, physical examination, and routine clinical safety laboratory tests in adults) conducted at 
screening and during the study. If the participant is found to have any newly diagnosed medical 
condition or infection, the investigator will ensure that the participant is provided with appropriate 
and adequate referrals within the health care system. The information gained from this study may be 
useful in the development of a safe and effective 25-valent PCV. The known risks of participation 
in this study are believed to be outweighed by the potential benefits and value of the information to 
be gained. 
 
14.5  Participant Confidentiality 
Every effort will be made to protect participant privacy and confidentiality. Personal identifiers will 
not be included in any study reports. Medical records containing identifying information will be 
made available for review when the study is monitored by the Sponsor or an authorized regulatory 

 
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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 sites. All participant 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 
participant ID to maintain participant confidentiality. Laboratory reports may include the name and 
date of birth of the participant 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 participant ID numbers to other identifying 
information will be stored in a separate, locked file in an area with limited access. Participants’ study 
information will not be released without their written permission, except as necessary for 
monitoring, or as required/permitted by law/regulatory authorities. 
 
14.6  Reimbursement 
Pending EC approval, participants will be compensated for their time and effort in this study. The 
study ICF will state the plan for reimbursement. Participants will not be charged for study 
vaccinations, research study visits, research-related examinations, or research-related laboratory 
tests. 
 
14.7  Storage of Specimens 
Stored study research samples will be labeled with a barcode that the study site can link to the study 
participant. All stored research samples will be recorded and any use documented. Samples may be 
stored at different repositories and laboratories to complete the analyses required to evaluate study 
primary and secondary objectives. As a part of the informed consent process, participants will be 
informed of and asked to agree to long-term storage of specimens for use in future, vaccine-related 
research. 
 
When samples are no longer needed for the purposes of the study, they will be kept or destroyed, 
depending on whether participants consent to remaining samples being used in future vaccine-related 
research. Their use will be governed by a repository plan.  No genetic testing will be done on the 
samples. 
 
15. PUBLICATION POLICY 
According to the policy of the International Committee of Medical Journal Editors (ICMJE) member 
journals, this clinical trial will be registered on clinicaltrials.gov. 
 
The information generated in this study will be used by the Sponsor in connection with the 
development of the product and therefore may be disclosed to government regulatory agencies in 
various countries. The Sponsor (or designee) will prepare a clinical study report according to ICH-
E3 guidelines. All partners recognize the importance of communicating study findings and therefore 

 
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will encourage their publication in reputable scientific journals and presentation at seminars or 
conferences, while protecting the integrity of the ongoing trial. Study results will be made publicly 
available in compliance with the WHO mandated timeframe for public disclosure of results from 
clinical trials. Any publication, lecture, manuscripts of the findings of this study by any individual 
involved with the study will be governed by the procedure outlined in the Clinical Trial Agreement. 
The ICMJE authorship criteria will be strictly followed for publication of any manuscripts arising 
from this trial. Within any presentation or publication, confidentiality of individual participants will 
be maintained. 
 
 
 

 
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F Targeted PE will be conducted only in the event of new symptom, sign or new AE; Injection site assessed at Visit 
2 
G Serum creatinine, ALT, AST  
H WBC count, Hgb, Plts  
I HIV 1/2 Ab, HBsAg, HCV Ab 
J Women of childbearing potential (WOCBP) only. Serum pregnancy testing is preferred at V0 (D0) and urine 
pregnancy testing is acceptable. Urine will be collected at V1(D1) and V3 (D29) for pregnancy testing. 
K Date and time documented 
 
 
 
 
 
 

 
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16.5 Appendix 5.  References 
1.  GBD 2016 Lower Respiratory Infections Collaborators. Estimates of the global, regional, and national 
morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990-2016: a 
systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect Dis. 2018 Nov;18(11):1191-
1210. 
2.  https://www.who.int/news-room/fact-sheets/detail/pneumonia (assessed on 4 Dec 2021).. 
3.  Iyer AS, et al. Age-related immune response to pneumococcal polysaccharide vaccination: lessons for 
the clinic. Expert Rev Vaccines. 2015;14(1):85- 97. 
4.  O’Brien KL, 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;366(1579):2790-8. 
6.  Simell B, et al. Pneumococcal Carriage Group. The fundamental link between pneumococcal carriage 
and disease, Expert Rev Vaccines. 2012l;11(7):841-55. 
7.  Shapiro ED, et al. The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J 
Med. 1991; 325:1453-1460. 
8.  Temple K, et al.. Antibody response to pneumococcal capsular polysaccharide vaccine in African 
children. Pediatr Infect Dis. 1991; 10: 386- 390. 
9.  Bettinger JA, et al. Canadian Immunization Monitoring Program, Active (IMPACT). The effect of routine 
vaccination on invasive pneumococcal infections in Canadian children, Immunization Monitoring Program, 
Active 2000-2007. Vaccine. 2010;28(9):2130-6. 
10.  Public Health Agency of Canada (PHAC). (2021). National Laboratory Surveillance of Invasive 
Streptococcal 
Disease 
in 
Canada, 
Annual 
Summary 
2019. 
https://www.canada.ca/en/public-
health/services/publications/drugs-health-products/national-laboratory-surveillance-invasive-streptococcal-
disease-canada-annual-summary-2019.html 
11.  Wijayasri S, et al. The shifting epidemiology and serotype distribution of invasive pneumococcal disease 
in Ontario, Canada, 2007-2017. PLoS ONE.2019;14(12): e0226353.  
12. Clarke E, et al. Immunogenicity and safety of a novel ten-valent pneumococcal conjugate vaccine in 
healthy infants in The Gambia: a phase 3, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 
2021;21(6):834-846.  
13. Adigweme I, et al. Immunogenicity and safety of a 10-valent pneumococcal conjugate vaccine 
administered as a 2 + 1 schedule to healthy infants in The Gambia: a single-centre, double-blind, active-
controlled, randomised, phase 3 trial. Lancet Infect Dis. 2023 23(5):609-620.  
14.  Summary Basis for Regulatory Action - PREVNAR 20. https://www.fda.gov/vaccines-blood-
biologics/vaccines/prevnar-20 
15 Summary Basis for Regulatory Action – VAXNEUVANCE.  https://www.fda.gov/vaccines-blood-
biologics/vaccines/vaxneuvance 
16. Summary Basis for Regulatory Action - PREVNAR 13. https://www.fda.gov/vaccines-blood-
biologics/vaccines/prevnar-13 

 
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17. Synflorix. CHMP assessment report for paediatric studies submitted in accordance with article 46 of 
regulation 
(EC) 
No1901/2006, 
as 
amended. 
https://www.ema.europa.eu/en/documents/variation-
report/synflorix-h-c-973-p46-0048-epar-assessment-report_en.pdf 
18. Nunes S, et al. Temporal trends and molecular epidemiology of recently described serotype 6C of 
Streptococcus pneumoniae. J Clin Microbiol. 2009 Feb;47(2):472-4.  
19.  Saha SK et al. Streptococcus pneumoniae Serotype-2 Childhood Meningitis in Bangladesh: A Newly 
Recognized Pneumococcal Infection Threat. PLoS One. 2012; doi: 10.1371/journal.pone.0032134  
20.  Gaensbauer JT, et al. Pediatric Invasive Pneumococcal Disease in Guatemala City: Importance of 
Serotype 2. Pediatr Infect Dis J. 2016 May; 35(5):e139-43.  
21. Amin-Chowdhury Z, et al. Characteristics of Invasive Pneumococcal Disease Caused by Emerging 
Serotypes After the Introduction of the 13-Valent Pneumococcal Conjugate Vaccine in England: A 
Prospective Observational Cohort Study, 2014-2018. Clin Infect Dis. 2020 Nov 5;71(8):e235-e243. 
22. Hausdorff WP,et al. Epidemiological differences among pneumococcal serotypes. Lancet Infect Dis. 
2005 Feb;5(2):83-93. 
23. Marsh RL, et al. Molecular characterisation of pneumococcal serotype 16F: Established predominant 
carriage and otitis media serotype in the 7vPCV era. Vaccine. 2007 Mar 22;25(13):2434-6. 
24. Ouldali N et al. Incidence of paediatric pneumococcal meningitis and emergence of new serotypes: a 
time-series analysis of a 16-year French national survey. Lancet Infect Dis 2018;18:983-91. 
25. Olarte L et al. Invasive Serotype 35B Pneumococci Including an Expanding Serotype Switch Lineage. 
Emerging Infect Dis 2018; 24:405. 
26. Pichichero ME. Protein carriers of conjugate vaccines: characteristics, development, and clinical 
trials. Hum Vaccin Immunother. 2013 Dec;9(12):2505-23. 
 
27. Voysey M, et al. The impact of administration of conjugate vaccines containing cross reacting 
material on Haemophilus influenzae type b antibody responses in infants: A systematic review and meta-
analysis of randomised controlled trials. Vaccine. 2016 Jul 25;34(34):3986-92.  
 
28. Dagan R, et al. Combination vaccines containing DTPa-Hib: impact 
of IPV and coadministration of CRM197 conjugates. Expert Rev Vaccines. 2008 Feb;7(1):97-115.  
 
29. Borrow R,  et al. Glycoconjugate vaccines and immune interactions, and implications for vaccination 
schedules. Expert Rev Vaccines. 2011 Nov;10(11):1621-31. 

 
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30. Sellaturay P, et al. Polyethylene glycol (PEG) is a cause of anaphylaxis to the Pfizer/BioNTech mRNA 
COVID-19 vaccine. Clin Exp Allergy. 2021 Jun;51(6):861-863.  
31. Garvey LH, Shuaib NS. Anaphylaxis to the first COVID-19 vaccine: is polyethylene glycol (PEG) the 
culprit? British J Anaesth. 2021;126(3):e106-e108.  
32. Stone CA Jr, et al. Immediate Hypersensitivity to Polyethylene Glycols and Polysorbates: More Common 
Than We Have Recognized. J Allergy Clin Immunol Pract. 2019 May-Jun;7(5):1533-1540 
33. Wenande E, Garvey LH. Immediate-type hypersensitivity to polyethylene glycols: a review. Clin Exp 
Allergy. 2016;46:907-922. 
34. Stidl R, et. al. Polyethylene Glycol Exposure with Antihemophilic Factor (Recombinant), PEGylated 
(rurioctocog alfa pegol) and Other Therapies Indicated for the Pediatric Population: History and Safety. 
Pharmaceuticals (Basel). 2018 Jul 26;11(3):75. 
35. Annex 3. Recommendations to assure the quality, safety and efficacy of pneumococcal conjugate 
vaccines. 
Replacement 
of 
WHO 
Technical 
Report 
Series, 
No. 
927, 
Annex2 
https://www.who.int/biologicals/vaccines/TRS_977_Annex_3.pdf.

 
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16.6 Appendix 6 Protocol Signature Page for Additional Investigators 
 
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.’ 
 
 
 
 
 
 
Signature of Site Principal Investigator  
 
 
 
 
Date 
 
Name:  
 
Title:  
 
Organization: